Crosstalk between alpha-1A and alpha-1B adrenoceptors in neonatal rat myocardium: implications in cardiac hypertrophy.
The myocardial effect 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-1 B ARs inhibit the activities of alpha-1A ARs in neonatal rat myocardium so that the inactivation of alpha-1 B 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)alpha, which did not occur in the absence of CEC. Alpha-1A AR-selective agonist A61603 was approximately 1000-fold more potent than PE as a positive inotropic agent; it caused the translocation of PKC alpha, 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.
Deng
X F
XF
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Sculptoreanu
A
A
Mulay
S
S
Peri
K G
KG
Li
J F
JF
Zheng
W H
WH
Chemtob
S
S
Varma
D R
DR
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology*; D006321:Heart / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000032:analysis; D009200:Myocardial Contraction / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
C094643:A 61603; D015220:Calcium Channels; D007093:Imidazoles; D007527:Isoenzymes; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; D010656:Phenylephrine; D011493:Protein Kinase C; D002118:Calcium