IMR Press / JIN / Volume 23 / Issue 3 / DOI: 10.31083/j.jin2303049
Open Access Review
Neuromodulation of Cardiac Ischemic Pain: Role of the Autonomic Nervous System and Vasopressin
Show Less
1 Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
*Correspondence: (Ewa Szczepanska-Sadowska)
J. Integr. Neurosci. 2024, 23(3), 49;
Submitted: 28 August 2023 | Revised: 2 November 2023 | Accepted: 15 November 2023 | Published: 1 March 2024
Copyright: © 2024 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Cardiac pain is an index of cardiac ischemia that helps the detection of cardiac hypoxia and adjustment of activity in the sufferer. Drivers and thresholds of cardiac pain markedly differ in different subjects and can oscillate in the same individual, showing a distinct circadian rhythmicity and clinical picture. In patients with syndrome X or silent ischemia, cardiac pain intensity may cause neurogenic stress that potentiates the cardiac work and intensifies the cardiac hypoxia and discomfort of the patient. The reasons for individual differences in cardiac pain sensation are not fully understood. Thus far, most attention has been focused on inappropriate regulation of the heart by the autonomic nervous system, autacoids, and cardiovascular hormones. Herein, we summarize evidence showing that the autonomic nervous system regulates cardiac pain sensation in cooperation with vasopressin (AVP). AVP is an essential analgesic compound and it exerts its antinociceptive function through actions in the brain (the periaqueductal gray, caudate nucleus, nucleus raphe magnus), spinal cord, and heart and coronary vessels. Vasopressin acts directly by means of V1 and V2 receptors as well as through multiple interactions with the autonomic nervous system and cardiovascular hormones, in particular, angiotensin II and endothelin. The pain regulatory effects of the autonomic nervous system and vasopressin are significantly impaired in cardiovascular diseases.

cardiac hypoxia
spinal cord
myocardial infarction
1. Introduction

Strong cardiac pain often precedes myocardial infarction and may be a useful warning sign of cardiac morbidity, allowing the adjustment of activity in the suffer in order to reduce the rate of oxygenation and decrease the performance of the heart. In some cardiac patients, pain intensity is not proportional to the ischemia itself and can provoke excessive neurogenic stress, which potentiates cardiovascular responses and cardiac work, thereby intensifying cardiac hypoxia and patient discomfort. For many years, relieving pain and anxiety has been a major goal of cardiovascular therapy [1, 2, 3]. Experimental and clinical studies have shown significant differences in individuals’ subjective experience of cardiac pain. The causes for this variety in cardiac pain sensations are currently not fully understood; however, the influence of age, sex and neuroendocrine and inflammatory factors have been frequently addressed [4, 5, 6, 7, 8].

Particular attention has been given to cardiac syndrome X (CSX) and to silent ischemia. Patients with CSX experience typical chest pain although they have normal arteriogram. It has been postulated that CSX is caused by abnormal function of cardiac microvessels [9, 10]. There is also evidence for inappropriate perception and regulation of pain [8, 11, 12], and for an altered processing of pain signals in the brain, which may result in a decreased pain threshold and lack of habituation to pain stimuli [13, 14].

The mechanisms responsible for silent ischemia, in which typical ambulatory symptoms of myocardial infarction occur in the absence of pain, are not yet fully understood; however, inappropriate activation of the autonomic nervous system has been postulated [15, 16].

Growing evidence indicates that pain stimulates the release of several cardiovascular compounds that may play a role in the modulation of pain. One of these compounds is arginine vasopressin (AVP), which operates as a member of the complex vasopressinergic system (VS), for which receptors are located in the brain and peripheral organs. The purpose of this review is to summarize the current knowledge of the role of AVP in the regulation of pain in cardiac pathology. Central and systemic cooperation of AVP with the autonomic nervous system and other cardiovascular peptides is also discussed.

2. Innervation of the Heart and Coronary Vessels

It is widely known that the heart receives afferent and efferent innervation from the autonomic nervous system and that heart failure significantly alters the effectiveness of the sympathetic and parasympathetic control of the heart [17, 18, 19, 20]. Studies on patients with severe angina pectoris have shown that spinal cord stimulation exerts beneficial antianginal effects and decreases ischemia, presumably due to the reduction of myocardial ischemia [21].

Transmission of pain signals from the heart to the brain. It has been shown that sensory innervation of the heart is supplied by both sympathetic and parasympathetic neurons [19, 20]. Convergence of stimuli from the somatic, nociceptive and spinothalamic tract neurons has been found in the C1-C3 segments of the spinal cord [22] that are involved in sensation of referred pain in the chest, arm, and diaphragm [22, 23, 24, 25]. Nociceptive information from the heart is transmitted to the dorsal root ganglia (DRG) and subsequently it ascends the insular cortex and the nucleus tractus solitaries (NTS) that receive input from the cardiac vagal afferents and pain processing neurons [26, 27, 28, 29]. In patients with coronary disease, stimulation of vagal afferents significantly reduces sympathetic tone and angina, and improves hemodynamic and electrocardiogram (ECG) parameters [30].

In patients with variant angina, the coronary vasospasm is preceded by stimulation of both sympathetic and parasympathetic activity [30, 31]. The sensory fibers transmitting nociceptive signals induced by cardiac ischemia have been identified as vagal afferent fibers projecting directly to the NTS, and as sympathetic afferents [17, 18].

Processing of pain signals in the brain. Several groups of neurons in the brain may participate in integration of pain signals and in modulation of cardiovascular responses. Emotional and other psychological signs modulate cardiac nociception through signals originating in the amygdala, raphe nucleus, and pons [17, 32, 33, 34].

Studies have shown that pericardial application of pain stimulating compounds or occlusion of the left anterior descending coronary artery induce activation of the caudal division of the NTS neurons [35], and that the NTS is involved in transmission of pain signals generated by chronic myocardial infarction [26]. There is also evidence for involvement of the periaqueductal grey (PAG) in the regulation of the autonomic nervous system and modulation of pain in healthy human subjects in whom brain function was investigated using resting state functional magnetic resonance imaging (fMRI) and voxel-based morphometry [36].

Cardiac pain has been also tested in patients with heart transplants. Heart transplantation is followed by sympathetic reinnervation of the heart; however, the process is slow and presumably not complete [37, 38]. Thus far there is no evidence for parasympathetic re-innervation. Presence of chest pain suggesting cardiac ischemia in recipients of heart transplants indicates the possibility of sensory reinnervation [31, 39].

3. Influence of Cardiac Environment and Autacoids on Pain Sensation

Cardiac ischemic pain involves components of inflammatory pain, which is triggered by inflammatory mediators released from the injured tissue. The significance of inflammatory pain is especially important in myocardial infarction during which the inflammation is associated with tissue hypoxia, acidification, and release of several autacoids [40, 41, 42]. The activation of microglia plays an essential role in the generation of inflammatory pain. Studies on Sprague Dawley (SD) rats have shown that cardiac pain produced by chronic occlusion of the coronary artery can be alleviated by intrathecal administration of minocycline, which is an inhibitor of microglia. It has been shown that this effect can be abolished by intrathecal application of fractalkine, which is an antagonist of minocycline [43].

Ischemic hypoxia is associated with myocardial acidification, which is caused mainly by the release of lactic acid and a significant decrease in pH. Myocardial ischemia lasting 5 minutes has been shown to reduce extracellular pH to ~7.0 and severe hypoxia can even reduce the pH to 6.7 [44, 45]. Experiments on cats showed that increased release of protons plays an essential role in the activation of sympathetic afferents [44]. Stimulation of cardiac sympathetic C afferents is associated with activation of the acid sensitive ion ASIC3 channel, which belongs to the family of degenerin/epithelial sodium channels [45]. It is likely that, during myocardial ischemia, this channel detects early changes in lactic acid and ATP [46], which belong to autacoids, and the latter acts on P2 (P2X) purinergic receptors [42, 47]. It has been shown that myocardial infarction significantly elevates expression of P2X3 purinergic receptor (P2X3R) mRNA in the stellate ganglion, and P2X2R and P2X3R mRNA and protein in the nodose ganglion [48, 49].

Several other autacoids are released in the ischemic heart and may participate in the stimulation of sensory afferents. Studies have shown that cardiac chemosensitive neurons can be activated by bradykinin, substance P (SP), leukotriens, lactate, adenosine, ATP, and potassium ions [17, 35, 50]. In patients with ischemic cardiac disease, atrial pacing inducing angina enhances the release of adenosine, bradykinin, and prostaglandin (PGI2) in the heart [18, 41, 51]. Bradykinin activates cardiac afferent fibers acting on kinin B2 receptors. Release of bradykinin in the heart is enhanced by ischemic preconditioning and causes stimulation of both ischemia-sensitive and ischemia-insensitive cardiac afferents. Signals generated by bradykinin in the heart are transmitted via cardiac sensory sympathetic afferents to the dorsal root ganglion [40]. Stimulation of cardiac nociceptors by bradykinin requires activation of transient receptor potential vanilloid 1 (TRPV1) channels and activation of the 1,4,5-triphospahte (IP3) pathway [52]. It is worth noting that, in the heart, B2 kinin receptors and TRPV1 are expressed on the same ischemia-sensitive sensory fibers [53, 54].

Ischemia-sensitive cardiac afferents projecting via the left sympathetic chain and rami communicantes of T2-T3 are stimulated by histamine, which acts through H1 receptors and subsequent activation of the Phospholipase C- Protein kinase C (PLC-PKC) intracellular pathway [55]. Cardiac ischemia also induces elevation of adenosine in the heart, while adenosine intensifies ischemic pain through activation of A1 receptors [56]. Studies on patients with stable angina have shown that intracoronary infusion of adenosine provokes cardiac pain, which is frequently associated with bradycardia [56, 57]. Autacoids are locally-acting compounds [42] and it is also likely that other interleukins, growth factors, cytokines, glycolipids, and lipids synthesized in the heart modulate cardiac pain and interact with AVP and other cardiovascular peptides. However, their role in this context has thus far not been investigated.

4. Role of Vasopressin in Pain Sensation
4.1 General Characteristics of Vasopressinergic System

Vasopressin is a cardiovascular neuropeptide with a wide spectrum of actions exerted in the brain and peripheral organs [58, 59, 60, 61, 62, 63]. In the brain, neurons synthetizing AVP are present mainly in the supraoptic (SON), paraventricular (PVN), and suprachiasmatic (SCN) nucleus. Axons of these neurons project mainly to the posterior pituitary where they release their product to the blood. In addition, several axonal projections innervate brain regions encompassing the nucleus ambiguous, NTS, lateral habenular nucleus, nucleus basalis of Meynert, substantia nigra, ventral hippocampus, central gray, and spinal cord [58, 59, 60, 61]. Among them are the regions controlling both the cardiovascular system and pain, such as the noradrenergic/adrenergic A2/C2 region, nucleus ambiguous, dorsal vagal complex, and subnuclei of the solitary tract [64, 65, 66]. The parvocellular neurons of the PVN send projections to the spinal cord [66, 67]. Secretion of vasopressin is stimulated by hyperosmolality, hyperthermia, hypotension, angiotensin II (Ang II), stress, pain, and inflammation. It also shows distinct diurnal rhythmicity [65, 68, 69, 70, 71, 72, 73]. Stress, pain, and inflammation play a particularly significant role in myocardial infarction and heart failure [73].

Vasopressin activates V1 receptors (V1R; subtypes: V1aR, V1bR) and V2 receptors (V2R) that are located in the brain areas involved in the regulation of pain and cardiovascular functions (Table 1). They are also present in several peripheral organs, including the cardiovascular system, lungs, kidney, liver, and gastrointestinal system [61, 74, 75, 76, 77, 78, 79, 80].

Table 1.Summary of association of vasopressin, angiotensins, and endothelin with regulation of cardiac pain and cardiac functions.
Compound Receptors involved in pain regulation Site of action Effect
Arginine vasopressin V1aR, V1bR, V2R Brain Analgesia, increase of vagal tone
Sites of synthesis: brain (PVN, SON, ScN), peripheral organs Spinal cord Analgesia in low concentration, hyperalgesia in high concentration
Stimuli: hyperosmolality, hypotension, pain, stress, inflammation, Ang II Heart and coronary vessels Cardiac hypertrophy, vasodilation of epicardial coronary vessels; vasoconstriction of resistance coronary vessels
Agiotensin II AT1R, AT2R Brain Hyperalgesia, increase of sympathetic tone
Sites of synthesis: brain and peripheral organs Spinal cord Hyperalgesia
Stimuli: hypotension, pain, stress, inflammation Heart and coronary vessels Cardiac hypertrophy, coronary vasoconstriction
Angiotensin 1-7 MasR Brain Analgesia, increase of vagal tone, decrease of sympathetic tone
Sites of synthesis: brain and peripheral organs Heart and coronary vessels Cardioprotection, coronary vasodilation
Stimuli: hypotension, pain, stress, inflammation
Endothelin-1 ETAR; ETBR Brain Hyperalgesia, increase of sympathetic tone; decrease of parasympathetic tone
Sites of synthesis: brain and peripheral organs Heart and coronary vessels Cardiac hypertrophy, coronary vasoconstriction
Stimuli: hypotension, stress, pain, inflammation

Abbreviations: PVN, paraventricular nucleus; ScN, suprachiasmatic nucleus; SON, supraoptic nucleus; AT1R, AT2R, angiotensin receptors; ETAR, ETBR, endothelin receptors; V1aR, V1bR, V2R, vasopressin receptors; Ang II, angiotensin II; MasR, angiotensin-(1-7) receptor.

4.2 Involvement of Vasopressin in Pain Regulation

Strong evidence indicates that vasopressin has multiple associations with the regulation of pain. Studies have shown that, in the rat, mechanical or thermal stimuli inducing pain cause activation of vasopressin neurons in the hypothalamo-neurohypophyseal system and release of AVP. Furthermore, it has been shown that pain can be eliminated by pre-application of a V1aR antagonist [68]. Studies on rats suggest that the nociceptive ascending pathway to the SON encompasses the caudal ventrolateral medulla and noradrenergic A1 region [70].

Centrally mediated analgesic effects of AVP. Systemic or intracerebroventricular (ICV) application of AVP elevates the pain threshold in the rat, and this effect can be eliminated by pretreatment with a V1R antagonist [(dPTyr(Me)AVP] but not the opiate antagonist naloxone [81, 82]. Similarly, intrathecal (it) administration of AVP to the spinal cord produces antinociception, which is not mediated by opiates, but can be eliminated by blockade of V1R and is absent in V1aR knock-out mice [82, 83, 84, 85]. Experiments on rats showed that intravenously applied AVP elicits dose-related effects on nociceptive processing in the spinal cord. Namely, it exerts an antinociceptive effect, expressed by reduction of action potentials mediated by C-type nociceptive fibers, although it elicits an opposite action when it is applied at higher doses. Both effects can be abolished by administration of a V1aR antagonist [86].

Strong evidence indicates that there are several sites in the brain where AVP may interact with neurons engaged in regulation of pain (Fig. 1; Table 1). Thus far, the most essential role has been attributed to the amygdala, PAG, and caudate nucleus (CdN). In the amygdala, vasopressin acting on V1a receptors also enhances the nocifensive reflexes related to pain [87, 88]. Experiments on rats showed that administration of AVP to the PAG increases pain threshold through stimulation of V1aR and also induces local elevation of leucine-enkephalin (L-Elk), methionine-enkephalin, and serotonin (5-HT). Moreover, the analgesic effects of AVP in PAG could be abolished by blockade of opiate receptors with naloxone [89], which indicates that, in specific brain regions, AVP interacts with opiates in regulation of pain. It should be noted that the PAG plays a significant role in regulation of cardiovascular function [90].

Fig. 1.

Associations of vasopressin, angiotensins and endothelin with regulation of pain. PVN, paraventricular nucleus; AVP, arginine vasopressin; ANGs, angiotensins; ET, endothelin; Ins, insula; Cing, cingulate gyrus; CVLM, caudal ventrolateral medulla; DMVNc, dorsal ventromedial nucleus of the vagus; NcAmb, nucleus ambiguous; NTS, nucleus tractus solitarius; PAG, periaqueductal grey; PFR, periphornical region; RVLM, rostral ventrolateral medulla; V1aR, vasopressin receptor; AT1aR, AT2R, angiotensin II receptors; ETAR, endothelin receptor; V1a, vasopressin V1a of type 1a; AT1a, angiotensin II of type 1a; AT2, angiotensin II of type 2; Mas, angiotensin-(1-7).

Pain increases release of AVP in the CdN and this effect is associated with stimulation of Ach release, which can be eliminated by application of AVP antagonists (V1ant, V2ant) [91, 92]. There is also evidence that AVP released from PVN neurons may regulate pain through the action exerted in the nucleus raphe magnus [92].

Systemically mediated effects of vasopressin. Systemically released AVP reaches the heart and coronary vessels and can regulate cardiac metabolism and blood oxygenation [59]. V1a receptors have been identified in the human heart, and their expression increases in patients with heart failure [93]. Earlier experiments performed on dogs have demonstrated that AVP acting on coronary vessels causes vasodilation of the epicardial vessels that is mediated by nitric oxide; however, it also elicits vasoconstriction and resistance of coronary vessels. Both effects require activation of V1aR (Table 1) [94].

A recent study in humans undergoing cardiopulmonary procedures revealed significant differences in responsiveness of coronary arterioles to vasopressin in patients with diabetes mellitus and in non-diabetic subjects [95]. Specifically, vessels from patients with poorly controlled diabetes mellitus responded with significantly stronger vasoconstriction than vessels from non-diabetic subjects. The difference could be eliminated by application of a V1aR antagonist (SR49059). In addition, cardioplegic arrest was followed by greater elevation of V1aR in vessels of diabetic patients and resulted in elevation of V1bR in the atrial myocardium of the diabetic subjects, while it was not effective in the atria of non-diabetic subjects [95].

Clinical evidence for the importance of AVP in pain regulation. Several years ago, it was reported that patients in the emergency department complaining of pain have significantly higher plasma AVP levels than control subjects [96]. Subsequently, other studies provided evidence that blood AVP and copeptin concentrations are significantly elevated in patients with acute myocardial infarction. Accordingly, it has been proposed that measuring copeptin concentration may help to identify patients with low and high risk of mortality [97, 98, 99].

Interaction of vasopressin with angiotensin, endothelin and other cardiovascular peptides. Cardiovascular disorders generated by cardiac infarction and/or cardiac failure cause release of several other cardiovascular compounds, which presumably interact with vasopressin in the regulation of pain. In this review, we have focused mainly on components of the renin-angiotensin system (RAS) and endothelin because the knowledge of their role in regulation of pain is relatively well advanced. Several components of RAS, such as angiotensinogen, angiotensin converting enzyme (ACE), and angiotensin receptors (AT1aR, AT2R), have been identified in the sensory dorsal root ganglia and in the brain structures involved in the regulation of pain [71, 100, 101, 102, 103, 104, 105]. Some of them are co-localized with substance P and calcitonin-gene related peptide, which are involved in the regulation of pain [105]. Studies on mice have shown that administration of angiotensin II intensifies nociceptive behavior through activation of angiotensin receptors (AT1R) and activation of p38MAPK [104]. In the rat model of peripheral neuropathy, administration of losartan attenuates allodynia and reduces expression of inflammatory proteins (Tumor necrosis factor-α (TNF-α), Tumor necrosis factor receptor 1 (TNFR1), Glial fibrillary acidic protein (GFAP)) in the dorsal root ganglia. Furthermore, blockade of AT1R by administration of telmisartan in Wistar rats with diabetic neuropathy significantly elevates the mechanical nociceptive threshold, which is reduced in diabetic subjects [102, 103]. In contrast, administration of angiotensin-(1-7) [Ang-(1-7)] induces antinociceptive behavior, which is associated with p38 mitogen activated protein kinases (p38MAPK) inhibition (Table 1). In addition, it reduces nociceptive responses to substance P (SP) and N-methyl-D-aspartate receptor (NMDA), which co-localize in the spinal cord with MAS oncogene receptor, which is a G protein coupled receptor activated by Ang-(1-7) [106, 107].

Cooperation of AVP, Ang II, and endothelin-1 (ET-1) with the autonomic nervous system in the regulation of cardiac pain is summarized in Fig. 1 Beneficial antinociceptive effect of stimulation of AT2R has been described in inflammatory and neuropathic pain [108].

Although substantial evidence shows that acute myocardial infarction causes strong activation of RAS and elevation of plasma Ang II concentration [71, 109, 110], not many studies have assessed the role of RAS in regulation of pain in cardiac pathology. Thus far, it has been shown that administration of ACE inhibitors intensifies pain in fibromyalgia; however, it is likely that this effect is mediated by decreased degradation of bradykinin [101]. ACE inhibitors proved to be effective in the treatment of cardiac syndrome X [9, 111] and were able to reduce pain during exercise [112].

Plasma ET-1 level is significantly elevated in patients with angina and myocardial infarction [113, 114, 115] and its level markedly increases during coronary artery spasm [116, 117]. There is also evidence that acute myocardial infarction induces release of endothelin from the heart, as elevation of ET-1 is higher in coronary blood than in systemic blood [118]. Experiments on cats suggest that myocardial infarction causes activation of endothelin receptor of type 1A (ET1A) receptors on cardiac sensory neurons of the thoracic root ganglia [119]. Patients suffering from chest pain associated with normal coronary arteriography have higher levels of plasma endothelin during the treadmill exercise test than control subjects. The latter finding suggests that endothelin may influence intensity of chest pain in patients with syndrome X [9, 120].

Systemic levels of other factors, such as orexin [121, 122], brain natriuretic peptide [123], and insulin [124], are also elevated during pain and it is likely that they may participate in the regulation of cardiac ischemic pain.

4.3 Role of Vasopressin in Circadian Rhythmicity of Cardiac Pain

Multiple studies draw attention to a diurnal periodicity of cardiac pain sensation. Onset of angina pain in patients with myocardial infarction shows a circadian rhythm with peaks between 06:00 h and 12:00 h and 20:00 h and 23:00 h [125, 126, 127, 128]. At present, the origin of the circadian periodicity of pain sensation is not fully elucidated, but there is evidence that the periodicity may follow the circadian rhythmicity of other brain functions, including secretion of neuroendocrine factors such as melatonin, vasopressin, components of RAS, and endothelin. Secretion and action of cardiovascular hormones shows circadian variability and effectiveness of a pharmacological medication may depend on the time of application of the treatment [128, 129, 130, 131, 132, 133].

There is strong evidence that vasopressin plays an essential role in synchronization of pain sensation and cardiovascular parameters with environmental light [60, 134]. Vasopressin is present in retinal cells projecting to the suprachiasmatic nucleus (SCN) and application of light evokes its release in this nucleus. Furthermore, secretion of AVP in the SCN manifests circadian rhythmicity, showing a peak in the early morning and a decline in the late afternoon [135, 136]. There is also evidence that vasopressin significantly contributes to the pacemaker function of the SCN. Neurons expressing AVP form a large population of SCN neurons, while the AVP promoter, which is a target for CLOCK/BMAL1 transcription factors, participates in generation of the circadian rhythm [134, 137, 138]. Experiments on mice provided evidence that AVP resets the clock function of the SCN through actions exerted on V1a/V1b receptors [139]. In humans, plasma vasopressin concentration shows a nocturnal increase with a peak between 24:00 h and 04:00 h [67, 140]. The nocturnal elevation of plasma AVP concentration is markedly attenuated in elderly subjects [141]. In post-stroke patients and patients with cardiac failure, the circadian rhythm of AVP secretion is abolished [141].

It is likely that vasopressin cooperates with Ang II and endothelin in the regulation of circadian rhythmicity. For instance, the circadian pattern of blood pressure fluctuations and pressor responses to restrain stress are significantly affected by systemic infusion of Ang II [142]. It appears that Ang II, acting on angiotensin II receptor of type 2 (AT2R), exerts a short-lasting antinociceptive effect, whereas prolonged stimulation of these receptors increases nociception at the beginning and end of the light phase. Both effects are attenuated by application of an AT2 antagonist (ditrifluoroacetate (PD 123319)) [143]. Inverted diurnal pain sensation was found in spontaneously hypertensive rats (SHR) and this dissimilarity could be corrected by blockade of AT1R with losartan [144].

Evidence is emerging that ET-1 may also belong to a family of cardiovascular peptides showing clear circadian rhythmicity. In the rat, expression of ET-1 mRNA in the SCN shows a peak around 04:00 h, whereas in the heart and lungs, it culminates between 12:00 h and 20:00 h [145]. Studies in mice suggest that plasma ET-1 level peaks during the night active period [146]. In human subjects, circulating ET-1 circadian peaks are present in the morning and afternoon [146, 147, 148]. The vasodilatory responses of endothelin and acetylcholine to iontophoresis show two peaks at 20:00 h and 08:00 h [147].

5. Summary, Limitations, and Outlook

Summary. Cardiac pain often signals hypoxia and/or damage of the heart. However, in some patients (for instance in cardiac syndrome X or in silent ischemia), its intensity is not proportional to the disturbance affecting the heart. Thus far, the reasons for significant divergence in susceptibility to cardiac pain signals have not been well established. This review summarized evidence showing that cardiac pain is regulated jointly by the autonomic nervous system, autacoids, vasopressin, and other cardiovascular peptides. The attention was focused mainly on vasopressin, because its role in cardiovascular pathology in association with the regulation of pain, and its interactions with other systems activated by cardiac ischemia, are relatively well recognized. A survey of studies published in recent years shows that the mechanisms controlling cardiac pain by cardiovascular peptides cooperate in the brain, spinal cord, cardiac muscle, and coronary vessels. The review reported new evidence that the joint regulation of pain by the autonomic nervous system and the vasopressinergic system is significantly altered in cardiovascular disease and can be significantly affected by implementation of pharmacological treatment.

Limitations. Pain regulation studies face several limitations resulting from interspecies differences and lack of appropriate methods allowing the evaluation of pain intensity in animals. The transfer of data from animal species to humans requires comparative studies that are often limited on ethical grounds. Furthermore, in patients with heart failure, testing of pain may provoke excessive negative cardiovascular responses requiring termination of the test. Interpretation of the results may be also impeded by the application of another pharmacological treatment which interferes with the metabolism or action of cardiovascular peptides. This review is a many-faceted study and, although it is based on a comprehensive survey of the literature, it cannot be excluded that some valuable articles were omitted.

Outlook. A complete understanding of the role of vasopressin and other cardiovascular peptides in the physiology and pathophysiology of pain is not yet possible; however, existing evidence encourages further studies to investigate mechanisms of action. It is very likely that such studies may help to identify a new specific pain relieving treatment that may be beneficial in the management of cardiovascular diseases.


AVP, arginine vasopressin; ANGs, angiotensins; ET, endothelin; Ins, insula; Cing, cingulate gyrus; CVLM, caudal ventrolateral medulla; DMVNc, dorsal ventromedial nucleus of the vagus; NcAmb, nucleus ambiguous; NTS, nucleus tractus solitarius; PAG, periaqueductal grey; PFR, periphornical region; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla; V1aR, vasopressin receptor; AT1aR, AT2R, angiotensin II receptors; MasR, angiotensin-(1-7) receptor; ETAR, endothelin receptor.

Author Contributions

ESz-S performed literature search and had written the review. The author contributed to editorial changes in the manuscript. The author read and approved the final manuscript. The author had participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.


The author wishes to thank to Marcin Kumosa from the Department of Experimental and Clinical Physiology of the Medical University of Warsaw for technical preparation of the Figure, and to Agnieszka Cudnoch-J\kedrzejewska, Tymoteusz Żera and other colleagues from the Department of Experimental and Clinical Physiology of the Medical University of Warsaw for discussion and support.


This work was supported by the Medical University of Warsaw Scientific Projects (1MA/N/2022). The work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The author declares no conflict of interest.

Ford TJ, Berry C. Angina: contemporary diagnosis and management. Heart. 2020; 106: 387–398.
Gulati M, Levy PD, Mukherjee D, Amsterdam E, Bhatt DL, Birtcher KK, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021; 144: e368–e454.
Thomas M, Jones PG, Arnold SV, Spertus JA. Interpretation of the Seattle Angina Questionnaire as an Outcome Measure in Clinical Trials and Clinical Care: A Review. JAMA Cardiology. 2021; 6: 593–599.
Cusack MR, Marber MS, Lambiase PD, Bucknall CA, Redwood SR. Systemic inflammation in unstable angina is the result of myocardial necrosis. Journal of the American College of Cardiology. 2002; 39: 1917–1923.
Jain A, Wadehra V, Timmis AD. Management of stable angina. Postgraduate Medical Journal. 2003; 79: 332–336.
Hung MJ, Hu P, Hung MY. Coronary artery spasm: review and update. International Journal of Medical Sciences. 2014; 11: 1161–1171.
Mavani GP, DeVita MV, Michelis MF. A review of the nonpressor and nonantidiuretic actions of the hormone vasopressin. Frontiers in Medicine. 2015; 2: 19.
Mehta PK, Bess C, Elias-Smale S, Vaccarino V, Quyyumi A, Pepine CJ, et al. Gender in cardiovascular medicine: chest pain and coronary artery disease. European Heart Journal. 2019; 40: 3819–3826.
Kaski JC, Aldama G, Cosín-Sales J. Cardiac syndrome X. Diagnosis, pathogenesis and management. American Journal of Cardiovascular Drugs: Drugs, Devices, and other Interventions. 2004; 4: 179–194.
Lanza GA, Morrone D, Pizzi C, Tritto I, Bergamaschi L, De Vita A, et al. Diagnostic approach for coronary microvascular dysfunction in patients with chest pain and no obstructive coronary artery disease. Trends in Cardiovascular Medicine. 2022; 32: 448–453.
Chauhan A, Mullins PA, Thuraisingham SI, Taylor G, Petch MC, Schofield PM. Abnormal cardiac pain perception in syndrome X. Journal of the American College of Cardiology. 1994; 24: 329–335.
Mehta PK, Quesada O, Al-Badri A, Fleg JL, Volgman AS, Pepine CJ, et al. Ischemia and no obstructive coronary arteries in patients with stable ischemic heart disease. International Journal of Cardiology. 2022; 348: 1–8.
Sestito A, Lanza GA, Le Pera D, De Armas L, Sgueglia GA, Infusino F, et al. Spinal cord stimulation normalizes abnormal cortical pain processing in patients with cardiac syndrome X. Pain. 2008; 139: 82–89.
Valeriani M, Sestito A, Le Pera D, De Armas L, Infusino F, Maiese T, et al. Abnormal cortical pain processing in patients with cardiac syndrome X. European Heart Journal. 2005; 26: 975–982.
Glazier JJ, Piessens J. Mechanisms of painless myocardial ischaemia. Journal of the Royal College of Physicians of London. 1991; 25: 102–104.
Gutterman DD. Silent myocardial ischemia. Circulation Journal. 2009; 73: 785–797.
Foreman RD. Mechanisms of cardiac pain. Annual Review of Physiology. 1999; 61: 143–167.
Fu LW, Longhurst JC. Bradykinin and thromboxane A2 reciprocally interact to synergistically stimulate cardiac spinal afferents during myocardial ischemia. American Journal of Physiology. Heart and Circulatory Physiology. 2010; 298: H235–H244.
Porter TR, Eckberg DL, Fritsch JM, Rea RF, Beightol LA, Schmedtje JF, Jr, et al. Autonomic pathophysiology in heart failure patients. Sympathetic-cholinergic interrelations. The Journal of Clinical Investigation. 1990; 85: 1362–1371.
Wink J, van Delft R, Notenboom RGE, Wouters PF, DeRuiter MC, Plevier JWM, et al. Human adult cardiac autonomic innervation: Controversies in anatomical knowledge and relevance for cardiac neuromodulation. Autonomic Neuroscience: Basic & Clinical. 2020; 227: 102674.
Mannheimer C, Eliasson T, Andersson B, Bergh CH, Augustinsson LE, Emanuelsson H, et al. Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. BMJ. 1993; 307: 477–480.
Chandler MJ, Zhang J, Qin C, Foreman RD. Spinal inhibitory effects of cardiopulmonary afferent inputs in monkeys: neuronal processing in high cervical segments. Journal of Neurophysiology. 2002; 87: 1290–1302.
Bolser DC, Hobbs SF, Chandler MJ, Ammons WS, Brennan TJ, Foreman RD. Convergence of phrenic and cardiopulmonary spinal afferent information on cervical and thoracic spinothalamic tract neurons in the monkey: implications for referred pain from the diaphragm and heart. Journal of Neurophysiology. 1991; 65: 1042–1054.
Chandler MJ, Zhang J, Foreman RD. Vagal, sympathetic and somatic sensory inputs to upper cervical (C1-C3) spinothalamic tract neurons in monkeys. Journal of Neurophysiology. 1996; 76: 2555–2567.
Coote JH, Chauhan RA. The sympathetic innervation of the heart: Important new insights. Autonomic Neuroscience: Basic & Clinical. 2016; 199: 17–23.
Li J, Zhang MM, Tu K, Wang J, Feng B, Zhang ZN, et al. The excitatory synaptic transmission of the nucleus of solitary tract was potentiated by chronic myocardial infarction in rats. PLoS ONE. 2015; 10: e0118827.
Rosen SD. From heart to brain: the genesis and processing of cardiac pain. The Canadian Journal of Cardiology. 2012; 28: S7–S19.
Rosen SD, Paulesu E, Wise RJS, Camici PG. Central neural contribution to the perception of chest pain in cardiac syndrome X. Heart. 2002; 87: 513–519.
Pan HL, Chen SR. Myocardial ischemia recruits mechanically insensitive cardiac sympathetic afferents in cats. Journal of Neurophysiology. 2002; 87: 660–668.
Zamotrinsky AV, Kondratiev B, de Jong JW. Vagal neurostimulation in patients with coronary artery disease. Autonomic Neuroscience: Basic & Clinical. 2001; 88: 109–116.
Chen YJ, Tsai CS, Huang TW. Chest pain in a heart transplant recipient: A case report. World Journal of Clinical Cases. 2021; 9: 3966–3970.
Inazumi T, Shimizu H, Mine T, Iwasaki T. Changes in autonomic nervous activity prior to spontaneous coronary spasm in patients with variant angina. Japanese Circulation Journal. 2000; 64: 197–201.
Foreman RD, Linderoth B, Ardell JL, Barron KW, Chandler MJ, Hull SS, Jr, et al. Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for its therapeutic use in angina pectoris. Cardiovascular Research. 2000; 47: 367–375.
Willis WD, Westlund KN. Neuroanatomy of the pain system and of the pathways that modulate pain. Journal of Clinical Neurophysiology. 1997; 14: 2–31.
Hua F, Harrison T, Qin C, Reifsteck A, Ricketts B, Carnel C, et al. c-Fos expression in rat brain stem and spinal cord in response to activation of cardiac ischemia-sensitive afferent neurons and electrostimulatory modulation. American Journal of Physiology. Heart and Circulatory Physiology. 2004; 287: H2728–H2738.
Makovac E, Venezia A, Hohenschurz-Schmidt D, Dipasquale O, Jackson JB, Medina S, et al. The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey. The Journal of Physiology. 2021; 599: 5243–5260.
Estorch M, Campreciós M, Flotats A, Marí C, Bernà L, Catafau AM, et al. Sympathetic reinnervation of cardiac allografts evaluated by 123I-MIBG imaging. Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 1999; 40: 911–916.
Lord SW, Clayton RH, Mitchell L, Dark JH, Murray A, McComb JM. Sympathetic reinnervation and heart rate variability after cardiac transplantation. Heart. 1997; 77: 532–538.
Stark RP, McGinn AL, Wilson RF. Chest pain in cardiac-transplant recipients. Evidence of sensory reinnervation after cardiac transplantation. The New England Journal of Medicine. 1991; 324: 1791–1794.
Fu LW, Longhurst JC. Regulation of cardiac afferent excitability in ischemia. Handbook of Experimental Pharmacology. 2009; 185–225.
Fu LW, Longhurst JC. A new function for ATP: activating cardiac sympathetic afferents during myocardial ischemia. American Journal of Physiology. Heart and Circulatory Physiology. 2010; 299: H1762–H1771.
Keppel Hesselink JM. Fundamentals of and Critical Issues in Lipid Autacoid Medicine: A Review. Pain and Therapy. 2017; 6: 153–164.
Wang J, Wu XC, Zhang MM, Ren JH, Sun Y, Liu JZ, et al. Spinal cord stimulation reduces cardiac pain through microglial deactivation in rats with chronic myocardial ischemia. Molecular Medicine Reports. 2021; 24: 835.
Pan HL, Longhurst JC, Eisenach JC, Chen SR. Role of protons in activation of cardiac sympathetic C-fibre afferents during ischaemia in cats. The Journal of Physiology. 1999; 518: 857–866.
Sutherland SP, Benson CJ, Adelman JP, McCleskey EW. Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98: 711–716.
Naves LA, McCleskey EW. An acid-sensing ion channel that detects ischemic pain. Brazilian Journal of Medical and Biological Research. 2005; 38: 1561–1569.
Longhurst JC, Tjen-A-Looi SC, Fu LW. Cardiac sympathetic afferent activation provoked by myocardial ischemia and reperfusion. Mechanisms and reflexes. Annals of the New York Academy of Sciences. 2001; 940: 74–95.
Wang Y, Li G, Liang S, Zhang A, Xu C, Gao Y, et al. Role of P2X3 receptor in myocardial ischemia injury and nociceptive sensory transmission. Autonomic Neuroscience. 2008; 139: 30–37.
Zhang C, Li G, Liang S, Xu C, Zhu G, Wang Y, et al. Myocardial ischemic nociceptive signaling mediated by P2X3 receptor in rat stellate ganglion neurons. Brain Research Bulletin. 2008; 75: 77–82.
Gnecchi-Ruscone T, Montano N, Contini M, Guazzi M, Lombardi F, Malliani A. Adenosine activates cardiac sympathetic afferent fibers and potentiates the excitation induced by coronary occlusion. Journal of the Autonomic Nervous System. 1995; 53: 175–184.
Edlund A, Berglund B, van Dorne D, Kaijser L, Nowak J, Patrono C, et al. Coronary flow regulation in patients with ischemic heart disease: release of purines and prostacyclin and the effect of inhibitors of prostaglandin formation. Circulation. 1985; 71: 1113–1120.
Wu ZZ, Pan HL. Role of TRPV1 and intracellular Ca2+ in excitation of cardiac sensory neurons by bradykinin. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2007; 293: R276–R283.
Pan HL, Chen SR. Sensing tissue ischemia: another new function for capsaicin receptors? Circulation. 2004; 110: 1826–1831.
Tjen-A-Looi SC, Pan HL, Longhurst JC. Endogenous bradykinin activates ischaemically sensitive cardiac visceral afferents through kinin B2 receptors in cats. The Journal of Physiology. 1998; 510: 633–641.
Fu LW, Schunack W, Longhurst JC. Histamine contributes to ischemia-related activation of cardiac spinal afferents: role of H1 receptors and PKC. Journal of Neurophysiology. 2005; 93: 713–722.
Gaspardone A, Crea F, Tomai F, Versaci F, Iamele M, Gioffrè G, et al. Muscular and cardiac adenosine-induced pain is mediated by A1 receptors. Journal of the American College of Cardiology. 1995; 25: 251–257.
Crea F, Gaspardone A, Kaski JC, Davies G, Maseri A. Relation between stimulation site of cardiac afferent nerves by adenosine and distribution of cardiac pain: results of a study in patients with stable angina. Journal of the American College of Cardiology. 1992; 20: 1498–1502.
Phillips PA, Kelly JM, Abrahams JM, Grzonka Z, Paxinos G, Mendelsohn FA, et al. Vasopressin receptors in rat brain and kidney: studies using a radio-iodinated V1 receptor antagonist. Journal of Hypertension. Supplement. 1988; 6: S550–S553.
Szczepanska-Sadowska E. The Heart as a Target of Vasopressin and Other Cardiovascular Peptides in Health and Cardiovascular Diseases. International Journal of Molecular Sciences. 2022; 23: 14414.
Szczepanska-Sadowska E, Cudnoch-Jedrzejewska A, Sadowski B. Differential role of specific cardiovascular neuropeptides in pain regulation: Relevance to cardiovascular diseases. Neuropeptides. 2020; 81: 102046.
Szczepanska-Sadowska E, Zera T, Sosnowski P, Cudnoch-Jedrzejewska A, Puszko A, Misicka A. Vasopressin and Related Peptides; Potential Value in Diagnosis, Prognosis and Treatment of Clinical Disorders. Current Drug Metabolism. 2017; 18: 306–345.
Wasilewski MA, Myers VD, Recchia FA, Feldman AM, Tilley DG. Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cellular Signalling. 2016; 28: 224–233.
Cechetto DF, Saper CB. Neurochemical organization of the hypothalamic projection to the spinal cord in the rat. The Journal of Comparative Neurology. 1988; 272: 579–604.
Sawchenko PE, Swanson LW. Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. The Journal of Comparative Neurology. 1982; 205: 260–272.
Forsling ML, Montgomery H, Halpin D, Windle RJ, Treacher DF. Daily patterns of secretion of neurohypophysial hormones in man: effect of age. Experimental Physiology. 1998; 83: 409–418.
Goncharuk VD, Buijs RM, Jhamandas JH, Swaab DF. Vasopressin (VP) and neuropeptide FF (NPFF) systems in the normal and hypertensive human brainstem. The Journal of Comparative Neurology. 2011; 519: 93–124.
Hallbeck M, Blomqvist A. Spinal cord-projecting vasopressinergic neurons in the rat paraventricular hypothalamus. The Journal of Comparative Neurology. 1999; 411: 201–211.
Baba K, Kawasaki M, Nishimura H, Suzuki H, Matsuura T, Ikeda N, et al. Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat. Scientific Reports. 2022; 12: 13046.
Das S, Komnenov D, Newhouse L, Rishi AK, Rossi NF. Paraventricular Nucleus V_1a Receptor Knockdown Blunts Neurocardiovascular Responses to Acute Stress in Male Rats after Chronic Mild Unpredictable Stress. Physiology & Behavior. 2022; 253: 113867.
Day TA, Sibbald JR. Noxious somatic stimuli excite neurosecretory vasopressin cells via A1 cell group. The American Journal of Physiology. 1990; 258: R1516–R1520.
Szczepanska-Sadowska E, Żera T, Kowara M, Cudnoch-Jedrzejewska A. The contribution of angiotensin peptides to cardiovascular regulation in health and disease. In: Angiotensin From the Kiney to Coronavirus. In Molecular Mediators in Health and Disease: How Cells Communicate (pp. 21–76). Academic Press-Elsevier: Cambridge, MA, USA, 2023.
Proczka M, Przybylski J, Cudnoch-Jędrzejewska A, Szczepańska-Sadowska E, Żera T. Vasopressin and Breathing: Review of Evidence for Respiratory Effects of the Antidiuretic Hormone. Frontiers in Physiology. 2021; 12: 744177.
Zheng H, Lim JY, Kim Y, Jung ST, Hwang SW. The role of oxytocin, vasopressin, and their receptors at nociceptors in peripheral pain modulation. Frontiers in Neuroendocrinology. 2021; 63: 100942.
Góźdź A, Szczepańska-Sadowska E, Maśliński W, Kumosa M, Szczepańska K, Dobruch J. Differential expression of vasopressin V1a and V1b receptors mRNA in the brain of renin transgenic TGR(mRen2)27 and Sprague-Dawley rats. Brain Research Bulletin. 2003; 59: 399–403.
Hernando F, Schoots O, Lolait SJ, Burbach JP. Immunohistochemical localization of the vasopressin V1b receptor in the rat brain and pituitary gland: anatomical support for its involvement in the central effects of vasopressin. Endocrinology. 2001; 142: 1659–1668.
Ostrowski NL, Lolait SJ, Bradley DJ, O’Carroll AM, Brownstein MJ, Young WS, 3rd. Distribution of V1a and V2 vasopressin receptor messenger ribonucleic acids in rat liver, kidney, pituitary and brain. Endocrinology. 1992; 131: 533–535.
Phillips PA, Abrahams JM, Kelly JM, Mooser V, Trinder D, Johnston CI. Localization of vasopressin binding sites in rat tissues using specific V1 and V2 selective ligands. Endocrinology. 1990; 126: 1478–1484.
Son MC, Brinton RD. Regulation and mechanism of L-type calcium channel activation via V1a vasopressin receptor activation in cultured cortical neurons. Neurobiology of Learning and Memory. 2001; 76: 388–402.
Szot P, Bale TL, Dorsa DM. Distribution of messenger RNA for the vasopressin V1a receptor in the CNS of male and female rats. Brain Research. Molecular Brain Research. 1994; 24: 1–10.
Young LJ, Toloczko D, Insel TR. Localization of vasopressin (V1a) receptor binding and mRNA in the rhesus monkey brain. Journal of Neuroendocrinology. 1999; 11: 291–297.
Berson BS, Berntson GG, Zipf W, Torello MW, Kirk WT. Vasopressin-induced antinociception: an investigation into its physiological and hormonal basis. Endocrinology. 1983; 113: 337–343.
Kordower JH, Bodnar RJ. Vasopressin analgesia: specificity of action and non-opioid effects. Peptides. 1984; 5: 747–756.
Honda K, Takano Y. New topics in vasopressin receptors and approach to novel drugs: involvement of vasopressin V1a and V1b receptors in nociceptive responses and morphine-induced effects. Journal of Pharmacological Sciences. 2009; 109: 38–43.
Peng F, Qu ZW, Qiu CY, Liao M, Hu WP. Spinal vasopressin alleviates formalin-induced nociception by enhancing GABAA receptor function in mice. Neuroscience Letters. 2015; 593: 61–65.
Watkins LR, Suberg SN, Thurston CL, Culhane ES. Role of spinal cord neuropeptides in pain sensitivity and analgesia: thyrotropin releasing hormone and vasopressin. Brain Research. 1986; 362: 308–317.
Juif PE, Poisbeau P. Neurohormonal effects of oxytocin and vasopressin receptor agonists on spinal pain processing in male rats. Pain. 2013; 154: 1449–1456.
Cragg B, Ji G, Neugebauer V. Differential contributions of vasopressin V1A and oxytocin receptors in the amygdala to pain-related behaviors in rats. Molecular Pain. 2016; 12: 1744806916676491.
Neugebauer V, Mazzitelli M, Cragg B, Ji G, Navratilova E, Porreca F. Amygdala, neuropeptides, and chronic pain-related affective behaviors. Neuropharmacology. 2020; 170: 108052.
Yang J, Yang Y, Xu HT, Chen JM, Liu WY, Lin BC. Arginine vasopressin induces periaqueductal gray release of enkephalin and endorphin relating to pain modulation in the rat. Regulatory Peptides. 2007; 142: 29–36.
Rossi F, Maione S, Berrino L. Periaqueductal gray area and cardiovascular function. Pharmacological Research. 1994; 29: 27–36.
Wang DX, Yang J, Gu ZX, Song CY, Liu WY, Zhang J, et al. Arginine vasopressin induces rat caudate nucleus releasing acetylcholine to participate in pain modulation. Peptides. 2010; 31: 701–705.
Yang J, Yuan H, Liu W, Song C, Xu H, Wang G, et al. Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the nucleus raphe magnus to participate in pain modulation. Peptides. 2009; 30: 1679–1682.
Zhu W, Tilley DG, Myers VD, Tsai EJ, Feldman AM. Increased vasopressin 1A receptor expression in failing human hearts. Journal of the American College of Cardiology. 2014; 63: 375–376.
Evora PRB, Pearson PJ, Rodrigues AJ, Viaro F, Schaff HV. Effect of arginine vasopressin on the canine epicardial coronary artery: experiments on V1-receptor-mediated production of nitric oxide. Arquivos Brasileiros De Cardiologia. 2003; 80: 483–494.
Sellke N, Kuczmarski A, Lawandy I, Cole VL, Ehsan A, Singh AK, et al. Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery. The Journal of Thoracic and Cardiovascular Surgery. 2018; 156: 2098–2107.
Kendler KS, Weitzman RE, Fisher DA. The effect of pain on plasma arginine vasopressin concentrations in man. Clinical Endocrinology. 1978; 8: 89–94.
Iovino M, Iacoviello M, De Pergola G, Licchelli B, Iovino E, Guastamacchia E, et al. Vasopressin in Heart Failure. Endocrine, Metabolic & Immune Disorders Drug Targets. 2018; 18: 458–465.
Lipinski MJ, Escárcega RO, D’Ascenzo F, Magalhães MA, Baker NC, Torguson R, et al. A systematic review and collaborative meta-analysis to determine the incremental value of copeptin for rapid rule-out of acute myocardial infarction. The American Journal of Cardiology. 2014; 113: 1581–1591.
Gilotra NA, Russell SD. Arginine vasopressin as a target in the treatment of acute heart failure. World Journal of Cardiology. 2014; 6: 1252–1261.
Borsook D, Sava S. Pain: Do ACE inhibitors exacerbate complex regional pain syndrome? Nature Reviews. Neurology. 2009; 5: 306–308.
Brusco I, Justino AB, Silva CR, Scussel R, Machado-de-Ávila RA, Oliveira SM. Inhibitors of angiotensin I converting enzyme potentiate fibromyalgia-like pain symptoms via kinin receptors in mice. European Journal of Pharmacology. 2021; 895: 173870.
Kalynovska N, Diallo M, Palecek J. Losartan treatment attenuates the development of neuropathic thermal hyperalgesia induced by peripheral nerve injury in rats. Life Sciences. 2019; 220: 147–155.
Kalynovska N, Diallo M, Sotakova-Kasparova D, Palecek J. Losartan attenuates neuroinflammation and neuropathic pain in paclitaxel-induced peripheral neuropathy. Journal of Cellular and Molecular Medicine. 2020; 24: 7949–7958.
Nemoto W, Nakagawasai O, Yaoita F, Kanno SI, Yomogida S, Ishikawa M, et al. Angiotensin II produces nociceptive behavior through spinal AT1 receptor-mediated p38 mitogen-activated protein kinase activation in mice. Molecular Pain. 2013; 9: 38.
Patil J, Schwab A, Nussberger J, Schaffner T, Saavedra JM, Imboden H. Intraneuronal angiotensinergic system in rat and human dorsal root ganglia. Regulatory Peptides. 2010; 162: 90–98.
Yamagata R, Nemoto W, Fujita M, Nakagawasai O, Tan-No K. Angiotensin (1-7) Attenuates the Nociceptive Behavior Induced by Substance P and NMDA via Spinal MAS1. Biological & Pharmaceutical Bulletin. 2021; 44: 742–746.
Nemoto W, Ogata Y, Nakagawasai O, Yaoita F, Tadano T, Tan-No K. Angiotensin (1-7) prevents angiotensin II-induced nociceptive behaviour via inhibition of p38 MAPK phosphorylation mediated through spinal Mas receptors in mice. European Journal of Pain. 2014; 18: 1471–1479.
Pulakat L, Sumners C. Angiotensin Type 2 Receptors: Painful, or Not? Frontiers in Pharmacology. 2020; 11: 571994.
Dargie HJ, McAlpine HM, Morton JJ. Neuroendocrine activation in acute myocardial infarction. Journal of Cardiovascular Pharmacology. 1987; 9 Suppl 2: S21–S24.
Remme WJ, de Leeuw PW, Bootsma M, Look MP, Kruijssen DA. Systemic neurohumoral activation and vasoconstriction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris. The American Journal of Cardiology. 1991; 68: 181–186.
Kaski JC, Elliott PM. Angina pectoris and normal coronary arteriograms: clinical presentation and hemodynamic characteristics. The American Journal of Cardiology. 1995; 76: 35D–42D.
Davies MK. Effects of ACE inhibitors on coronary haemodynamics and angina pectoris. British Heart Journal. 1994; 72: S52–S56.
Hoffmann E, Assennato P, Donatelli M, Colletti I, Valenti TM. Plasma endothelin-1 levels in patients with angina pectoris and normal coronary angiograms. American Heart Journal. 1998; 135: 684–688.
Ray SG, McMurray JJ, Morton JJ, Dargie HJ. Circulating endothelin in acute ischaemic syndromes. British Heart Journal. 1992; 67: 383–386.
Qiu S, Théroux P, Marcil M, Solymoss BC. Plasma endothelin-1 levels in stable and unstable angina. Cardiology. 1993; 82: 12–19.
Li L, Jin YP, Xia SD, Feng C. The Biochemical Markers Associated with the Occurrence of Coronary Spasm. BioMed Research International. 2019; 2019: 4834202.
Matsuyama K, Yasue H, Okumura K, Saito Y, Nakao K, Shirakami G, et al. Increased plasma level of endothelin-1-like immunoreactivity during coronary spasm in patients with coronary spastic angina. The American Journal of Cardiology. 1991; 68: 991–995.
Taylor AJ, Bobik A, Richards M, Kaye D, Raines G, Gould P, et al. Myocardial endothelin-1 release and indices of inflammation during angioplasty for acute myocardial infarction and stable coronary artery disease. American Heart Journal. 2004; 148: e10.
Cox ID, Salomone O, Brown SJ, Hann C, Kaski JC. Serum endothelin levels and pain perception in patients with cardiac syndrome X and in healthy controls. The American Journal of Cardiology. 1997; 80: 637–640.
Fu LW, Guo ZL, Longhurst JC. Endogenous endothelin stimulates cardiac sympathetic afferents during ischaemia. The Journal of Physiology. 2010; 588: 2473–2486.
Razavi BM, Hosseinzadeh H. A review of the role of orexin system in pain modulation. Biomedicine & Pharmacotherapy. 2017; 90: 187–193.
Toyama S, Shimoyama N, Shimoyama M. The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain. Neuropeptides. 2017; 61: 95–100.
Zhang FX, Liu XJ, Gong LQ, Yao JR, Li KC, Li ZY, et al. Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons. The Journal of Neuroscience. 2010; 30: 10927–10938.
Chauhan A, Foote J, Petch MC, Schofield PM. Hyperinsulinemia, coronary artery disease and syndrome X. Journal of the American College of Cardiology. 1994; 23: 364–368.
Cooke HM, Lynch A. Biorhythms and chronotherapy in cardiovascular disease. American Journal of Health-System Pharmacy. 1994; 51: 2569–2580.
Kuniyoshi FHS, Garcia-Touchard A, Gami AS, Romero-Corral A, van der Walt C, Pusalavidyasagar S, et al. Day-night variation of acute myocardial infarction in obstructive sleep apnea. Journal of the American College of Cardiology. 2008; 52: 343–346.
Larochelle P. Circadian variation in blood pressure: dipper or nondipper. Journal of Clinical Hypertension. 2002; 4: 3–8.
Thompson DR, Sutton TW, Jowett NI, Pohl JE. Circadian variation in the frequency of onset of chest pain in acute myocardial infarction. British Heart Journal. 1991; 65: 177–178.
Hurwitz S, Cohen RJ, Williams GH. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest. Journal of Applied Physiology. 2004; 96: 1406–1414.
Ichikawa S, Sakamaki T, Tonooka S, Sugai Y. The diurnal rhythm of plasma aldosterone, plasma renin activity, plasma cortisol and serum growth hormone and subnormal responsiveness of aldosterone to angiotensin-II in the patients with normotensive acromegaly. Endocrinologia Japonica. 1976; 23: 75–82.
Yee KM, Pringle SD, Struthers AD. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. Journal of the American College of Cardiology. 2001; 37: 1800–1807.
Oh SN, Myung SK, Jho HJ. Analgesic Efficacy of Melatonin: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials. Journal of Clinical Medicine. 2020; 9: 1553.
Xie S, Fan W, He H, Huang F. Role of Melatonin in the Regulation of Pain. Journal of Pain Research. 2020; 13: 331–343.
Ono D, Honma KI, Honma S. Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock. Frontiers in Neuroscience. 2021; 15: 650154.
Kalsbeek A, Fliers E, Hofman MA, Swaab DF, Buijs RM. Vasopressin and the output of the hypothalamic biological clock. Journal of Neuroendocrinology. 2010; 22: 362–372.
Tsuji T, Allchorne AJ, Zhang M, Tsuji C, Tobin VA, Pineda R, et al. Vasopressin casts light on the suprachiasmatic nucleus. The Journal of Physiology. 2017; 595: 3497–3514.
Jin X, Shearman LP, Weaver DR, Zylka MJ, de Vries GJ, Reppert SM. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell. 1999; 96: 57–68.
Reghunandanan V. Vasopressin in circadian function of SCN. Journal of Biosciences. 2020; 45: 140.
Rohr KE, Inda T, Evans JA. Vasopressin Resets the Central Circadian Clock in a Manner Influenced by Sex and Vasoactive Intestinal Polypeptide Signaling. Neuroendocrinology. 2022; 112: 904–916.
George CP, Messerli FH, Genest J, Nowaczynski W, Boucher R, Kuchel Orofo-Oftega M. Diurnal variation of plasma vasopressin in man. The Journal of Clinical Endocrinology and Metabolism. 1975; 41: 332–338.
Sakakibara R, Uchiyama T, Liu Z, Yamamoto T, Ito T, Yamanishi T, et al. Nocturnal polyuria with abnormal circadian rhythm of plasma arginine vasopressin in post-stroke patients. Internal Medicine. 2005; 44: 281–284.
Braga ANG, da Silva Lemos M, da Silva JR, Fontes WRP, dos Santos RAS. Effects of angiotensins on day-night fluctuations and stress-induced changes in blood pressure. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2002; 282: R1663–R1671.
Pechlivanova DM, Markova PP, Popov D, Stoynev AG. The role of the angiotensin AT2 receptor on the diurnal variations of nociception and motor coordination in rats. Peptides. 2013; 39: 152–156.
Pechlivanova DM, Markova PP, Stoynev AG. Effect of the AT₁ receptor antagonist losartan on diurnal variation in pain threshold in spontaneously hypertensive rats. Methods and Findings in Experimental and Clinical Pharmacology. 2010; 32: 663–668.
Hanai S, Masuo Y, Shirai H, Oishi K, Saida K, Ishida N. Differential circadian expression of endothelin-1 mRNA in the rat suprachiasmatic nucleus and peripheral tissues. Neuroscience Letters. 2005; 377: 65–68.
Douma LG, Barral D, Gumz ML. Interplay of the Circadian Clock and Endothelin System. Physiology. 2021; 36: 35–43.
Elherik K, Khan F, McLaren M, Kennedy G, Belch JJF. Circadian variation in vascular tone and endothelial cell function in normal males. Clinical Science. 2002; 102: 547–552.
Herold M, Cornélissen G, Loeckinger A, Koeberle D, Koenig P, Halberg F. About 8-hour variation of circulating human endothelin-1. Peptides. 1998; 19: 821–825.

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Back to top