INFLUENCE OF CARDIAC DYSFUNCTION ON FAST SODIUM CURRENT REGULATION BYFORSKOLIN

There are several reports of an altered beta-adrenergic pathway in hea rt failure. Since the fast cardiac sodium current (I-Na+) is also subj ect to beta-receptor dependent regulation, we investigated its regulat ion in a model of cardiac dysfunction. Adenylyl cyclase was stimulated directly with forskolin as one step in the beta-adrenergic pathway. T welve-week-old Wistar rats were infarcted by ligation of the left ante rior descending coronary artery. Eight weeks later, the induced hemody namic changes were evaluated. The left ventricular end-diastolic press ure (LVEDP) was used as a measure of the hemodynamic effects of the my ocardial infarction. With the loose patch clamp technique, I-Na+ was m easured in intact papillary muscles at an external sodium concentratio n of 150 mmol/L. Potential dependent availability was tested with puls es to 0 mV from various conditioning potentials. In animals with minor infarction (n = 7, LVEDP = 7.7 +/- 0.9 mmHg), forskolin (3 mu mol/L) increased the maximal available I-Na+ to 109% +/- 13% of base-line val ues. This increase was nearly the same in the group with significant i nfarctions (n = 7, LVEDP = 15.7 +/- 1.6 mmHg) to 113% +/- 6%. Thus, al though we previously observed a reduction of the isoproterenol induced increase of I-Na+ in rats with significant myocardial infarctions, th is increase remains the same when adenylyl cyclase is stimulated direc tly. This is consistent with a direct beta-receptor down-regulation or desensitization.