Transient hypoxia is experienced by healthy subjects whenever they are exposed to reduced oxygen content in the inspired air, however prolonged and recurrent hypoxia is one of the most serious complications of sleep apnea disorders and cardiovascular and respiratory pathologies [1, 2]. It has long been known that hypoxia induces remarkable increases of blood pressure due to stimulation of chemoreceptors [2–5], and more recently, it has been shown that the pressure responses tend to be greater in patients with cardiovascular diseases than in healthy subjects [1, 6–8]. The above findings inspired investigators to search for mechanisms responsible for hypertensive effects of hypoxia.

It is known that hypoxia activates neurons of the autonomic nervous system (ANS) engaged in the regulation of cardiovascular functions [4, 5]. The hypoxic signals alarming the ANS are generated in specialized groups of cells of carotid and aortic chemoreceptor bodies as well as in hypoxia sensitive neurons of the brain and peripheral organs [9–11]. Recently, it has been shown that enhanced activity of the superior cervical ganglion causes sensitization of the carotid body in spontaneously hypertensive rats (SHR), and that this effect results in greater pressor and sympathoexcitatory responses to the carotid body stimulation [9]. In addition, deficit of oxygen may promote release of neuroendocrine factors involved in the regulation of the cardiovascular system, such as vasopressin, oxytocin, angiotensins and aldosterone [12–18].

Majority of mammals synthesize arginine vasopressin (AVP), while the pig and hippopotamus produce lysine vasopressin (lysipressin, LVP) and the non-mammal vertebrates secrete arginine vasotocin (AVT). The AVP gene consists of three exones encoding the N-terminal signal peptide, vasopressin, neurophysin II and C-terminal peptide, known as copeptin. Vasopressin and copeptin are released in equimolar quantities, but AVP shows great variability due to its binding to platelets and therefore copeptin is frequently estimated in biological samples as a surrogate of vasopressin release [19–22].

The present review draws special attention to the role of AVP in the development of hypertension during hypoxia. In particular, it discusses the mechanisms through which hypoxia modulates regulation of blood pressure and release of AVP. In addition, the consequences of enhanced release of AVP for tissues oxygenation and cardiovascular regulation are analyzed.

Experimental and clinical studies combined with immunocytochemical and radioimmunological measurements clearly show that vasopressin is synthesized mainly in the hypothalamus, specifically in the magnocellular (MNC) and parvocellular (PNC) neuroendocrine cells of the paraventricular nucleus (PVN), supraoptic nucleus (SON), and suprachiasmatic nucleus. The prevailing number of the MNC neurons send axons to the posterior pituitary, however some of the axons end in the median eminence (ME) of the hypothalamus. Axons of the MCN neurons form close contacts with capillaries either in the posterior pituitary or in the ME, where AVP is released into the blood [23–25]. The PNC innervate the neighboring hypothalamic neurons. They send also multiple projections to several regions of the central nervous system (CNS), namely to the bed nucleus of the stria terminalis (BNST), the medial amygdaloid nucleus, the dorsomedial hypothalamic nucleus, the locus coeruleus (LC), the vertical diagonal band of Broca and the olfactory bulb, as well as to the nucleus ambiguous, nucleus of the solitary tract (NTS), the lateral habenular nucleus, the basal nucleus of Meynert, the substantia nigra, the ventral hippocampus, the central gray, the rostral ventrolateral medulla (RVLM) and the spinal cord [23, 24, 26–33].

Experimental and clinical studies provide evidence that both peripheral and central release of vasopressin are influenced by a variety of regulatory factors [34–36]. AVP release is considerably elevated during hypernatremia and hyperosmolality, hypovolemia, heamorrhage, hypoxia, hyperthermia, stress and pain and it is significantly decreased during hypoosmolality, hypervolemia and elevation of blood pressure. Mechanisms involved in the regulation of vasopressinergic system by these challenges have been discussed extensively in several previous studies [21, 22, 26, 35, 37–43]. Among factors affecting electrophysiological properties of vasopressinergic neurons and release of vasopressin are noradrenaline, gamma-aminobutyric acid (GABA) and glutamate. It has been shown that neurosecretory cells of SON and PVN nuclei receive inputs from A1 noradrenergic, GABAergic and glutamatergic neurons of the brain stem and forebrain [44–51]. Effectiveness of these neurotransmitters is modulated by several locally acting neuropeptides and by gasotransmitters, specifically by angiotensin II, cytokines, and nitric oxide, and by some other local factors [52–57].

Acting in the brain and peripheral organs, vasopressin exerts several regulatory effects, which are of primary importance for regulation of water-electrolyte balance, blood pressure, breathing, metabolism, behavior, learning and memory, sensitivity to stress and pain [21, 22, 26, 27, 32, 38, 42, 58–65]. As discussed below, hypoxia belongs to potent stimulators of the vasopressinergic systems, and accumulating evidence indicates that vasopressin also plays a significant role in the regulation of breathing [37–39, 66].

Regulatory functions of vasopressin are mediated by V1a receptors (V1aRs), V1bRs and V2Rs, which are present in multiple regions of the CNS and in several peripheral organs (Figure 1) [22, 24, 67–75]. Vasopressin can also interact with oxytocin receptors [21, 76]. Besides, specificity of neuroregulatory effects of vasopressin in the CNS depends on interaction with several neurotransmitters and neuromodulators [26, 27, 33, 42, 60, 62, 63, 77–79]. In peripheral organs, V1Rs have been detected in testis, superior cervical ganglion, carotid bodies, liver, kidney, thymus, heart, blood vessels, lung, spleen, uterus, and breast [58, 70, 80–83].

V2Rs were found mainly in the kidney, but there is also evidence for their presence in other organs (Figure 1) [84–86]. Specifically, V2R binding sites were detected in endothelial cells, where they can participate in the regulation of von Willebrand factor secretion [87, 88]. V2R messenger RNA (mRNA) and binding sites have also been identified in the heart and the brain of the rat in early postnatal life [59, 89].

Several studies indicate that secretion of vasopressin, expression of its receptors and its action are significantly affected by multiple homeostatic and pathological challenges such as hypernatremia, hyponatremia, dehydration, hypovolemia, hypervolemia, stress, hypertension, cardiac failure, neurological and psychiatric diseases [35, 69, 90–106].

Arterial chemoreceptors include the carotid bodies strategically located at the bifurcation of the common carotid artery and the aortic bodies situated in the aortic arch. Hypoxia is the primary stimulus for arterial chemoreceptors, especially the carotid bodies (Figure 1). Activation of the arterial chemoreceptors triggers the arterial chemoreflex, which leads to sympathoexcitation, changes in cardiovagal balance, increase in phrenic nerve activity, and pulmonary ventilation and arousal [10, 107, 108]. The involvement of carotid bodies in driving sympathetic activity in hypertension, obstructive sleep apnea, and heart failure is well documented in preclinical and clinical studies. However, the role of aortic bodies is less defined and still requires further investigations.

Increased activity of the arterial chemoreceptors, especially the carotid bodies, has been postulated and found to be causative for experimental arterial hypertension [8, 109–113] and confirmed by clinical studies [114–116]. Increased activity of the arterial chemoreflex is seen before the onset of hypertension in SHR [117], which is in line with findings in normotensive young adults with family history of hypertension, who often manifest increased sensitivity of arterial chemoreflex [8]. There seems to be a selective enhancement of the sympathetic response, with tonically increased activity of the arterial chemoreflex evoked from the carotid bodies as well as increased sensitivity of the chemoreceptors to hypoxic stimuli in hypertension [10, 118, 119]. There is also accumulating evidence that purinergic P2X receptors in the carotid body are involved in this selective drive to the sympathetic system [120–122], thus suggesting that distinct mediators may be involved in specific components of the arterial chemoreflex [10]. The causative role of arterial chemoreceptors in hypertension is further demonstrated by blood pressure lowering effects of removal, denervation, or suppression with hyperoxia of the carotid bodies in animal models of hypertension and in hypertensive patients [110, 112, 114–116].

In this light, it is essential to note that hypoxia increases neurohypophyseal blood flow [123–125] and elevates plasma levels of AVP both in animals and humans [39, 126–128] (Figure 1). The effect of hypoxia on AVP release at least in part depends on the sensory input from the carotid bodies [124, 126]. It has been postulated that the increase in plasma AVP concentration helps in preventing the hypoxia-induced vasodilation, supporting in this way peripheral vascular resistance [129, 130].

Furthermore, AVP released into the circulation may directly target chemosensitive glomus cells of the carotid bodies, which express V1aRs [83] as well as G protein q/11 and phosphokinase C that are key intracellular components of the V1aR signaling [131]. These findings indicate that circulating AVP may affect the glomus cells expressing V1aRs and presumably modulate the activity of the carotid body, thus, providing a potential feedback loop between the hypoxia-mediated release of AVP and activity of the chemoreceptors (Figure 2). In addition, decreased carotid body blood flow activates arterial chemoreflex and has been suggested as a putative mechanism involved in elevated activity of the reflex in hypertension [109, 132]. Thus, it is probable that AVP may also enhance arterial chemoreceptors’ activity by increasing vascular resistance of the carotid body artery thereby decreasing the carotid body blood flow with resultant sensitization of the chemoreceptors.

Vasopressin released into the bloodstream also binds to the circumventricular organs that lack the blood-brain barrier. In particular, V1aRs are expressed in the area postrema [133, 134] and binding of AVP to these receptors alters neuronal activity in the surrounding cardiovascular centers [135, 136] and inhibits phrenic nerve activity [133]. In contrast, it has been suggested that AVP acting locally in the carotid bodies may increase its sensitivity [83] and thus counterbalance the inhibitory effects of the neurohormone binding to V1aRs in the area postrema. This action could fine-tune respiratory and hemodynamic responses to hypoxia [38, 83]. In addition, AVP binding to its receptors in the area postrema sensitizes the arterial baroreflex thus, it helps to maintain blood pressure buffering responses [22, 137]. Despite the sensitizing effect on the baroreflex, intracerebroventricular infusions of AVP that allow for binding of AVP with its receptors in the circumventricular organs trigger pressor response under most experimental paradigms [22, 137] (Figure 2). The question arises whether systemically released AVP modulates engagement of chemoreceptors in regulation of blood pressure in normotensive subjects. In this regard, it has been shown that systemic inhibition of V1aRs do not affect pressor response to acutely evoked arterial chemoreflex with cyanide [138]. Thus, it appears that in normotensive rats AVP plays an insignificant role in hemodynamic response to arterial chemoreflex activation. Undoubtedly, the role of AVP and its V1aR in the carotid body under conditions of arterial hypertension awaits further elucidation.

Hypoxia and elevated blood AVP concentration are frequent attributes of cardiovascular diseases and both exert pro-hypertensive effects. There is strong evidence that hypoxia potently stimulates central and systemic release of AVP and that numerous actions of this hormone determine responsiveness of the cardiovascular system to hypoxia (Figures 1 and 2). Survey of literature carried out in the present review draws attention to mechanisms underlying mutual interactions between hypoxia and activation of systemic and central vasopressin systems in health and cardiovascular diseases. It is concluded that during hypoxia, vasopressin exerts pro-hypertensive effects via intensification of stimulation of chemoreceptors and through interactions with other cardiovascular regulatory factors, mainly catecholamines, angiotensins, natriuretic peptides, steroid hormones and gasotransmitters These effects are potentiated in hypertension and cardiac failure. However, vasopressin may also exert some positive effects through actions mediated by receptors located in specific cardiovascular regions.