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Vol. 286, Issue 1, 489-496, July 1998
Department of Pharmacology and Therapeutics (X.-F.D., J.-F.L.,
W.-H.Z., S.C., D.R.V.),
Lady Davis Institute for Medical Research
(A.S.) and Departments of
Medicine and Physiology (S.M.), McGill
University, Montreal, Quebec, Canada; and
Ste-Justine Hospital,
Research Center (K.G.P., S.C.), Montreal, Quebec, Canada
The myocardial effects of alpha-1A adrenoceptor
(alpha-1 AR) agonists in neonatal rats are mediated by
alpha-1A AR and not by alpha-1B AR,
although 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-1A 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) expression. CEC
did not modify the hypertrophic effect of angiotensin II. The
potentiation of the effects of PE by CEC was associated with a
translocation of Ca++-dependent protein kinase C (PKC)
,
which did not occur in the absence of CEC. Alpha-1A
AR-selective agonist A61603 was ~1000-fold more potent than PE as a
positive inotropic agent; it caused the translocation of PKC, which
was not affected by CEC. 5-Methylurapidil antagonized the effects of PE
and A61603, suggesting that these were mediated via
alpha-1A ARs. Alpha-1D AR antagonist BMY 7378 did not modify PE-induced translocation of PKC. CEC potentiated the
effects of PE on Ca++ transients in Fura 2-AM-loaded
dispersed cardiomyocytes, and this potentiation was prevented by
nifedipine. In whole-cell patch-clamp recordings of cultured
cardiomyocytes, CEC potentiated the effect of norepinephrine on
Ca++ channel currents, which was blocked by
5-methylurapidil. We conclude that alpha-1A ARs are
positively and alpha-1B ARs are negatively coupled to
nifedipine-sensitive Ca++ channels, possibly
via Gi protein, and this antagonistic
relationship between alpha-A AR and
alpha-1B AR in the neonatal heart might be required
physiologically for normal alpha-1 AR-mediated responses and myocardial development.
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