Antihypertensive treatment improves endothelium-dependent hyperpolarization in the mesenteric artery of spontaneously hypertensive rats

Abstract

Background - The vascular endothelium releases endothelium-derived hyperpolarizing factor (EDHF). The mesenteric arteries of 6- to 8-month~old spontaneously hypertensive rats (SHRs) exhibit an impairment of the hyperpolarization induced by acetylcholine via EDHF. Methods and Results - We determined whether antihypertensive treatment can improve EDHF-mediated responses in SHRs. Beginning at age 8 to 9 months, the animals were treated with either enalapril (40 mg · kg-1 · d-1) (SHR-Es) or a combination of hydralazine (25 mg · kg-1 · d-1) and hydrochlorothiazide (7.5 mg · kg-1 · d-1) (SHR-Hs) for 3 months. The control groups were age-matched SHRs (SHR-Cs) and Wistar Kyoto rats (WKYs). The two treatments lowered the blood pressure to comparable extents. The acetylcholine-induced hyperpolarization in the roesenteric artery of treated SHRs improved to a level comparable to that in WKYs (acetylcholine 10-5 mol/L with norepinephrine 10-5 mol/L: SHR-E, -14.4±1.8; SHR-H, -12.0±1.3; SHR-C, - 7.2±1.2; and WKY, -13.3±2.3 mV). EDHF-mediated relaxation, as assessed by relaxation to acetylcholine resistant to N(G)-nitro-L-arginine in norepinephrine-contracted rings, was markedly improved in treated SHRs (maximal relaxation: SHR-E, 79.3±3.2%; SHR-H, 47.4±8.6%; SHR-C, 4.8±2.4%; and WKY, 45.1±6.0%). When the rings were contracted with 77 mmol/L KCl to eliminate EDHF response, no difference was found in relaxation to acetylcholine among the four groups. Similarly, the hyperpolarization and relaxation to levcromakalim, a K+ channel opener, were comparable among the groups. Conclusions - Antihypertensive treatment improved EDHF-mediated hyperpolarization and relaxation in the mesenteric artery in SHRs, whereas NO-mediated relaxation did not appear to be modulated by drug therapy. Thus, alterations in the EDHF system may play a pivotal role in endothelial dysfunction and its improvement with drug therapy in SHRs.