REVERSAL OF ENDOTHELIN-1 RELEASE BY STIMULATION OF ENDOTHELIAL ALPHA(2)-ADRENOCEPTOR CONTRIBUTES TO CEREBRAL VASORRELAXATION

Agonists acting on the vascular endothelium can modulate the release o f a number of factors that interact with the surrounding smooth muscle cells and influence their tone. One such factor is the vasoconstricti ng agent endothelin-1 (ET-1), which has been implicated in several dis ease states, including stroke. However, very little is known about the physiological role of ET-1 in the cerebral circulation. We demonstrat e that activation of alpha(2)-adrenoceptors in human pial artery endot helial cells reduces both constitutive and agonist-stimulated release of immunoreactive ET-1. That this has physiological relevance is suppo rted by our demonstration that in segments of rabbit middle cerebral a rteries, alpha(2)-adrenoceptor activation reduces the release of endot helium-derived ET-1 and causes an endothelium-dependent relaxation. Th e adrenoceptor-dependent relaxation was not blocked by combined additi on of indomethacin and N-omega-nitro-L-arginine in 25 mmol/L KCl-depol arizing physiological solution but was selectively antagonized by a su bthreshold concentration of exogenous ET-1. Our data suggest that acti vation of endothelial alpha(2)-adrenoceptor would favor a decrease in ET-1 production and possibly promote vascular relaxation.