Physiology of the vasopressin receptors

This review article summarizes the structure, signalling pathways, and tissue distribution of the vasopressin receptors, V₁ vascular, V₂ renal, V₃ pituitary, and oxytocin receptors, as well as the P₂ class of purinoceptors. The physiological effects of vasopressin on its receptors are described. The future direction with regard to the role of the V_1a receptor in circulatory shock states is discussed; further studies with V_1a receptor agonists are warranted to further develop treatment strategies to reduce mortality in life threatening diseases like septic shock.

Introduction

The neurohypophysial hormones vasopressin (VP) and oxytocin (OT) were originally detected by Oliver and Schäfer in 1895.¹ In the following decades, the amino acid sequences, structures, and the synthesis of the hormones were elucidated.² Since the 1950s, research examining the hormones, as well as the development of specific agonists and antagonists for VP and OT receptors has followed for a better elucidation of the specific contributions to physiology of each peptide. VP and OT are synthesized within the magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei (SON and PVN), and are transported along their axons to the posterior pituitary where they are stored and ultimately released into the blood stream, to regulate salt and water homeostasis as well as vascular tone. However, even the magnocellular neurons of the SON and PVN can release the hormones from their dendrites to produce important local effects.³ VP is a nonapeptide with a disulfide bridge between two cysteine aminoacids.⁴ OT and VP are encoded by separate genes but they lie on the same chromosome, at 20p, separated by a segment of DNA only 12 kilobases long.⁵ Although OT and VP differ only by one amino acid, they have very different physiologic effects. OT is important in parturition, lactation, and sexual behaviour. VP in addition to its antidiuretic activity is essential for the cardiovascular homeostasis and has emerged as a rational therapy for vasodilatory shock states during the last decade.⁶ The VP analogues arginine vasopressin (AVP), lysine vasopressin (LVP), and terlipressin (TP) have been proven effective in restoring arterial hypotension and reducing catecholamine requirements in experimental and clinical settings of hypotension. These VP analogues develop their effects through the different VP receptors (R), namely V₁R (vascular), V₂R (renal), V₃R (pituitary), and oxytocin receptors, as well as the P₂ class of purinoreceptors. The different structure, signalling pathways, and tissue distributions of these receptors lead to characteristic cardiovascular effects.⁶ The two main receptors are the V₁R and V₂R. The V₁R is located on vascular smooth muscle cells and mediates vasoconstriction and enhancement of prostaglandin release. V₂Rs are found on the distal convoluted tubules and medullary collecting ducts and mainly mediate an anti-diuretic effect. A third receptor, the V₃R is located on the anterior hypophysis and pancreatic isles and seems to facilitate the release of corticotropin (ACTH) and intervenes in insulin secretion. It has been shown that the VP analogues differ in their pharmacokinetic profile, for example the effective half-life of TP is 6 hours vs. 5–15 minutes for AVP, and the V₁/V₂ receptor ratio of TP is 2.2:1 vs. AVP.⁷ AVP has been traditionally used for variceal bleeding and hepatorenal syndrome. However, its recent introduction as a rescue therapy during cardiac arrest and septic shock extends its potential clinical role.⁸ Below, we give a detailed description of the function and physiology of VP receptors, and summarize the effects of AVP and its analogues on the specific receptor. We further discuss future directions of V₁R agonists in the setting of circulatory shock.