MECHANISMS OF CENTRAL ENDOTHELIN-INDUCED HYPOTENSION

The aims of the present study were i) to determine the type of endothelin receptor(s) mediating the hypotension produced by central administration of endothelin-1 (ET-1), ii) to delineate the hemodynamic factors contributing to this hypotension and iii) to differentiate between the neural and cerebrovascular actions of ET-1. Towards these objectives, we monitoreal blood flow from the choroid plexus of the IVth cerebral ventricle (4CV) as an index of local cerebral blood flow (CBF); also, aortic blood flow (ABF) and cutaneous microvascular blood flow (CMF) of the hindpaw were monitored. In anesthetized, ventilated rats, ET-1 (1,3 and 10 pmol) applied to the 4CV produced significant decreases in mean arterial blood pressure (15 +/- 4%, 34 +/- 3% and 37 +/- 3% respectively); hypotension was sustained at the two higher doses. ET-1 also produced a profound and sustained reduction in CBF (36 +/- 10%, 54 +/- 10% and 57 +/- 11% respectively). Prior administration of a low dose (1 nmol) of the ET(A) receptor selective antagonist, BQ-123 [cyclo (D-Trp-D-Asp-L-Pro-D-Val-L-Leu)], abolished only the central ET-1-induced hypotension; the decreases in CBF were not altered (57 +/- 11% and 56 +/- 6% respectively after 3 and and 10 pmol). Pretreatment with a high dose (20 nmol) of BQ-123 attenuated but did not abolish the CBF response to 10 pmol of ET-1 (- 26 +/- 1% vs. - 57 +/- 11%). In a separate series of experiments, centrally applied ET-1 (10 pmol) produced, concomitant with hypotension, a significant decrease in systemic vascular resistance (53 +/- 12%) and a significant increase in CMF (71 +/- 17%); a transient increase in ABF also occurred. Heart rate was not significantly affected at any dose of ET-1. It is indicated that central ET-1-induced hypotension is due to peripheral vasodilation. This effect is mediated via neuronal ET(A) receptors in the brainstem. It is also suggested that non ET(A) subtype receptors mediate vasoconstriction within the choroid plexus.