Both nitric oxide and prostaglandin-mediated responses are impaired in skeletal muscle arterioles of hypertensive rats

Objective To investigate the role played by endothelium-derived dilator factors in the regulation of peripheral vascular resistance by determining whether the dysfunction of the endothelium contributes to the reduced dilator responsiveness of skeletal muscle arterioles in hypertension. Methods The endothelial function of isolated, cannulated, pressurized (at 80 mmHg) gracilis muscle arterioles (45-50 mu m diameter) of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) was compared by utilizing vasoactive agents of known action. Results Acetylcholine (ACh, 10(-9), 10(-8) and 5 x 10(-8) mol/l) and sodium nitroprusside (SNP, 10(-8), 10(-7) and 10(-6) mol/l) elicited similar dilations in arterioles of WKY rats and SHR. Substance P (10(-9), 10(-8) and 5 x 10(-8) mol/l) caused significantly less dilation (by approximately 70%) of SHR arterioles compared with WKY rat arterioles. The calcium ionophore A23187 (5 x 10(-8), 5 x 10(-7) and 10(-6) mol/l) elicited dilations in WKY rat arterioles (9.1 +/- 1.1, 24.0 +/- 1.5, and 39.0 +/- 3.4%, respectively), whereas it evoked constrictions (6.5 +/- 1.1, 14.9 +/- 1.5, and 25.5 +/- 1.6%, respectively) in SHR arterioles. Removal of endothelium, inhibition of prostaglandin synthesis (indomethacin) or blockade of prostaglandin H-2 (PGH(2)) receptors (by SQ 29 548) eliminated A23187-induced constrictions of SHR arterioles, The nitric oxide synthase blocker, N-G-nitro-L-arginine elicited a significantly greater inhibition of substance P-induced dilations and a greater reduction in basal diameter of WKY rat arterioles than it did in those from SHR. Conclusions These data suggest that, in SHR arterioles, the synthesis and/or action of nitric oxide is, or are, impaired and the metabolism of arachidonic acid is altered, resulting in an enhanced production of PGH(2). The simultaneous dysfunction of these two dilator pathways of arteriolar endothelium could contribute significantly to the enhanced peripheral resistance observed in hypertension.