HETEROGENEITY IN VASCULAR SMOOTH-MUSCLE RESPONSIVENESS TO ANGIOTENSIN-II - ROLE OF ENDOTHELIN

We compared the role of endothelium and of endothelin in mediating the vasoconstrictor responses to angiotensin II (Ang II) in three vascular smooth muscle preparations-aorta, mesenteric artery, and tail artery-isolated from adult male Sprague-Dawley rats. The vasoconstrictor potency for Ang II in blood vessels with endothelium varied in the following rank order: aorta>mesenteric artery>tail artery. Although the maximal tension responses to Ang II were similar for mesenteric and tail arteries, it was significantly lower in aorta. Endothelium removal led to a leftward shift in the concentration-response curves to Ang II in the aorta but a rightward shift in the mesenteric artery. Strikingly, Ang II failed to evoke tension responses in tail artery in the absence of endothelium. The endothelin-A (ET(A))-selective antagonist BQ-123 blocked the responses to Ang II in a noncompetitive manner, with partial and complete attenuation of responses in the endothelium-intact mesenteric and tail artery preparations, respectively. In contrast, BQ-123 did not affect the responses to Ang II in the aorta. BQ-123 also failed to affect the responses to Ang II in endothelium-denuded mesenteric artery rings. The Ang II type 1 (AT(1)) receptor-selective antagonist losartan competitively blocked the responses to Ang II in the three tissues (pA(2), 8.3 to 8.7) when endothelium was present. These data suggest that there are endothelium-dependent regional variations in vascular tissue sensitivity to Ang II. The vasoconstrictor response to Ang II in rat aorta involves activation of AT(1) receptors located on vascular smooth muscle cells, whereas the response in mesenteric artery involves activation of both vascular and endothelial AT(1) receptors. In contrast, the responses to Ang II in the tail artery may be mediated by the indirect stimulation of vascular smooth muscle ET(A) receptors subsequent to the activation of endothelial AT(1) receptors likely linked to the release of endothelins.