ALPHA-ADRENERGIC STIMULATION IN MYOCARDIAL CELLS

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We have previously shown that the positive inotropic action of alpha1- adrenoceptor (alpha1-AR) stimulation, at least in part is due to an enhanced myofilament responsiveness to Ca2+ mediated by protein kinase C (PKC)-dependent activation of Na+/H+ exchange and an increase in cytosolic pH (pHi). We have also 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+. In additional experiments we have examined the effect of alpha1A- and alpha1B-AR stimulation on pHi and the PKC-dependence of the alpha1B-AR effect on pHi and contraction of isolated myocardial cells. In HCO3-/CO2- buffered saline, alpha1A increased cytosolic pH. In contrast alpha1B decreased cytosolic pH and this effect persisted in HCO3-/CO2-free solution. alpha1B-mediated cytosolic acidification was abolished by staurosporine, a protein kinase C inhibitor, and by protein kinase C down-regulation with prolonged exposure to 4beta-phorbol 12-myristate 13-acetate. Changes in twitch amplitude paralleled those in cytosolic pH due either to alpha1A- or alpha1B- adrenoceptor stimulation. Our results show that alpha1A-AR and alpha-1B-AR have opposite effects on pHi homeostasis of isolated myocardial cells.