Endothelium-derived contracting factors in resistance arteries of young spontaneously hypertensive rats before development of overt hypertension.

Abstract

Vascular relaxations are impaired in adult spontaneously hypertensive rats (SHRs) because of increased production of an endothelium-derived, cyclooxygenase-dependent contractile factor or factors. To test the hypothesis that alterations in endothelial function precede and contribute to the development of overt hypertension in SHRs, we compared in myographs endothelium-mediated relaxations of mesenteric resistance arteries from 4-week-old SHRs and Wistar-Kyoto (WKY) rats. Acetylcholine (10(-9) to 10(-4) M) induced comparable relaxations in SHR and WKY arteries precontracted (ED50) with norepinephrine. In arteries obtained from SHRs but not from WKY rats, relaxations were replaced by contractile responses with higher concentrations of acetylcholine (10(-6) to 10(-5) M). The contractile responses were endothelium dependent, were augmented by nitro L-arginine (10(-4) M), and were prevented by pretreatment with indomethacin (10(-5) M) or 3-amino-1,2,4-triazole (10(-3) M), an inhibitor of superoxide anion production via the cyclooxygenase pathway. Inhibition of thromboxane synthetase (CGS-13080, 5 x 10(-5) M) and antagonism of prostaglandin H2/thromboxane A2 receptors (SQ-29,548, 5 x 10(-5) M) failed to block the contractile response to acetylcholine in SHR arteries. Acetylcholine-mediated relaxations were significantly impaired in mesenteric arteries from 16-week-old SHRs but not from WKY rats. Endothelium-independent relaxations produced by sodium nitroprusside and contractile responses to norepinephrine and endothelin were comparable in arteries from SHRs and WKY rats of all ages. In summary, endothelium-dependent relaxations of mesenteric arteries from "prehypertensive" SHR rats were impaired by the production of a contractile factor (or factors) that appears to be superoxide anions.