Selective activation of alpha1A-adrenergic receptors in neonatal cardiac myocytes is sufficient to cause hypertrophy and differential regulation of alpha1-adrenergic receptor subtype mRNAs.
Prolonged stimulation of cardiac alpha1-adrenergic receptors causes myocyte hypertrophy, although the receptor subtypes involved remain controversial. We have used a potent and selective alpha1A agonist, A-61603, to test whether activation of the alpha1A-adrenergic receptor subtype is sufficient to mediate the morphological, biochemical and molecular alterations associated with cardiomyocyte hypertrophy. In neonatal rat cardiomyocyte cultures, 48 h incubation with 50 nm A-61603 led to a marked increase in myocardial cell size that was associated with a significant elevation in the rate of protein synthesis. The increased rate of incorporation of radiolabelled amino acids into protein stimulated by A-61603 was totally abolished by the selective alpha1A antagonist KMD-3213. A-61603 increased ANF secretion three-fold, and ANF mRNA 12-fold above control levels in cardiomyocyte cultures. RNase protection analysis demonstrated a A-61603-mediated two to three-fold increase in alpha1A-adrenergic receptor mRNA with a concomitant 50% decrease in alpha1B mRNA levels by 48 h. Identical responses of differential regulation of alpha1A- and alpha1B-adrenergic receptor mRNA were observed with phenylephrine. Both the stimulation of alpha1A- and repression alpha1B-adrenergic receptor mRNA caused by A-61603 could be abolished by 10-20 nm KMD-3213. The present data provide evidence that selective activation of alpha 1A-adrenergic receptors on cardiomyocytes is sufficient to mediate the phenotypic changes associated with cardiac hypertrophy. In addition, the differential regulation of alpha1A and alpha1B mRNA in response to selective alpha1A-adrenergic receptor stimulation suggests that cross-talk between receptor subtypes may be involved in regulating receptor populations during chronic agonist exposure.
Autelitano
D J
DJ
Molecular Physiology Laboratory, Baker Medical Research Institute, Prahran, Victoria, 3181, Australia.
Woodcock
E A
EA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000473:pathology*; D002478:Cells, Cultured; D006321:Heart / Q000254:growth & development; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology*; D011433:Propranolol / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
C094643:A 61603; C547715:Adra1a protein, rat; C547718:Adra1b protein, rat; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D007211:Indoles; D011506:Proteins; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; D009320:Atrial Natriuretic Factor; D011433:Propranolol; C095285:silodosin