Effects of pimobendan and UD-CG-212 CL on calcium exchange and contraction in isolated rabbit aorta.
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.