Vascular actions of natriuretic peptides

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.

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