Hypoxia, ischemia, pain and stress, which are frequent attributes of cardiovascular diseases, are also effective stimuli for vasopressin release.

Many studies provide evidence that hypoxia and/or ischemia provoke the significant release of vasopressin and its surrogate, copeptin ^{[1][2][3][4][5][6]}[57,58,59,60,61,62]. Moreover, it has been shown that intermittent hypoxia induces direct activation of vasopressinergic neurons in the PVN ^[7][8][63,64] and that its effect is strongly potentiated by the central administration of Ang II ^[9][65].

Release of AVP into the systemic circulation during hypoxia is associated with vasoconstriction, which is mediated by V1aR and accounts for generation of significant pressor response ^[4][10][60,66]. However, in some vascular beds (cerebral and pulmonary circulation) AVP can cause vasodilation, which is presumably mediated by the release of nitric oxide ^[11][12][13][38,67,68]. The pressor effect of AVP during hypoxia is also exerted by the stimulation of the presympathetic neurons located in the PVN and RVLM. The blockade of V1aR within the RVLM modulates the cardiovascular responses evoked by chronic intermittent hypoxia (CIH) and reduces baseline blood pressure in CIH-conditioned rats ^[14][69]. It should be noted that acting on V1aR vasopressin modulates function of the carotid chemoreflex and causes a decrease in the respiratory rate ^[15][33]. It is likely that the regulation of the carotid chemoreflex by AVP is related to changes of glucose metabolism. Central and systemic application of AVP causes hyperglycemia, which is similar to that observed during hypoxia. Moreover, both the hypoxic and the hyperglycemic responses can be abolished by administration of the V1aR antagonist ^[16][70].

There is evidence that AVP plays a positive role in the regulation of the pulmonary blood flow during hypoxia. Chronic administration of AVP in moderate concentration induced a significant reduction of the mean pulmonary arterial pressure and prevented the development of pulmonary hypertension ^[17][71].

Pain frequently informs on pathological processes developing in the cardiovascular system. Strong pain is a symptom of the coronary ischemia and may provoke stress and anxiety that intensify the discomfort of the disease and cause activation of the sympathetic nervous system and the release of cardiovascular peptides ^[18][72]. Cardiac pain is transmitted to the spinal cord by sympathetic nociceptors and afferents possessing cell bodies located in the thoracic spinal ganglia. It is also generated in parasympathetic nociceptors conveying impulses by means of vagal afferents to the inferior nucleus of the vagus nerve ^[19][20][73,74].

Pain belongs to non-osmotic factors potently stimulating the release of AVP ^[20][74]. Exposure to pain elevates AVP content in perfusates of the PVN and of some other brain structures involved in the regulation of pain (e.g., the periaqueductal gray—PAG; the raphe nuclei; the caudate nucleus—CdN) ^{[18][19][20][21][22][23][24][25]}[72,73,74,75,76,77,78,79]. On the other hand, systemic, intraventricular, intrathecal or topical application of this peptide into specific regions of the brain alleviates pain ^{[18][26][27][28][29][30]}[72,80,81,82,83,84]. It appears that the analgesic effect of AVP is caused by the stimulation of V1aR in the CdN, PAG, raphe magnus nucleus (RMN) and spinal cord ^{[18][26][27][28][31][32][33]}[72,80,81,82,85,86,87]. Systemic administrations of AVP or oxytocin (OT) also exert analgesic effects ^[18][27][72,81]. It is possible that the pain alleviating action of OT is mediated by V1aR because it is mimicked by AVP and can be completely blocked by the V1aR antagonist (SR49059), but not by the OT receptor antagonist (L-368899). The analgesic effect of AVP requires the activation of acid-sensing ion channels in the dorsal root ganglia and it cannot be induced in V1aR knockout mice ^[34][88].

Neurogenic stress is frequently present in cardiovascular diseases, especially in cardiac ischemia, and has a significant negative effect on the course of the disease. Experimental studies show that the neurogenic stress provokes the release of AVP, and that the stimulation of V1aR by AVP plays a significant role in the potentiation of the magnitude of the cardiovascular and behavioral responses to stress in hypertension and heart failure ^{[35][36][37][38][39]}[43,44,45,89,90].

A myocardial infarction (MI) stimulates VPS, causing the significant activation of vasopressinergic magnocellular neurons in the SON and the elevation of plasma AVP levels ^[40][41][42][91,92,93]. Studies on human beings revealed that acute MI results in a significant increase in the concentration of vasopressin and/or copeptine in blood samples collected from patients with acute myocardial infarction ^{[43][44][45][46][47]}[94,95,96,97,98]. In addition, experiments performed on rats showed that heart failure causes activation of the cardiac vasopressin system ^[48][20].

Experimental studies suggest that the elevated release of AVP during cardiovascular disturbances may play a positive role during the recovery from ischemia. For instance, in the rat model of cardiac ischemia-reperfusion injury, intravenous administration of AVP prevented the post-ischemic bradycardia and diminished the incidence of ventricular arrhythmia. Furthermore, administration of AVP reduced the size of the infarct and decreased the expression of some biochemical parameters, which are used as measures of cardiac ischemia (lactate dehydrogenase—LDH; creatine kinase-MB—CK-MB). These effects were significantly reduced by the administration of SR49059, which is a V1R antagonist ^[49][99]. In the porcine model of ischemic ventricular fibrillation induced by occlusion of the left coronary artery, the administration of AVP more effectively augmented the coronary perfusion pressure than the administration of epinephrine ^[50][100]. On the other hand, in experiments on dogs, it was found that the ischemia of the left ventricular myocardium is associated with enhanced contractile response of the coronary microvessels to AVP ^[51][101]. Thus, the mechanism for action of VPS in the post-infarct state is not yet sufficiently elucidated, and it is likely that AVP may engage different processes, depending on its concentration and interaction with other factors.

It appears that the influence of vasopressin on the heart is significantly altered in diabetes mellitus, as it has been shown that AVP exerts a greater vasoconstrictive effect in coronary vessels obtained from patients with diabetes mellitus who underwent cardioplegic arrest and cardiopulmonary bypass than in vessels obtained from patients undergoing the same procedures but not suffering from diabetes ^[52][102]. The enhanced contractility of the coronary vessels in diabetic patients was mediated by increased stimulation of V1aR because it was significantly diminished in the presence of the specific V1aR antagonist (SR 4059). The diabetic patients also had a higher expression of V1aR in their atrial tissue samples ^[52][102].

Several studies suggest that the administration of vasopressin may exert beneficial effects during the recovery period in some forms of heart failure. Studies performed on the porcine model of cardiac arrest induced by ventricular fibrillation revealed that vasopressin applied alone, or in association with epinephrine, exerted positive cardiovascular effects, such as elevations of coronary perfusion pressure and cerebral blood flow ^[53][54][103,104]. In studies on pigs exposed to hemorrhagic shock and cardiac arrest administration of vasopressin resulted in prolonged survival, reduced acidosis and improved renal blood flow ^[55][105]. In a swine resuscitation model, intravenous administration of AVP a few minutes prior to ventricular fibrillation elicited a significant increase in the mid left anterior descending coronary artery cross sectional area and normalized the sinus rhythm ^[56][55].

Studies performed on a porcine cardiopulmonary resuscitation model, in which the animals were treated with different combinations of placebo, AVP and epinephrine, the successful restoration of spontaneous circulation was possible in the group treated with a combination of AVP and epinephrine, but not in the group treated with epinephrine alone ^[54][104]. In the same cardiopulmonary resuscitation model, the joined application of epinephrine, AVP and nitroglycerine significantly increased the left ventricular blood flow and global cerebral blood flow. Moreover, combined administration of AVP and epinephrine produced a greater elevation of the cerebral blood flow than the infusion of epinephrine alone ^[57][106]. Analysis of data from 7 studies comparing the efficiency of various vasopressors used for the return of spontaneous circulation (ROSC) revealed that AVP significantly improved ROSC during ventricular fibrillation evoked by severe hypothermia ^[58][107].

Cardiopulmonary resuscitation in human patients with cardiac arrest is associated with a significant elevation in blood levels for AVP, ACTH, cortisol and renin concentration ^[59][60][108,109]. Positive effects of intravenous administration of 40 U of AVP on the survival of patients with cardiac arrest induced by ventricular fibrillation or vasodilatory shock were reported ^[61][62][63][110,111,112]. In addition, investigations performed on patients with septic shock revealed that administration of AVP in relatively low doses increases blood pressure and urine output and enhances the responsiveness to catecholamines. However, it should be noted that in some patients with vasodilatory shock, application of vasopressin elicited adverse effects (e.g., Russell ^[64][113]). A survey of studies analyzing effects of different vasopressors and their combinations indicated that application of AVP or V1aR agonist (selpressin) permits a reduction in the dose of norepinephrine, which is necessary for cardiovascular stabilization in patients with vasodilatory shocks resulting from sepsis, acute myocardial infarction or cardiovascular surgery ^[64][65][7,113]. AVP and V1R agonist (terlipressin) have been successfully used for the treatment of gastrointestinal bleeding, although some patients responded with arrhythmic complications, manifested by a prolonged QT interval and torsade de pointes ^[66][67][114,115]. Retrospective analysis of adult patients admitted to the medical intensive care unit because of arrhythmia revealed that the early (within 6 h) administration of AVP significantly reduced the new onset arrhythmias and decreased the requirements for catecholamine therapy ^[68][116].

A triple-blind randomized trial, analyzing the survival of patients with cardiac arrest admitted to Canadian emergency departments, critical care units and hospitals, did not show an advantage in favor of vasopressin over epinephrine ^[69][117]. Similar conclusions can be drawn from a meta-analysis of 1519 patients with cardiac arrest in USA hospitals ^[70][118].