DIFFERENTIAL-EFFECTS OF PHOSPHORAMIDON ON CONTRACTILE RESPONSES TO ANGIOTENSIN-II IN RAT-BLOOD VESSELS

1 Cumulative concentration-tension response (C-R) curves to angiotensin II (AII), big endothelin-1 (big ET-1), ET-1 and arginine vasopressin (AVP) were determined in endothelium intact-ring preparations of aorta, mesenteric artery and tail artery isolated from adult male Sprague-Dawley rats in the presence or absence of the neutral metalloprotease inhibitor, phosphoramidon. 2 The order of sensitivity of the three rat vascular smooth muscle preparations to AII, big ET-1 and ET-1 was aorta>mesenteric artery>tail artery whereas that for AVP was reversed, namely, tail artery>mesenteric artery>aorta. 3 Phosphoramidon blocked the responses to AII in a concentration-dependent manner, whereas even very high concentrations of phosphoramidon (100 mu M) failed to affect the tension responses evoked by ET-1 and AVP in all three preparations. Low concentrations of phosphoramidon (10 mu M) produced significant increases in EC(50) values for AII in tail artery (P<0.01) and mesenteric artery (P<0.05) but not in aorta. The rank order of sensitivity to the inhibition by phosphoramidon was tail artery>mesenteric artery>aorta. Phosphoramidon-evoked rightward shifts in the C-R curves to AII were much higher than those to big ET-1 in both mesenteric artery and tail artery. 4 In endothelium-denuded preparations, AII failed to evoke any increases in tension in tail artery while the responsiveness of the mesenteric artery to AII was reduced significantly relative to endothelium-intact tissues with a rightward shift in the C-R curve and a decrease in the maximal response. On the other hand, the C-R curve to AII was shifted to the left in aorta following removal of the endothelium. Importantly, ET-1 and AVP evoked vasoconstrictor responses were unaffected by the inclusion of a high concentration of phosphoramidon (100 mu M) in endothelium-denuded aorta and mesenteric artery. 5 The results suggest that AII-evoked tension responses of blood vessels such as tail artery are completely endothelium-dependent; in relatively larger blood vessels such as mesenteric artery they are partially endothelium-dependent while in much bigger conduit type blood vessel such as aorta, they are endothelium-independent. It is concluded that the vasoconstrictor responses to AII in mesenteric artery and tail artery may be mediated by the release of endothelins from the endothelium by increased formation from big ET, an effect that is blocked by phosphoramidon.