Pharmacological analysis of the inhibitory effects of KRN2391 on endothelin-1-induced contraction in isolated large coronary artery of the pig.
1. The relaxant effect of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridine-carboximidamide-mo nomethanesulfonate (with both K+ channel opener and nitrate actions), nifedipine (Ca2+ channel blocker), nitroglycerin (nitrate) and cromakalim (K+ channel opener) were investigated in isolated porcine large coronary arteries contracted by endothelin-1. These drugs inhibited endothelin-1-induced contraction in a concentration-dependent manner. 2. The relaxation induced by KRN2391 was nearly complete at their maximum effects, but nifedipine and cromakalim could not produce complete relaxation. 3. The concentration-relaxation curves for KRN2391 underwent a rightward shift in the presence of methylene blue or glibenclamide. The concentration ratios of KRN2391 calculated based on EC50 values were 2.8 and 3.7 in the presence of methylene blue and glibenclamide, respectively. 4. The concentration-relaxation curves for nitroglycerin and cromakalin underwent a rightward shift in the presence of methylene blue and glibenclamide, respectively, and the concentration ratios of nitroglycerin and cromakalim were 12.0 and 6.3. 5. These relaxant effects of KRN2391 and nitroglycerin on endothelin-1-induced contraction of porcine coronary artery were greater than those of cromakalim and nifedipine. This potent relaxant action of KRN2391 on endothelin-induced contraction is thought to be based on both a nitrate action and a K+ channel opening action.
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
K
K
Harada
A
A
Miwa
T
T
Yokoyama
T
T
Izawa
N
N
Ogawa
Y
Y
Jinno
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D005996:Nitroglycerin / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D016232:Endothelins; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; C070492:N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate; D005996:Nitroglycerin; D005905:Glyburide; D002118:Calcium