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Am J Physiol Heart Circ Physiol 280: H132-H141, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 1, H132-H141, January 2001

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

Kazuhide Nishimaru, May Kobayashi, Tomoyuki Matsuda, Yoshio Tanaka, Hikaru Tanaka, and Koki Shigenobu

Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba 274-8510, Japan

Mechanisms underlying the negative inotropic response to alpha -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 alpha -adrenoceptor stimulation of adult mouse ventricular myocardium is mediated by enhancement of Ca2+ efflux through the Na+/Ca2+ exchanger.

alpha -adrenoceptors; cardiac muscle; contractile force; negative inotropism; Na+/Ca2+ exchanger; mouse myocardium


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