Evidence for selective effects of chronic hypertension on cerebral artery vasodilatation to protease-activated receptor-2 activation

Background and Purpose-Protease-activated receptor-2 (PAR-2) can be activat ed after proteolysis of the amino terminal of the receptor by trypsin or by synthetic peptides with a sequence corresponding to the endogenous tethere d ligand exposed by trypsin (eg, SLIGRL-NH2). PAR-2 mediates nitric oxide ( NO)-dependent dilatation in cerebral arteries, but it is unknown whether PA R-2 function is altered in cardiovascular diseases. Since hypertension sele ctively impairs NO-mediated cerebral vasodilatation in response to acetylch oline and bradykinin, we sought to determine whether PAR-2-mediated vasodil atation is similarly adversely affected by this disease state. Methods-We studied basilar artery responses in Wistar-Kyoto rats (WKY) (nor motensive) and spontaneously hypertensive rats (SHR) in vivo (cranial windo w preparation) and in vitro (isolated arterial rings). The vasodilator effe cts of acetylcholine, sodium nitroprusside, and activators of PAR-2 and pro tease-activated receptor-1 (PAR-1) were compared in WKY versus SHR. Immunoh istochemical localization of PAR-2 was also assessed in the basilar artery. Results-Increases in basilar artery diameter in response to acetylcholine w ere 65% to 85% smaller in SHR versus WKY, whereas responses to sodium nitro prusside were not, different. In contrast to acetylcholine, vasodilatation in vivo to SLIGRL-NH2 was largely preserved in SHR, and SLIGRL-NH2 was appr oximate to 3-fold more potent in causing vasorelaxation in SHR versus WKY i n vitro. In both strains, responses to SLIGRL-NH2 were abolished by NG-nitr o-L-arginine, an inhibitor of NO synthesis. Activators of PAR-1 had little or no effect on the rat basilar artery. PAR-2-like immunoreactivity was obs erved in both the endothelial and smooth muscle cells of the basilar artery in both strains of rat. Conclusions-These data indicate that NO-mediated vasodilatation to PAR-2 ac tivation is selectively preserved or augmented in SHR and may suggest prote ctive roles for PAR-2 in the cerebral circulation during chronic hypertensi on.