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  • Title: Role of phosphodiesterase in regulation of calcium current in isolated cardiac myocytes.
    Author: Simmons MA, Hartzell HC.
    Journal: Mol Pharmacol; 1988 Jun; 33(6):664-71. PubMed ID: 2454387.
    Abstract:
    It has previously been shown that intracellular perfusion of isolated cardiac myocytes with cGMP reduces the amplitude of the trans-sarcolemmal calcium current (ICa) elevated by cAMP-dependent mechanisms. To test the hypothesis that cGMP acts by stimulating a cyclic nucleotide phosphodiesterase (PDE) activity, PDE activity and the effects of methylisobutylxanthine (MIX), a PDE inhibitor, on ICa were examined in cardiomyocytes dissociated from frog ventricle. PDE activity was determined by measuring hydrolysis of [33P]cAMP in subcellular fractions. Using 100 microM cAMP as substrate, approximately 50% of the PDE activity was found in the 20,000 x g particulate fraction. Basal activity in this fraction had a Vmax of 15.4 nmol [corrected] of cAMP hydrolyzed/min/mg of protein and a Km of 113 microM cAMP. The PDE activity of the particulate fraction was stimulated significantly by cGMP. Half-maximal stimulation was observed with 1.1 microM cGMP. This value is virtually identical to the value for the concentration of intracellular cGMP that produced a half-maximal reduction of cAMP-elevated ICa in electrophysiological experiments. The cGMP-stimulated PDE activity had a Vmax of 9.5 nmol/min/mg [corrected] and a Km of 12.3 microM cAMP. MIX (100 microM) selectively inhibited the cGMP-stimulated PDE activity (IC50 = 20 microM). To determine whether PDEs modulate the amplitude of ICa, the effects of MIX were examined on basal ICa and cAMP-elevated ICa. MIX produced small increases in the basal ICa and increased ICa in the presence of 1 microM intracellular cAMP. MIX at 100 microM potentiated the effects of submaximal doses of isoproterenol and shifted the dose-response curve for cAMP to the left but did not affect the dose-response curve for 8-bromo-cAMP. MIX reversed the effect of cGMP on the cAMP-elevated ICa. We conclude that cyclic nucleotide PDEs play an important role in modulating the cardiac calcium current. The hypothesis that cGMP inhibits the cAMP-elevated ICa by activating a PDE is supported by the finding that MIX inhibited both the cGMP-stimulated PDE activity and the effect of cGMP on ICa at similar concentrations.
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