Effects of alpha1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression.
BACKGROUND
Modulation of the transduction efficiency through G-protein coupled receptors, caused by external stimulation, is essential in designing antihypertrophic treatment strategies in the dysfunctional heart. We compared protein-kinase C (PKC)-dependent regulation of positive inotropic effect via alpha1-adrenoreceptor (ADR)/Gq protein in hyperdynamic versus hypertrophied myocardium.


METHODS
Inotropic (work performing isolated heart) and cellular effects of alpha1-adrenoreceptor stimulation were studied in nontransgenic (Ntg) and transgenic (Tg) mice with cardiac specific overexpression of L-type voltage-dependent calcium channels (L-type VDCC).


RESULTS
Transgenic hyperdynamic and hypertrophic myocardium (due to overexpression of the L-type VDCC alpha1 subunit) were characterized by a lack of positive inotropic effect (PIE) to alpha1-ADR stimulation with phenylephrine (PE), as compared to a positive response in Ntg hearts. This was partially restored by PKC inhibition with chelerythrine and staurosporine only at the hyperdynamic stage. The inability of PKC inhibition to increase positive inotropy was associated with markedly decreased cardiac-specific caveolin-3 expression, and no changes in Galphaq, PLC-beta1, caveolin-1 and alpha1-adrenoreceptor expression.


CONCLUSIONS
In the hyperdynamic myocardium, PKC activation may be one of the switches responsible for an impaired alpha1-adrenergic positive inotropic response. In the hypertrophied myocardium, the interruption of the transduction from Galphaq-protein coupled receptors to downstream effectors may be due to the down-regulation of caveolin-3 expression.
Department of Surgery, Cardiovascular Research Center, Institute of Molecular Pharmacology and Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati OH 45267-0828, USA.
Natalia N
NN
Petrashevskaya
Ilona
I
Bodi
Sheryl E
SE
Koch
Shahab A
SA
Akhter
Arnold
A
Schwartz
D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D020746:Calcium Channels, L-Type / Q000235:genetics*; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010617:Phenanthridines / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013268:Stimulation, Chemical
D000316:Adrenergic alpha-Agonists; D000470:Alkaloids; D053119:Benzophenanthridines; D020746:Calcium Channels, L-Type; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D010617:Phenanthridines; D010656:Phenylephrine; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine