MODULATION OF VASCULAR TONE BY ENDOTHELIN-1 - ROLE OF PRELOAD, ENDOTHELIAL INTEGRITY AND CONCENTRATION OF ENDOTHELIN-1

1 Endothelin-1 (ET-1) has been shown to exert both arterial relaxant and constrictor effects, To examine the mechanisms of these divergent effects, rat aortic rings were suspended in an organ bath (baseline preload, 5 g) and exposed to ET-1 (10(-11) to 10(-7) M). ET-1 contracted these rings in a concentration-dependent fashion. 2 When aortic rings were contracted with noradrenaline (NA) to 1 g of tension, ET-1 caused further contraction of these rings. In rings precontracted to 2 to 4 g of tension, low concentrations of ET-1 (10(-11) to 10(-9) M) caused a significant relaxation, but high concentrations (greater-than-or-equal-to 5 x 10(-9) M) caused a marked contraction, indicating both relaxant and contractile effects of ET-1 depending on the preload and ET-1 concentration. 3 To determine the mechanism of ET-1-induced relaxation, aortic rings were pretreated with the cyclo-oxygenase inhibitor indomethacin, N(G)-monomethyl-L-arginine (L-NMMA) an inhibitor of synthesis of endothelium-derived relaxing factor (EDRF), or oxyhaemoglobin (Hb) which decreases the activity of EDRF, prior to their exposure to ET-1. Both indomethacin and L-NMMA markedly (P < 0.01) attenuated ET-1-induced relaxation, whereas Hb totally abolished it. Removal of the endothelium from aortic rings also abolished ET-1-mediated relaxation. 4 The relaxant effect of ET-1 in NA-precontracted rings was associated with marked accumulation of guanosine 3':5'-cyclic monophosphate (cyclic GMP), whereas ET-1-induced contraction of quiescent rings was not. 5 In manually stretched rings (4 g of tension), ET-1 caused only concentration-dependent contraction, but no cyclic GMP accumulation. 6 Thus, ET-1 contracts rat aortic rings with intact endothelium and those which are passively stretched. However, stimulation of rat aortic rings with NA to modest tension alters the contractile effect of ET-1 to a potent relaxant effect. The ET-1-mediated relaxation in this setting appears to be endothelium-dependent and is related to release of both cyclo-oxygenase products and EDRF.