Effects of pimobendan, its active metabolite UD-CG 212, and milrinone on isolated blood vessels.
The effects of pimobendan, 2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydo-2H-6-pyridazinyl ) benzimidazole (UD-CG 212), and milrinone were investigated on isometric contraction of vascular preparations in rats and guinea-pigs. The drugs dose dependently relaxed aortic, carotid and femoral arterial and mesenteric venous preparations precontracted with KCl or norepinephrine. The rank order of potency (negative log EC50 value) for these drugs was dependent upon the sources of the preparations and stimulants used. The relaxation response to milrinone was reversible, that to UD-CG 212 was poorly reversible, and that to pimobendan was intermediate. Relaxation responses to cromakalim were inhibited by 0.1 microM glibenclamide, whereas those to pimobendan, UD-CG 212 and milrinone were inhibited by glibenclamide only at doses as high as 10-30 microM. The drugs potentiated the relaxation response to isoproterenol but not glyceryl trinitrate, and noncompetitively inhibited arterial contractions accompanied by voltage-dependent Ca2+ influxes. It is suggested that the drugs are potent vasorelaxants, acting directly on vascular smooth muscle and that the vasorelaxant effects are mediated through cyclic AMP-dependent mechanisms.
Fujimoto
S
S
Department of Pharmacology, Nagoya City University Medical School, Japan.
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011728:Pyridones; D014665:Vasodilator Agents; C041648:pimobendan; C047936:UD CG 212 Cl; D020105:Milrinone; D005905:Glyburide