The effects of modulation of calcium influx through the voltage-sensitive calcium channel on cardiomyocyte hypertrophy.
In human hypertrophic cardiomyopathy and hypertension associated ventricular hypertrophy, chronic use of calcium channel blockers results in a significant regression of hypertrophy. The main objective of this study was to test the hypothesis that modulation of calcium influx through the voltage-sensitive L-type Ca2+ channel directly affects myocardial hypertrophy. Agents that modified calcium influx through the L channel, reduced or enhanced mechanical activity, or uncoupled excitation-contraction coupling were evaluated in cell culture models of myocardial hypertrophy. The calcium channel blocker, verapamil, significantly reduced serum-stimulated cardiomyocyte hypertrophy in a stereoselective manner. The 1,4-dihydropyridine (DHP) calcium channel blocker, nifedipine, also significantly inhibited cardiomyocyte hypertrophy while the DHP calcium channel activator, Bay K 8644, promoted a significant increase in serum-stimulated hypertrophy. Norepinephrine (NE) and, to a lesser degree, isoproterenol (ISO) modulated serum-stimulated hypertrophy. KCl, verapamil, and nifedipine at concentrations that completely arrested beating produced comparable reductions in serum-stimulated hypertrophy. The excitation-contraction uncoupler, 2,3-butanedione monoxime (BDM), KCl and verapamil reduced hypertrophy in high density spontaneously contracting serum-free cardiomyocytes. Addition of NE or serum to BDM treated cells partially offset this reduced hypertrophy. In conclusion, agents that altered calcium influx through the L-type Ca2+ channel or inhibited mechanical activity affected cardiomyocyte hypertrophy. The negative inotropic or chronotropic effects of calcium channel blockers on the heart may contribute to their efficacy in the treatment of myocardial hypertrophy.
Lubic
S P
SP
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143, USA.
Giacomini
K M
KM
Giacomini
J C
JC
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D006321:Heart / Q000503:physiopathology*; D009638:Norepinephrine / Q000494:pharmacology; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002118:Calcium; D009638:Norepinephrine