Acute and chronic impact of pressure on vascular responsiveness

Abstract

Hypertension leads to vascular complications including endothelial dysfunction, heart failure and stroke. The purpose of the present studies was to investigate the chronic and acute impact of high pressure on vascular responsiveness.

In Study I, isometric tension measurements demonstrated that contractions to phenylephrine, in the presence of indomethacin (inhibitor of cyclooxygenase), were smaller in aortae of spontaneously hypertensive rats (SHR) with, than in those without, endothelium, while they were comparable in such preparations of normotensive Wistar-Kyoto rat (WKY); the difference in SHR aortae was not affected by L-NAME [inhibitor of nitric oxide synthase (NOS)]. This endothelium-dependent, NOS-independent inhibition of phenylephrine-induced contraction was greater in older SHR (36 versus 18 weeks), and abolished by NO scavengers and ODQ (inhibitor of soluble guanylyl cyclase). It was observed not only in the presence of indomethacin but also apocynin (antioxidant), but inhibited by diphenyleneiodonium (inhibitor of cytochrome P450 reductase). These results suggest that the endothelium-dependent, eNOS-independent inhibition is caused by NO produced by cytochrome P450 reductase in the endothelium of the SHR aorta.

Study II investigated the mechanisms underlying the reduced contractions to prostaglandin E2 [agonist of prostaglandin E2 and thromboxane-prostanoid (TP) receptors] by a previous exposure to phenylephrine (agonist of α1-adrenoceptor) in the aortic smooth muscle of the SHR. This inhibition induced by the pre-activation of α1-adrenoceptor was augmented in aortae of older SHR (36 versus 18 weeks) and was not present in WKY preparations. Pre-exposure to the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, also inhibited subsequent contractions to prostaglandin E2 in SHR aortae. Inhibition of PKC by calphostin C abolished the effect of pre-exposure to phenylephrine. The mRNA expressions of PKC isoforms differed in WKY and SHR smooth muscle. These experiments suggest that in the SHR but not the WKY aorta, α1-adrenergic activation causes heterologous desensitization of TP receptor through activation of a specific PKC isoform(s).

In Study III, experiments were performed in a pressure myograph to determine whether or not acute elevation of transmural pressure in the isolated carotid artery of adult mouse (10-12 weeks) impairs endothelium-dependent dilatation by increasing angiotensin II expression or by directly activating AT1 receptors. Transient exposure of arteries to increased pressure (150 mmHg, three hours) inhibited endothelium-dependent, NO-mediated dilatations to acetylcholine, but did not affect responses to the NO donor DETA-NONOate. Inhibiting angiotensin II signaling or angiotensin converting enzyme prevented the impairment of endothelium-dependent dilatation by elevated pressure. Elevated pressure increased the expression of angiotensinogen [precursor of angiotensin II]. Thus, exposure of carotid arteries to elevated pressure leads to local release of angiotensin II, which activates AT1 receptors to cause endothelial dysfunction.

In summary, chronic increased pressure increased the endothelial NO release produced by cytochrome P450 reductase from nitrate and developed the heterologous desensitization of TP receptor caused by PKC in SHR aorta. Acute increased pressure impaired endothelium-dependent NO-mediated vasodilatation by activation of local angiotensin system in adult mouse carotid artery. These processes likely contribute to the pathogenesis of hypertension-induced vascular dysfunction and organ injury.