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Department of Physiology, University of Pennsylvania, Philadelphia 19104-6085.

1. The effect of heparin on L-type Ca2+ channels in rabbit, rat and guinea-pig cardiac myocytes was studied using the whole-cell patch clamp method. 2. Sodium salts of heparin uniformly suppressed the Ca2+ current, ICa, independent of their molecular weight, in the rat and guinea-pig ventricular and rabbit atrial myocytes. The suppression of ICa by heparin was dose dependent and reached its maximum, about 30%, around 10 microM. Heparin did not alter the voltage-dependence or the steady-state inactivation properties of ICa. These effects were specific to heparin as another polysaccharide, dextran, failed to have any effect on ICa. 3. The suppressive effect of heparin was not diminished when [Ca2+]o was increased to 10 mM, or when Ba2+ was the charge carrier through the Ca2+ channel. 4. Spectrophotometric assays showed that heparin-induced changes in [Ca2+]o generally were too small to alter ICa significantly. 5. In myocytes buffered with 0.1 mM EGTA, the suppressive effect of heparin was more prominent on the inactivating than on the maintained component of ICa. 6. When extracellular Na+ was replaced by Cs+, the heparin suppressive effect was accompanied by a 10 mV shift of both the voltage dependence of activation and the steady-state inactivation parameters toward more negative potentials. 7. When both Mg2+ and Na+ were omitted from the bathing solutions, the suppressive effect of heparin was significantly enhanced such that almost 80% of the current was blocked. 8. In Cs(+)-based solutions 10 mM [Mg2+]o suppressed ICa by about 70% and heparin partially relieved this block. Heparin, however, did not counteract the Mg(2+)-induced suppression of ICa in Na(+)-based solution. 9. Extracellularly applied heparin did not alter the isoprenaline-induced enhancement of ICa or interfere with the blocking effect of phorbol esters on ICa. 10. Heparin thus appears to interfere with the permeation of Ca2+ through the channel by a mechanism regulating the Ca(2+)-induced inactivation of the Ca2+ channel. Na+ and Mg2+ appear to alter the kinetics and the magnitude of the suppressive effect of heparin on the Ca2+ channel, suggesting an interaction of these cations with either the Ca2+ or the heparin-binding sites of the channel.

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