EVIDENCE THAT ANGIOTENSIN-II, ENDOTHELINS AND NITRIC-OXIDE REGULATE MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY IN RAT AORTA

We measured the activity of mitogen-activated protein (MAP) kinases, e nzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme ac tivity was not affected in the adventitia. The MAP kinase activation w as inhibited by either the angiotensin AT(1) receptor antagonist losar tan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT( 2) receptor antagonist PD 123,319 and the endothelin ETB receptor anta gonist BQ 788 did not affect the MAP kinase activation. The NO synthas e inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) caused an activ ation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitrop russide inhibited the MAP kinase activation induced by endothelium rem oval or angiotensin II. These results suggest that even in isolated ar teries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media ar e tonically released to cause MAP kinase-stimulating effects in medial smooth muscle. (C) 1998 Elsevier Science B.V.