Vascular actions of natriuretic peptides
Creators: name: Barber, Melissa N.
Publisher: name: Monash University
Year: 2021
Subjects: classificationCode: 320199
subject: Cardiovascular medicine and haematology not elsewhere classified
classificationCode: 321499
subject: Pharmacology and pharmaceutical sciences not elsewhere classified

description: Atherosclerosis is a widespread clinical problem that underlies many serious cardiovascular conditions. Restenosis, following surgical intervention to restore flow through atherosclerotic arteries, is also a major clinical problem complicating treatment of this disease. Most pharmacological treatments of atherosclerosis target pro-atherogenic processes. The natriuretic peptides are one of the few endogenous systems that may counter atherogenesis through their anti-proliferative effects in the vasculature. This thesis focussed on the roles of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNF) in a model of intimal hyperplasia, the rabbit peri-arterial collar model. This model has many features similar to those of human atherosclerosis and restenosis, namely intimal thickening, increased sensitivity to serotonin and impaired endothelium-dependent relaxation. The model entails placement of a non-occlusive, silastic collar around each carotid artery of the rabbit. After 7 or 14 days, the carotid arteries were removed for analysis. Studies were undertaken using the following three paradigms: chronic in vivo treatment with the natriuretic peptides; in vitro investigations of the vascular effects of natriuretic peptides; and finally chronic manipulation of the endogenous vascular natriuretic peptide system in vivo.Peri-arterial infusion of CNP and ANP into the collar over 7 days significantly improved endothelium-dependent relaxation in collared arteries, however these peptides had no effect on the histological changes due to collaring. When CNP was locally infused into the carotid artery via a carotid artery side branch (intra-luminal), there was a small but significant reduction in intimal thickening. ANP had no such effect. ANP and CNP act via different particulate guanylate cyclase-linked receptors, the NPA and NPB receptor respectively. Thus, either guanylate cyclase-linked natriuretic peptide receptor may improve endothelial function but the CNP specific, NPB receptor, probably mediates the anti-proliferative effects.Studies reported in this thesis demonstrated that immunostaining for the pro-atherogenic mediator plasminogen activator inhibitor-1 (PAI-1) is increased in arteries collared for 7 days when compared with normal, uncollared arteries. CNP infusion, either peri-arterially or intra-luminally, suppressed the increase in expression of PAI-1 in collared arteries. CNP treatment, peri-arterially or intra-luminally also reduced the number of acrophages detected in collared arteries. Therefore CNP may target a number of atherogenic and inflammatory mediators, as well as having its own direct effects.This thesis was scanned from the print manuscript for digital preservation and is copyright the author. Researchers can access this thesis by asking their local university, institution or public library to make a request on their behalf.