alpha-Adrenoceptor stimulation-mediated negative inotropism and enhanced Na+/Ca2+ exchange in mouse ventricle

Mechanisms underlying the negative inotropic response to alpha -adrenocepto r stimulation in adult mouse ventricular myocardium were studied. In isolat ed ventricular tissue, phenylephrine (PE), in the presence of propranolol, decreased contractile force by similar to 40% of basal value. The negative inotropic response was similarly observed under low extracellular Ca2+ conc entration ([Ca2+](o)) conditions but was significantly smaller under high-[ Ca2+](o) conditions and was not observed under low-[Na+](o) conditions. The negative inotropic response was not affected by nicardipine, ryanodine, ou abain, or dimethylamiloride (DMA), inhibitors of L-type Ca2+ channel, Ca2release channel, Na+-K+ pump, or Na+/H+ exchanger, respectively. KB-R7943, an inhibitor of Na+/Ca2+ exchanger, suppressed the negative inotropic respo nse mediated by PE. PE reduced the magnitude of postrest contractions. PE c aused a decrease in duration of the late plateau phase of action potential and a slight increase in resting membrane potential; time courses of these effects were similar to that of the negative inotropic effect. In whole cel l voltage-clamped myocytes, PE increased the L- type Ca2+ and Na+/Ca2+ exch anger currents but had no effect on the inwardly rectifying K+, transient o utward K+, or Na+-K+- pump currents. These results suggest that the sustain ed negative inotropic response to alpha -adrenoceptor stimulation of adult mouse ventricular myocardium is mediated by enhancement of Ca2+ efflux thro ugh the Na+/Ca2+ exchanger.