Pressor systems in hypertension and congestive heart failure. Role of vasopressin.

Abstract

Elevated peripheral vascular resistance, which characterizes hypertension and congestive heart failure (the latter regardless of absolute blood pressure level) is maintained to a large extent by the combined effects of three major neurohormonal pressor mechanisms: the renin-angiotensin system, the sympathoadrenal system, and arginine vasopressin. Blockade of one of these mechanisms may lead to compensatory stimulation of the others, thus offsetting in part the hemodynamic benefits of a specific intervention. Combination therapy, designed to attack all three systems (with use of an angiotensin converting enzyme inhibitor, a sympathetic blocker such as clonidine, and an antagonist of the vasopressor action of vasopressin), may help in the treatment of such cases. To illustrate this strategy, two experimental studies, one case of malignant hypertension, and one case of congestive heart failure are presented. (Hypertension 1990;16:587-593) I t is generally recognized that a given level of arterial blood pressure is maintained to a large extent by the combined effects of three major neurohormonal pressor mechanisms: the renin-angiotensin system (RAS), the sympathetic nervous system (SNS), and arginine vasopressin (AVP). Several lines of experimental and clinical work over the years have demonstrated the participation of any one of these pressor mechanisms in the development and maintenance of various types of hypertension-or even in the maintenance of normotension. The first two, the RAS and the SNS, have been extensively investigated, and their research has yielded invaluable new treatments for hypertension and congestive heart failure that have now become part of the routine therapeutic armamentarium. The third, AVP, has long been known as the antidiuretic hormone that regulates fluid homeostasis. Only recently has it become the focus of experimental and clinical investigation as an important vasopressor mechanism with potential relevance in clinical situations characterized by elevated systemic vascular resistance such as hypertension and congestive heart failure. The fact Our own earlier studies with the compound d(CH 2 ) 5 -0-(Me)Tyr-AVP, revealed that the pressor function of AVP was most apparent on salt loading, 7 -8 was closely interrelated to those of the RAS and the SNS, and was maximized when the other two were impaired or eliminated.910 These findings were confirmed and amplified subsequently by other investigators. 1112 Because AVP analogues are known to have species-specific action, we set out to investigate the possible relevance of these findings in human pathophysiology. We took the above mentioned Vi antagonist through the various steps of pharmacological development to obtain an investigational new drug (IND) exemption number from the Food and Drug Administration (FDA) for its use in humans. 13 With this new pharmacological tool, we attempted to clarify the interaction of the three pressor systems-the RAS, the SNS, and AVP-in human hypertension and congestive heart failure. The following two case...

Oxytocin receptors expressed and coupled to Ca2+ signalling in a human vascular smooth muscle cell line

“…However, the study did not examine which subtype of the vasopressin/oxytocin receptor family mediates this response, since the selective ligands were lacking. Several antagonists that have been recently developed to be selective for oxytocin receptor would be potentially valuable in further studying the expression and functional role for oxytocin receptor in the intact human vascular system (Gavras, 1990;Laszlo et al, 1991).…”

Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent

“…Therefore, the implication of vasopressin as a primary mediator of angiotensinergic hypertension simultaneously 1) identifies vasopressin as a possible mediator of other newly recognized functions of the brain RAS (e.g., metabolic control, learning and memory, etc. ); and 2) identifies angiotensinsensitive, vasopressin-producing brain structures (e.g., the supraoptic nucleus) as major cardiovascular regulatory centers that may deserve substantially more investigation for therapeutically targeting hypertension and other disorders, especially in selected human populations with low-renin hypertension (2,3,7,15,19,39,48,49,75).…”

“…Interestingly, a population of AVP-expressing neurons project from the PVN to the hindbrain and spinal cord and appear to be involved in the regulation of sympathetic nervous activity (reviewed in Refs. 1, 10, 52), suggesting a possible AVP-mediated cross-talk between these two mechanisms.Although some studies have failed to document a substantial role for AVP in blood pressure control in heterogenous groups of human subjects (49), AVP has been implicated as a significant contributor to blood pressure control in selected populations of humans (19,48). Specifically, African Americans (3), the elderly (15), and patients with congestive heart failure (19) or chronic renal failure (2) all exhibit AVP-dependent hemodynamic changes (7).…”

“…Although some studies have failed to document a substantial role for AVP in blood pressure control in heterogenous groups of human subjects (49), AVP has been implicated as a significant contributor to blood pressure control in selected populations of humans (19,48). Specifically, African Americans (3), the elderly (15), and patients with congestive heart failure (19) or chronic renal failure (2) all exhibit AVP-dependent hemodynamic changes (7).…”

“…Specifically, African Americans (3), the elderly (15), and patients with congestive heart failure (19) or chronic renal failure (2) all exhibit AVP-dependent hemodynamic changes (7). Importantly, these populations of humans all exhibit low levels of circulating renin (75).…”