Information about the effects of oxytocin on the cardiovascular system has been provided by a number of experimental studies. Oxytocin receptors are present in the heart, in the vessels, and in the cardiovascular regions of the brain [35,109,198,199,200,201]. In the vascular endothelial cells of large vessels and cardiac microvessels, they co-localize with endothelial nitric oxide (NO) synthase (eNOS) [106]. In the estrogen-sensitive regions of the brain, such as the hypothalamus and the amygdala, the induction and transcription of OXTR are regulated by estrogens and depend on the stimulation of estrogen receptors (ER). Stimulation of ERα enhances induction of OXTR, while activation of ERβ helps to maintain the transcription of OXTR [113,202].

The majority of experimental findings indicate that the administration of oxytocin exerts a hypotensive effect and that the magnitude of this effect depends on its central and peripheral actions (Figure 2). In normotensive rats remaining at rest, ICV administration of OXY significantly decreases blood pressure, but does not influence the heart rate [203,204]. It has been shown that the subchronic (5 days) subcutaneous application of OXY increases the hypotensive action of clonidine, and this action is abolished by the blockade of alpha-2 receptors (α2R). The latter finding suggests the involvement of α-2 noradrenergic receptors in the hypotensive action of OXY [205]. In Sprague Dawley rats, OXTR mRNA was detected in the vena cava, the pulmonary vein, and the aorta. Its presence was associated with a high expression of ANP mRNA in the vena cava and the pulmonary vein. OXTR mRNA was also identified in the mesenteric arteries and the uterine arcuate arteries of female Sprague Dawley rats. The expression of OXTR mRNA was enhanced by estrogen in the aorta and the vena cava [103,206] and it is worth noting that oxytocin did not cause vasodilation of the systemic arteries. In contrast, in high concentrations, OXY elicited vasoconstriction, which was mediated by the stimulation of V1aR [206].

Transcripts of OXTR were demonstrated both in the atrial and ventricular sections of the heart. It has been shown that activation of the oxytocin receptors plays an essential role in the release of ANP in the heart [34]. In vitro observations on pluripotent P19 embryonic stem cells have shown that OXY induces differentiation of these cells into cardiomyocytes [207].

Extensive findings from animal-derived models indicate that oxytocin may play a beneficial role in the regulation of cardiovascular functions in hypertension. In particular, peripheral subcutaneous injections of OXY in SHR rats resulted in hypotension and caused greater diurnal and nocturnal reductions in blood pressure [208,209]. It appears that the beneficial effect of oxytocin on blood pressure develops during the early postnatal period [210,211]. The buffering role of oxytocin in the regulation of blood pressure in SHR is impaired and even reversed during exposure to an alarming stress [171,172]. SHR rats respond to the application of acute stress with greater increases in blood pressure than WKY rats and this difference is abolished by the chronic ICV administration of OXY [172]. Hypertension is associated with the altered expression of oxytocin in the central nervous system and the adrenal glands of SHR [156]. Reduced expression of OXTR was found in SHR in the NTS and the dorsal brain stem [157,158]. More recently, it was shown that oxytocin released by neurons projecting from the PVN to the dorsal motor nucleus of the vagus prevents the development of hypertension in rats chronically exposed to hypoxia/hypercapnia—an animal model of human hypertension associated with OSAS [27].

Some studies suggest the engagement of oxytocin in hypertension-induced cardiac remodeling. In particular, it has been found that the blockade of cardiac OXTR facilitates the development of fibrosis and causes a reduction in the LV ejection fraction in SHR rats [200]. SHR also manifests elevated levels of OXY and OXTR in the left ventricle of the heart [212].

The cardiac oxytocinergic system plays an essential role in cardiac remodeling and cardioprotection during cardiac ischemia and post-infarct heart failure [161,213,214,215,216,217,218,219]. In the isolated heart rat model, submitted to a one hour ischemia-reperfusion-perfusion procedure, the administration of oxytocin during the early reperfusion phase reduced the size of the myocardial infarct and increased the coronary blood flow. This was associated with a decreased production of reactive oxygen species (ROS), a reduced expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and reduced apoptosis, reduced arrhythmia, and reduced ventricular fibrillation [217,218,219,220]. In addition, OXY increased the phosphorylated Hsp27 protein level and the atrial natriuretic peptide level in the cardiac left ventricle [217]. It should be noted that the cardioprotective actions of OXY are mediated through OXTR activation. The infusion of oxytocin elevated cell death in siRNA-mediated knockout cells with reduced expression of OXTR via binding with vasopressin receptors [220]. Centrally administered OXY decreases both the pressor response and the tachycardic response after exposure to an alarming stress in rats with myocardial infarction, but not in the sham-operated controls [221].

In the rat model of heart failure induced by pressure overloading of the left ventricle lasting four weeks, chronic stimulation of PVN neurons in adult Sprague Dawley rats resulted in several beneficial effects, such as a decrease in blood pressure and heart rate, a reduction of cellular hypertrophy, a reduction of fibrosis, a reduction of IL-1β concentration, and an improvement of the LV function [222]. Gutkowska et al. showed that oxytocin may prevent the development of diabetic cardiomyopathy. A downregulation of OXY gene expression in the heart of the db/db mouse model of type 2 diabetes mellitus has been reported [223]. Male db/db mice respond with a higher expression of cardiac OXTR, a lower fasting blood glucose level, reduced body fat accumulation, reduced ROS production, reduced cardiomyocyte hypertrophy, reduced fibrosis, and reduced apoptosis to prolonged (12 weeks) administration of oxytocin [215,224]. However, chronic overstimulation of OXTR may result in opposite and highly detrimental effects. It has been shown that 14-week-old transgenic α-MHC-Oxtr mice overexpressing oxytocin receptors manifest significantly greater left ventricle end-diastolic volume, prominent cardiac fibrosis, and enhanced expression of pro-fibrogenic genes. There is also a higher mortality rate among transgenic α-MHC-Oxtr mice than among the wild-type control strain [225].

To date, little is known about the cardiovascular effects of OXY in humans and further studies are needed. In line with experimental findings, OXY and its analogue carbetocin exert hypotensive effects during delivery. Rosseland et al. reported marked hypotension and an increase in the stroke volume after OXY/carbetocin administration during cesarean section [226]. Furthermore, in another study, the intravenous infusion of OXY during cesarean section resulted in stenocardia, transient profound tachycardia, hypotension, and electrocardiographic signs of myocardial ischemia [227]. It is worth noting that intranasal OXY administration caused a short-term increase in heart-rate variability in healthy volunteers [228].

Vasopressin regulates blood pressure, blood flow, and body fluid volume through actions mediated by receptors located on vasopressin sensitive cardiovascular neurons in the brain and in the spinal cord, and on AVP receptors in numerous peripheral organs [29,60,69,73,123,125,126,130,175,229,230,231,232,233] (Figure 3). All types of vasopressin receptors are engaged in these actions. The central pressor action of vasopressin is mediated mainly by V1aR located in the RVLM and the rostral ventral respiratory column [234,235,236].

Stimulation of V1aR also plays an essential role in the vasoconstriction of systemic, coronary, and renal vessels [237,238,239,240]. However, stimulation of V1aR also causes vasodilation of the pulmonary arteries [241]. In the kidney, V1aR is present in the basolateral membranes of the thick ascending limbs of Henle’s loop (TAL) and the collecting ducts (CD), and in the juxtaglomerular apparatus [242,243]. Experiments on V1aR deficient mice (V1aR^−/−) strongly suggest that activation of V1aR in the kidney plays an essential role in the stimulation of the RAS and in the activation of the V2R-AQP2 pathway. Elimination of V1aR in these mice resulted in polyuria and the diminution of renin-containing granular cells and the plasma renin level, as well as in the reduction of V2R expression in the collecting ducts [244,245]. Downregulation of V1a receptors is observed in the vascular smooth muscles in sepsis elicited by the application of lipopolysaccharide or proinflammatory cytokines, and this may account for the reduced responsiveness to vasopressin in septic shock [246].

V1bR is located mainly in the brain, the pituitary, the pancreas, and the kidneys [55,247,248]. In the brain, V1bR mediates the activation of the PVN presympathetic neurons by vasopressin [235,249]. They are also engaged in the stimulation of insulin release from the pancreatic islet cells, and the release of ACTH from the anterior pituitary [250,251]. Expression of V1b receptor mRNA in the anterior pituitary is mediated by glucocorticoids [250]. V1bR is located mainly in the inner medulla in the kidney. There is evidence that stimulation of renal V1bR can counterbalance the antidiuretic effect of vasopressin mediated by V2R [252]. It is likely that the counteractive effects of the stimulation of V1bR and V2 receptors by vasopressin may account for the potent natriuretic effect observed after the combined administration of insulin and vasopressin in rats [253].

Vasopressin has long been known as an antidiuretic hormone due to its water retaining action in the kidney, exerted by V2 receptors. In the renal tubules, V2R is located mainly in the collecting duct cells, where it is coupled to Gs proteins. The stimulation of V2R results in the activation of adenylate cyclase, the formation of cAMP, and the activation of protein kinase A (PKA). This leads to the fast activation of AQP2 molecules and their translocation from the cytoplasmic vesicles to the apical cellular membrane where they form water channels. The channels enable the shift of water from the tubules to the cells and subsequently to the basolateral membrane. PKA also intensifies the synthesis of AQP2 molecules [254,255,256]. Activation of V2R increases water permeability in the kidney and enhances the shift of urea and sodium. Acting on V2 receptors, AVP enhances the transcription of the epithelial sodium channels (ENaC) and urea transporters, and promotes the synthesis of renin [254,255,256,257,258]. Consequently, the stimulation of V2R reduces water and sodium excretion and their blockade results in diuresis and natriuresis. The effectiveness of these actions depends on the state of hydration of the body and the availability of other factors operating in the renal tubules, such as Ang II and aldosterone. Aldosterone cooperates with AVP in the regulation of sodium transport via the epithelial sodium channels in the distal portion of the nephron [259]. Experiments on rats with diabetes insipidus have shown that aldosterone reduces the expression of AQP2 in the inner stripe of the outer medulla and increases free water clearance and creatinine clearance, whereas the mineralocorticoid receptor antagonist, spironolactone, elevates AQP2 expression and decreases creatinine clearance [260]. The stimulation of V2 receptors causes their internalization and recycling. This recycling is associated with increased sensitivity of the collecting ducts to vasopressin. The process of recycling is intensified in cardiac failure induced by the ligation of the left anterior descending coronary artery and may account for increased sensitivity to the antidiuretic action of vasopressin in heart failure [261].

Although the kidney is the main target organ expressing V2R, studies exploring the expression of V2R mRNA and the functional consequences of V2R blockade have shown that these receptors may also play a role in the regulation of the gastrointestinal tract, the heart, and the brain [37,58,80,236,262]. Experiments on embryonic stem cells have shown that vasopressin contributes to cardiac differentiation and its action is accomplished by the stimulation of V2 receptors and NO synthesis [263].

The blockade of vasopressin receptors may exert beneficial effects in the treatment of various forms of cardiac failure. The application of antagonists selectively blocking V2 receptors in the rat induces a significant aquaphoric effect and improves hemodynamics [264]. Experiments on pigs with cardiac failure induced by rapid pacing showed that the systemic administration of the V1a receptor antagonist (SR49059) elicited beneficial effects illustrated by a reduction of the left ventricle dimension and peak wall stress, although it did not improve cardiac muscle contractility. The authors reported that the effectiveness of the treatment of heart failure was significantly greater after simultaneous application of V1aR and angiotensin II antagonists [265]. The altered expression of V1aR has been reported in rats with myocardial infarction and in rats exposed to chronic stress. The infarcted rats manifested a reduced V1aR mRNA expression in the preoptic, diencephalic, and mesocenphalopontine regions of the brain. In contrast, the expression of V1aR receptors was significantly elevated in the brain medulla and in the renal cortex of chronically stressed rats [266]. Taking into account the pressor effect of the stimulation of V1a receptors in the brain, it is likely that the downregulation of these receptors during the post-infarct state is a protective response, which is suppressed during stress. There is evidence that the stimulation of V1aR may reduce the cerebral blood flow during dehydration and that this response is associated with an increased production of ROS and can be effectively abolished by the blockade of V1aR [267].

The results from clinical observations are in line with the experimental data. Patients with heart failure manifest a significantly greater expression of V1aR in the left ventricle myocardium than subjects with non-failing hearts [268]. To date, the application of various types of V1aR and V2R antagonists in the treatment of heart failure has provided inconclusive results in human clinical trials [269,270,271]. Nonetheless, recent clinical guidelines on the diagnosis and the treatment of heart failure issued by the European Society of Cardiology indicate that tolvaptan, a selective V2R antagonist, can be considered for the treatment of heart failure patients with hyponatremia [272]. Recently, promising results have been obtained in a double-blind, randomized phase II AVANTI study following the effects of the application of pecavaptan, a dual V1a/V2 antagonist in patients with heart failure and fluid overload. This study revealed that treatment with pecavaptan significantly enhances decongestion of the heart and improves the maintenance of the body fluid balance in patients with acute heart failure [273].

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