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

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 mesenteric 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 relax ation, as assessed by relaxation to acetylcholine resistant to NG-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 KCI 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.