title: Possible role of P-450-derived metabolites in endothelium-dependent relaxation of rat small mesenteric arteries.
abstract: We reported previously that acetylcholine (ACh)-induced endothelium-dependent relaxation of rat mesenteric microvessels depended both on nitric oxide (NO) and on a charybdotoxin (CTX)-sensitive endothelium-derived hyperpolarizing vasodilator. Cytochrome P450 (CYP)-dependent arachidonic acid metabolites act in some systems as hyperpolarizing vasodilators. We sought to quantitate contributions of such metabolites to the CTX-sensitive component of ACh-induced vasodilation in isolated rat mesenteric resistance arteries. ACh relaxed these vessels nearly completely (93.3+/-1.2%, n = 71); cyclooxygenase inhibition with indomethacin did not diminish this response (94.3+/-11.4%, n = 9). NO synthase inhibition with Nitro-L-arginine (NNLA) reduced relaxation by 30% (n = 54, p<0.05). Pretreatment of vessels with CYP inhibitors, either clotrimazole (CTM) or 17-octadecynoic acid (17-ODYA), or with selective K+ channel inhibitors, either tetraethyammonium acetate (TEA) or CTX, each led to similar small reductions in maximal relaxation (17%, 22%, 16%, and 9% respectively, n = 3-6). Combined pretreatment with NNLA + either (CTM or 17-ODYA) or (TEA or CTX) each led to similar maximal relaxations (52.2+/-4.8%, 50.6+/-9.2, 37.6+/-8.6%, and 44.1+/-11.5%, respectively, n = 6-35; p<0.05 for NNLA+[CTM or TEA or CTX] vs NNLA alone). Combined pretreatment with NNLA+CTM+(CTX or TEA) led to similar maximal relaxations (43.0+/-7.3%, 43.7+/-15%, n = 6-11) that did not differ from values in vessels pretreated with either NNLA+CTM or NNLA+(CTX or TEA). We conclude that the ACh-induced vasodilation was insensitive to cyclooxygenase inhibition, partially sensitive to NO synthase inhibition, and that the K+ channel blockers TEA and CTX identified the same minor component of ACh relaxation as did the CYP inhibitor CTM.
authors.affiliation: Department of Medicine, University of Chicago, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Davidson-Garcia
authors.forename: C
authors.initials: C
authors.lastname: Nalbantian-Brandt
authors.forename: J G
authors.initials: JG
authors.lastname: Umans
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D018999:Charybdotoxin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D001127:Arginine Vasopressin; D018999:Charybdotoxin; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D000109:Acetylcholine