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

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Abstract
Mechanisms underlying the negative inotropic response to α-adrenoceptor stimulation in adult mouse ventricular myocardium were studied. In isolated ventricular tissue, phenylephrine (PE), in the presence of propranolol, decreased contractile force by ∼40% of basal value. The negative inotropic response was similarly observed under low extracellular Ca2+ concentration ([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, ouabain, or dimethylamiloride (DMA), inhibitors of L-type Ca2+ channel, Ca2+ release channel, Na+-K+ pump, or Na+/H+exchanger, respectively. KB-R7943, an inhibitor of Na+/Ca2+ exchanger, suppressed the negative inotropic response mediated by PE. PE reduced the magnitude of postrest contractions. PE caused 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 cell voltage-clamped myocytes, PE increased the L-type Ca2+ and Na+/Ca2+ exchanger currents but had no effect on the inwardly rectifying K+, transient outward K+, or Na+-K+-pump currents. These results suggest that the sustained negative inotropic response to α-adrenoceptor stimulation of adult mouse ventricular myocardium is mediated by enhancement of Ca2+ efflux through the Na+/Ca2+ exchanger.

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