Mechanism of hyperthyroidism-induced modulation of the L-type Ca2+ current in guinea pig ventricular myocytes.
The positive inotropic effects of thyroid hormone in the heart, increased force and velocity of contraction have been mostly attributed to modulation of myosin ATPase isoenzymes (V1, V2 and V3), and sarcoplasmic reticulum Ca2+ pumping activity. In addition, we have suggested that the effects on ventricular contraction result from a thyroid hormone-induced increase in L-type Ca2+ current (ICa,L). Due to the central role of ICa,L in excitation-contraction coupling, we studied mechanisms whereby thyroid hormone augments this current. Since thyroid hormone modulates adenylate cyclase activity in various tissues, we tested the hypothesis that the hormone activates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A activation, Ca2+ channel phosphorylation and increased ICa,L. We therefore stimulated or inhibited different sites along the "adenylate cyclase cascade", and measured ICa,L and isometric twitch in ventricular myocytes and papillary muscles from euthyroid and hyperthyroid guinea pigs. Our major findings were as follows. In euthyroid myocytes, 0.1 microM isoproterenol (Iso) increased ICa,L (at VM = 0 mV) from -7.04 +/- 0.72 to -22.26 +/- 1.88 pA/pF, P < 0.05, while in hyperthyroid myocytes (ICa,L = -21.48 +/- 2.94 pA/pF), Iso was ineffective. In euthyroid myocytes, intracellular application of cAMP (50 microM) was as potent as Iso, but ineffective in hyperthyroid myocytes. In hyperthyroid myocytes, a protein kinase A inhibitor (2 microM) lowered ICa,L from -26.82 +/- 1.54 to -10.17 +/- 1.70 pApF (P < 0.05), but had no effect in euthyroid myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Mager
S
S
Department of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion, Israel.
Palti
Y
Y
Binah
O
O
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D004594:Electrophysiology; D006168:Guinea Pigs; D006980:Hyperthyroidism / Q000378:metabolism*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007537:Isometric Contraction / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects; D047428:Protein Kinase Inhibitors
D015220:Calcium Channels; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D000242:Cyclic AMP; D007545:Isoproterenol; D000109:Acetylcholine