Effects of the benzimidazole derivatives pimobendan and 2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6- pyridazinyl) benzimidazole . HCl on phosphodiesterase activity and force of contraction in guinea-pig hearts.
The effects of pimobendan (UD-CG 115 BS) and UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6- pyridazinyl)benzimidazole X HCl) on force of contraction, beating frequency, and on adenylate cyclase and phosphodiesterase activity were investigated in isolated preparations from guinea-pig hearts. Both benzimidazole derivatives exerted a concentration-dependent positive inotropic effect in guinea-pig papillary muscles. The efficacies were similar to that of dihydroouabain. The positive inotropic effect of both benzimidazoles was accompanied by an enhancement of the rate of force development and a prolongation of the contraction. Both benzimidazole derivatives inhibited phosphodiesterase (PDE) activity in a crude preparation from guinea-pig ventricles. However, at the concentrations producing maximal positive inotropic effects in papillary muscles, pimobendan and UD-CG 212 Cl diminished PDE activity only by about 20-30%. Since both benzimidazoles did not affect adenylate cyclase in a particulate membrane preparation a stimulation of the cAMP synthesis can be ruled out. As recently reported for pimobendan, this study provides functional evidence that the positive inotropic effect of UD-CG 212 Cl is also at least partially mediated by cAMP. Firstly, the positive inotropic effect of UD-CG 212 Cl was inhibited by carbachol, adenosine and (-)-N6-phenyl-isopropyladenosine. Secondly, UD-CG 212 Cl potentiated the inotropic effects of isoprenaline and histamine. UD-CG 212 Cl had no positive chronotropic effect and pimobendan increased the beating frequency only slightly.(ABSTRACT TRUNCATED AT 250 WORDS)
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Berger
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Meyer
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Scholz
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Starbatty
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C000977:dihydroouabain; D010660:Phenylisopropyladenosine; C041648:pimobendan; D010042:Ouabain; D006632:Histamine; D002217:Carbachol; D000262:Adenylyl Cyclases; D000241:Adenosine; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine