The biology of arginine vasopressin in cardiovascular disease

Jordan, Laura V. M (2003) The biology of arginine vasopressin in cardiovascular disease. MD thesis, University of Glasgow.

Abstract

Arginine vasopressin (AVP) is a 9 amino acid, posterior pituitary, peptide hormone that plays a pivotal role in both salt and water homeostasis and blood pressure control. These effects are mediated primarily through 2 main receptor types; the former through the renal tubular V2 receptor (V2R) and the later the smooth muscle cell Via receptor (V1A). AVP has received little attention since its discovery in 1885 and the precise actions of this hormone in both physiology and disease often remains unclear. Recent research has brought to light that AVP does have a number of actions relevant to the progression of cardiovascular diseases (CVDs) and that the AVP receptors are often differentially regulated in a number of these conditions. Fully understanding what these changes are, and how they contribute to CVDs, will open doors for the development of new therapeutic agents to ultimately help reduce morbidity and mortality within our populations. The aims of this thesis were threefold. 1. To fully characterise in vitro 5 novel AVP receptor antagonists (drugs A-E) and from these to select the single most promising agent and undertake further in vitro and in vivo study. 2. To investigate the possibility of additive cardiovascular benefits of ACE inhibition with V1AR antagonism in an adult, hypertensive rat model. 3. To examine the regulation of AVP and its V1ARS in a hypertensive rat model with 8 weeks of streptozocin induced diabetes mellitus (STZ-DM). Within an in vitro experimental setting, drugs A-E displaced specific V1A and V2R antagonists in a dose-dependent manner. Drug A most closely resembled AVP in this regard and was thus selected for further in vitro and in vivo study. A dose of 10 mg/kg was found to be effective acutely with maximal receptor inhibition at 2 hours. Significant inhibition was seen for 4 hours at the V1AR and 8 hours at the V2R. When administered in a chronic 5 day setting to normotensive rats, systolic blood pressure (SBP) remained unaltered and a diminishing aquaresis was seen. In experimental, adult, genetic hypertension, 2 weeks of administration of the V1AR antagonist OPC 21268 did not have any antihypertensive benefits while the ACE inhibitor, ramipril, and combination treatment with ramipril and OPC 21268 lowered SBP to the same extent. Likewise, only the ramipril treated animals demonstrated any reductions in cardiac weights. These results imply that V1AR antagonism does not have a role to play in combating established genetic hypertension in the 2 week setting but does not rule out any longer term structural benefits that may come to light in the context of a more prolonged study. In the setting of 8 weeks of experimental, hypertensive STZ-DM, AVP was elevated with hepatic and renal V1ARS being up-regulated in association with this. This up-regulation was in terms of receptor numbers only (Bmax), as receptor affinity (Kd) remained unaltered when compared to hypertensive non-diabetic controls. Interestingly, the corresponding receptor mRNA levels were not elevated raising the possibility of a post- transcriptional effect. This is the first study to demonstrate an up-regulation of the AVP receptor system in the context of hypertension and DM. AVP, via stimulation of its V1A and V2RS, elicits important biological actions that have been shown to contribute to the pathophysiology of many forms of CVDs such as hypertension and DM. Therapeutic agents to block the AVP receptor are constantly being developed and assessed. In order to determine its ultimate clinical usefulness Drug A should now undergo further trials in disease models such as cardiac failure and low renin hypertension, a category of hypertension seen mainly in the elderly, African-American and diabetic populations where AVP has been shown to play a more prominent pathological role. It has been shown in this thesis that the AVP V1AR system is up-regulated in DM combined with hypertension. Consequently, AVP V1AR blockade provides an exciting new potential therapeutic target that could play an integral role in any future treatment strategies to help combat the ongoing epidemic of this cardiovascular disease.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Adviser: John Connell
• Keywords: Physiology, Medicine
• Date of Award: 2003
• Depositing User: Enlighten Team
• Unique ID: glathesis:2003-74189
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Sep 2019 15:33
• Last Modified: 23 Sep 2019 15:33
• URI: https://theses.gla.ac.uk/id/eprint/74189