CROSSTALK BETWEEN ALPHA-1A AND ALPHA-1B ADRENOCEPTORS IN NEONATAL RATMYOCARDIUM - IMPLICATIONS IN CARDIAC-HYPERTROPHY

The myocardial effects of alpha-1A adrenoceptor (alpha-l AR) agonists in neonatal rats are mediated by alpha-1A AR and not by alpha-1B AR, a lthough both receptor subtypes are equally expressed; the functions of alpha-1B AR are not known. Here, we report that alpha-1B ARs inhibit the activities of alpha-IA ARs in neonatal rat myocardium so that the inactivation of alpha-1B ARs by chloroethylclonidine (CEC) potentiated the effects of nonselective alpha-1 AR agonist phenylephrine (PE) on myocardial protein synthesis and early gene (c-fos and c-jun) expressi on. CEC did not modify the hypertrophic effect of angiotensin II. The potentiation of the effects of PE by CEC was associated with a translo cation of Ca++-dependent protein kinase C (PKC)alpha, which did not oc cur in the absence of CEC. Alpha-1A AR-selective agonist A61603 was si milar to 1000-fold more potent than PE as a positive inotropic agent; it caused the translocation of PKC alpha, which was not affected by CE C. 5-Methylurapidil antagonized the effects of PE and A61603, suggesti ng that these were mediated via alpha-1A ARs. Alpha-1D AR antagonist B MY 7378 did not modify RE-induced translocation of PKC. CEC potentiate d the effects of PE on Ca++ transients in Fura 2-AM-loaded dispersed c ardiomyocytes, and this potentiation was prevented by nifedipine. In w hole-cell patch-clamp recordings of cultured cardiomyocytes, CEC poten tiated the effect of norepinephrine on Ca++ channel currents, which wa s blocked by 5-methylurapidil. We conclude that alpha-1A ARs are posit ively and alpha-1B ARs are negatively coupled to nifedipine-sensitive Ca++ channels, possibly via G(i) protein, and this antagonistic relati onship between alpha-A AR and alpha-1B AR in the neonatal heart might be required physiologically for normal alpha-1 AR-mediated responses a nd myocardial development.