Age-related changes in endothelium-dependent hyperpolarization in the rat mesenteric artery

Abstract

This study was designed to determine the age-related changes in the endothelium-dependent hyperpolarization to acetylcholine (ACh) and its contribution to relaxation in the isolated mesenteric artery from normotensive and hypertensive rats. Membrane potentials and contractions were recorded in arteries from male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) that were 5-6 wk old (young), 6-8 mo old (adult), and 20-26 mo old (aged). Endothelium-dependent hyperpolarizations produced by ACh, applied both at the resting state of the membrane and under conditions of depolarization with norepinephrine (10(-5) M), were markedly impaired in aged WKY rats, adult SHR, and aged SHR. Endothelium-dependent relaxations to ACh in arterial rings precontracted with 10(-5) M norepinephrine were also impaired in aged WKY rats, adult SHR, and aged SHR even in the presence of indomethacin. Furthermore, in these rats, N omega-nitro-L-arginine, an inhibitor of nitric oxide formation, showed potent inhibitory effects on the relaxations, whereas the 20 mM high K+ solution that reduces hyperpolarization had less pronounced effects. Hyperpolarizations and relaxations to cromakalim (10(-5) M), a K(+)-channel opener, were on the whole preserved in aged rats. It would thus appear that the endothelium-dependent hyperpolarization to ACh is reduced with aging as well as by hypertension, and this would, in part, account for the impaired relaxation to ACh in arteries of both aged rats and hypertensive rats.

Antihypertensive Treatment Improves Endothelium-Dependent Hyperpolarization in the Mesenteric Artery of Spontaneously Hypertensive Rats

“…Endothelium-dependent hyperpolarization decreases with increasing age, even in normotensive rats. 25 The underlying mechanisms by which drug therapy improved the EDHF-mediated hyperpolarization are not known from the present study, but we can speculate about several mechanisms. Because hyperpolarization in response to levcromakalim, a direct activator of ATP-sensitive K ϩ channels, 38 was not modulated by antihypertensive treatment, alteration in smooth muscle properties may not be involved.…”

“…10,35,37 We previously showed that ACh-induced hyperpolarization and relaxation via EDHF are markedly impaired in the arteries of 6-to 8-month-old SHRs compared with age-matched WKYs. 10,25 Van de Voorde et al 24 reported an impairment of endothelium-dependent hyperpolarization in response to carbachol in the aortas of rats with renal hypertension. Endothelium-dependent hyperpolarization decreases with increasing age, even in normotensive rats.…”

“…17,20,23,24 We previously reported a severe impairment of the ACh-induced hyperpolarization and relaxation via EDHF in the mesenteric arteries of 6-to 8-month-old SHRs. 10,25 Considering the importance of the endothelium in the control of vascular tone, 26 we thought that it was important to determine whether endothelial dysfunction in hypertension is reversible or preventable. It has been shown that acute treatment with perindoprilat, an ACE inhibitor, potentiates endothelium-dependent hyperpolarization to bradykinin in the canine and human coronary arteries in vitro.…”

Endothelium-Derived Hyperpolarizing Factor–Mediated Renal Vasodilatory Response Is Impaired During Acute and Chronic Hyperhomocysteinemia

“…Other risk factors for atherothrombotic cardiovascular disease have also been reported to affect the EDHF pathway, including hypertension, 17,18 hypercholesterolemia, 19 diabetes mellitus, 12 and aging. 20 Interference with the integrity of the EDHF pathway may thus be a final common pathway through which these risk factors cause microangiopathy and end-organ damage. In conclusion, EDHF-mediated vasodilation is impaired in the renal microcirculation of acute and chronically hyperhomocysteinemic rats.…”

Ischemia-Induced Release of Amino Acids in the Hippocampus of Aged Hypertensive Rats

“…The higher susceptibility of the vasculature in the aged SHR to ischemia may also be responsible for the impaired vasodilatation in the recovery periods. Age-related impairment of dilatory functions of ves sels in both normotensive rats and SHR (Mayhan et al , 1990;Fujii et al , 1993) has been reported.…”