title: Effects of pimobendan and UD-CG-212 CL on calcium exchange and contraction in isolated rabbit aorta.
abstract: The effects of pimobendan and its O-demethylmetabolite UD-CG-212 CL on contractile responses and transmembrane Ca fluxes were studied on rabbit isolated aortic rings. Both pimobendan and UD-CG-212 CL (10(-7) M-5 X 10(-4) M) concentration-dependently inhibited the contractile responses induced by KCl (80 mM) and noradrenaline (10(-6) M). This inhibitory effect was observed when these compounds were added either before or after the induced contractions, but was reduced in aortic rings after removal of endothelium. Pimobendan and UD-CG-212 CL shifted the concentration-response curve to noradrenaline downwards and to the right and inhibited the contractile responses elicited by addition of Ca (1-5 mM) to Ca-free high K solution. Pimobendan also inhibited the contractile responses induced by caffeine (20 mM) in aortic rings incubated in normal or in Ca-free medium. At 5 X 10(-4) M, pimobendan inhibited 45Ca influx in resting as well as in aortic rings stimulated by high K and noradrenaline and increased the rate of 45Ca efflux in nonstimulated aortae. It is concluded that pimobendan and its O-dimethylmetabolite UD-CG-212 CL exhibit vasodilator properties in the isolated rabbit aorta by their acting at multiple sites of action, thus decreasing the availability of Ca required for smooth muscle activation.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Tejerina
authors.forename: J
authors.initials: J
authors.lastname: Sesin
authors.forename: C
authors.initials: C
authors.lastname: Delgado
authors.forename: P
authors.initials: P
authors.lastname: Gonzalez
authors.forename: J
authors.initials: J
authors.lastname: Tamargo
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D002132:Calcium Radioisotopes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C041648:pimobendan; D002110:Caffeine; C047936:UD CG 212 Cl; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine