ALPHA-ADRENERGIC STIMULATION IN MYOCARDIAL CELLS

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Different aspects of myocardial alpha1-adrenoceptor (alpha1-AR) stimulation were examined: 1) The positive inotropic action of alpha1- adrenoceptor stimulation, at least in part is due to an enhanced myofilament responsiveness to Ca2+ mediated by activation of Na+/H+ exchange and an increase in cytosolic pH (pHi). We tested the hypothesis that the increase in pHi may be due to protein kinase C-mediated activation of Na+/H+ exchange. In experiments with isolated rat myocytes alpha1-AR stimulation with phenylephrine and nadolol enhanced contraction and pHi. However, following PKC inhibition with staurosporine or downregulation with overnight exposure to a tumor-promoting phorbol ester, alpha1-AR stimulation had no effect on pHi and decreased twitch amplitude. Thus, PKC-mediated activation of Na+/H+ exchange increases pHi and contributes to the positive inotropic action of alpha1-AR stimulation. In contrast, inhibition of PKC-dependent effects makes apparent a negative inotropic effect of alpha1-AR stimulation. 2) We examined the effect of alpha1-AR subtypes, alpha1A and alpha1B on contraction, Cai and myofilament response to Ca2+ of isolated myocardial cells. alpha1A-AR stimulation (phenylephrine, nadolol and alpha1B-AR inactivation with chloroethylclonidine) increased contraction, Cai transient amplitude and myofilament response to Ca2+. In contrast alpha1B-AR stimulation (phenylephrine, nadolol and alpha1A-blockade with WB-4101) decreased contraction, Cai transient amplitude and downregulated the alpha1A-AR effect to increase myofilament response to Ca2+. 3) Myocardial damage and arrhythmias due to reperfusion after ischemia are worsened by alpha1-AR stimulation and improved by acidosis. We examined the effect of alpha1-AR on pHi and aftercontractions during recovery from hypercarbic acidosis. alpha1-AR increased pHi and the frequency of aftercontractions upon recovery from acidosis. Both effects were prevented by ethylisopropylamiloride (EIPA), a blocker of Na+/H+ exchange. Under similar experimental conditions alpha1A-AR stimulation enhanced and alpha1B-AR stimulation markedly decreased the frequency of aftercontractions over the effect on non-selective alpha1-AR stimulation.