Vascular endothelin-1 expression and effect of an endothelin ETA antagonist on structure and function of small arteries from stroke-prone spontaneously hypertensive rats.

Abstract

There is some evidence that the endothelin (ET) system may participate in blood pressure elevation and in vascular hypertrophy in stroke-prone spontaneously hypertensive rats (SHR-SP). To further understand the involvement of the ET system in this hypertensive model, we examined preproendothelin-1 (preproET-1) mRNA abundance in blood vessels of 5-week and 18-week SHR-SP in comparison to SHR, and treated 12-week old SHR-SP with the ETA-selective receptor antagonist A-127722.5 (30 mg/kg/day in the drinking water) for 10 weeks. Abundance of preproET-1 mRNA by Northern blot analysis was increased more than twofold in aorta and mesenteric arteries of SHR-SP relative to SHR at 18 weeks but not at 5 weeks of age. SHR-SP treated with A-127722.5 had a tail-cuff systolic blood pressure at 22 weeks of age of 241 +/- 2 mm Hg vs. 251 +/- 3 mm Hg in untreated SHR-SP (p < 0.05). Heart:body weight ratio was no different in both groups, but aortic segment:body weight ratio was slightly but significantly smaller in treated SHR-SP (p < 0.05). Pressurized mesenteric small arteries from treated SHR-SP had a smaller media width (12.6 +/- 0.6 microns vs. 14.9 +/- 0.5 microns; p < 0.05) and media:lumen ratio (5.8 +/- 0.2% vs. 7.3 +/- 0.3%; p < 0.01), whereas media cross-sectional area and lumen diameter tended to decrease and increase, respectively, without achieving statistical significance. Acetylcholine-induced relaxation was improved in treated SHR-SP (99.6 +/- 0.6% vs. 90.0 +/- 3.6%; p < 0.05), whereas relaxation responses to sodium nitroprusside were similar in both groups. These results show increases of preproET-1 expression in blood vessels that appear to be secondary to blood pressure elevation. There is a small ET-dependent component in blood pressure elevation and in conduit and resistance artery changes in adult stroke-prone SHR.