MECHANISMS OF CENTRAL ENDOTHELIN-INDUCED HYPOTENSION

The aims of the present study were i) to determine the type of endothe lin receptor(s) mediating the hypotension produced by central administ ration of endothelin-1 (ET-1), ii) to delineate the hemodynamic factor s contributing to this hypotension and iii) to differentiate between t he neural and cerebrovascular actions of ET-1. Towards these objective s, we monitoreal blood flow from the choroid plexus of the IVth cerebr al ventricle (4CV) as an index of local cerebral blood flow (CBF); als o, 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% re spectively); hypotension was sustained at the two higher doses. ET-1 a lso produced a profound and sustained reduction in CBF (36 +/- 10%, 54 +/- 10% and 57 +/- 11% respectively). Prior administration of a low d ose (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-ind uced hypotension; the decreases in CBF were not altered (57 +/- 11% an d 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 separ ate series of experiments, centrally applied ET-1 (10 pmol) produced, concomitant with hypotension, a significant decrease in systemic vascu lar resistance (53 +/- 12%) and a significant increase in CMF (71 +/- 17%); a transient increase in ABF also occurred. Heart rate was not si gnificantly affected at any dose of ET-1. It is indicated that central ET-1-induced hypotension is due to peripheral vasodilation. This effe ct is mediated via neuronal ET(A) receptors in the brainstem. It is al so suggested that non ET(A) subtype receptors mediate vasoconstriction within the choroid plexus.