ENDOTHELIN PLAYS A ROLE IN THE MAINTENANCE OF BLOOD-PRESSURE IN NORMOTENSIVE GUINEA-PIGS

The objective of the present study was to evaluate if endothelin plays a role in the maintenance of arterial blood pressure in normotensive guinea pigs. For this purpose, the effects of a new mixed (ET(A) + ET( B)) endothelin receptor antagonist, Ro 47-0203 (bosentan), were evalua ted in vitro on aortic rings and in anesthetized and conscious guinea pigs. In vitro, bosentan was a potent (pA(2) = 7.5) and competitive en dothelin receptor antagonist as shown by the parallel rightward shift of the concentration-response curve for endothelin-1 on guinea pig aor tic rings in presence of increasing concentrations of bosentan. In viv o, bosentan significantly decreased arterial blood pressure of both an esthetized and conscious guinea pigs. This effect was similar to the e ffect of BQ-123, a selective ET(A) receptor antagonist. No additional effect was observed when bosentan was given on top of BQ-123. Neither inhibition of the renin angiotensin system with remikiren, cyclooxygen ase inhibition with indomethacin, bradykinin antagonism with Hoe 140, ganglionic blockade with chlorisondamine, parasympathetic inhibition w ith atropine nor nitric oxide synthase blockade with L-NAME altered th e effect of bosentan. In conclusion, the present results show that end othelin contributes to the maintenance of arterial blood pressure in n ormal normotensive guinea pigs most likely through stimulation of ET(A ) receptors.