SIGNAL TRANSDUCTION OF ALPHA-ADRENERGIC STIMULATION IN CARDIAC MYOCYTES

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The positive inotrophic action of alpha-adrenergic stimulation is due to an increase in the cytosolic [Ca 2+], (Cai) transient which triggers the contraction and to an enhanced myofilament responsiveness to Ca 2+. In a variety of cell types alpha-adrenergic stimulation activates Na+/H+ exchange and increases cytosolic pH (pHi) via this mechanism. In the heart alkalosis is known to have a positive inotropic action due to an increased myofilament sensitivity to Ca 2+. We tested the hypothesis that, at least in part, the positive inotropic action of alpha -adrenergic stimulation may be due to an increased pH i. The effect of alpha-adrenergic stimulation with phenylephrine and nadolol was assessed in ventricular myocytes from the adult rat loaded with the pH probe SNARF-1 and bathed in a bicarbonate buffer with 1.5 mM [Ca 2+]. Alpha-adrenergic stimulation enhanced twitch amplitude and pH i. There was a significant correlation between the increase in twitch amplitude and pHi. Both effects were antagonized by ethylisopropylamiloride, a Na+/H+ exchange inhibitor. Other experiments aimed at characterizing the role of two known alpha 1 receptor subtypes, alpha 1A and alpha 1B, on myocardial contraction and pHi. The two alpha 1 receptor subtypes are distinguished by their sensitivity to chloroethylclonidine (alpha 1B) and WB-4101 (alpha 1A). The positive inotropic effect of alpha-adrenergic stimulation was abolished by WB-4101. In contrast, the addition of chloroethylclonidine in the presence of alpha- adrenergic stimulation caused a further enhancement in contractility. Thus, alpha 1A and alpha 1B receptors have opposing effect on myocardial contraction and additional experiments will aim at establishing the role of each alpha 1 receptor subtype on pHi homeostasis.