Evidence that nitric oxide regulates AT1-receptor agonist and antagonist efficacy in rat injured carotid artery.
Vascular injury stimulates AT1-receptor expression and nitric oxide (NO) production in smooth muscle cells (SMCs). We examined the ability of AT1 agonists and antagonists to regulate vascular tone ex vivo in injured arteries and the possible modulation by SMC-derived NO. Rings of rat carotid arteries were isolated at day 7 after endothelial denudation and stimulated with angiotensin (Ang) II in the absence or presence of the AT1 antagonists losartan, L-158,809, or EXP-3174. Freshly denuded contralateral arteries were used as controls. AngII-induced contractions were similar in control and injured arteries. Losartan caused an insurmountable inhibition of AngII-induced contractions in injured but not control arteries. Enhanced inhibition of AngII in injured arteries also was observed in the presence of L-158,809 and EXP-3174. In the presence of the NO synthesis inhibitor nitromonomethyl-L-arginine (L-NMMA), maximal contractions to AngII were greater in injured than in control vessels, and AT1-receptor blockade with losartan was surmountable in all vessels. Mechanical removal of superficial neointimal SMCs attenuated NO production and normalized the efficacy of losartan in injured arteries. These results suggest a role for NO in reducing the biologic effects of AT1-receptor agonists and potentiating the efficacy of AT1 antagonists in vessels undergoing remodeling after injury.
Lemay
J
J
Department of Pharmacology, University of Montreal, CHUM Research Center, Quebec, Canada.
Hou
Y
Y
deBlois
D
D
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology*; D020212:Carotid Artery Injuries / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000293:injuries / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000819:agonists*; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C066026:losartan carboxylic acid; D019808:Losartan