Vasodilator effects of organotransition-metal nitrosyl complexes, novel nitric oxide donors.
Nitrovasodilators cause endothelium-independent relaxation of blood vessels by generating nitric oxide (NO). We examined the relaxation and depressor effects of two organotransition-metal nitrosyl complexes, CpCr(NO)2Cl and CpMo(NO)2Cl, relative to those of the prototypal nitrovasodilators, nitroglycerin, and sodium nitroprusside (SNP), in phenylephrine-preconstricted aortic rings and conscious, unrestrained rats. CpCr(NO)2Cl, CpMo(NO)2Cl, nitroglycerin and SNP caused dose-dependent relaxation of aortic rings at maximal responses (Emax) of -118+/-4, -113+/-4, -104+/-1, and -128+/-5% and EC50 of 0.14+/-0.04, 22+/-4, 1.23+/-0.65, and 0.063+/-0.013 microM, respectively. The dose-response curve of CpCr(NO)2Cl was displaced to the right by hemoglobin, as well as methylene blue, showing involvement of the NO/cGMP pathway. Unlike nitroglycerin, preexposure for 1 h to CpCr(NO)2Cl did not alter subsequent relaxation response to the compound. Intravenous bolus injections of CpCr(NO)2Cl, CpMo(NO)2Cl, nitroglycerin, and SNP caused dose-dependent decreases in MAP with Emax of -42+/-2, -51+/-8, -56+/-6, and -58+/-2 mm Hg and EC50 of 0.041+/-0.010, 13+/-4, 1.6+/-0.4, and 0.037+/-0.004 micromol/kg, respectively. These results show that CpCr(NO)2Cl and CpMo(NO)2Cl are efficacious nitrovasodilators in vitro and in vivo.
Wang
Y X
YX
Department of Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, Canada.
Legzdins
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P
Poon
J S
JS
Pang
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CC
D000818:Animals; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006454:Hemoglobins; D020030:Nitric Oxide Donors; D009942:Organometallic Compounds; D014665:Vasodilator Agents; C403628:chloro(eta(5)-cyclopentadienyl)-dinitrosylmolybdenum(III); C403627:chloro(eta(5)-cyclopentadienyl)dinitrosylchromine(III); D009599:Nitroprusside; D010656:Phenylephrine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D005996:Nitroglycerin; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester