TETRAMETHYLAMMONIUM ACTIVATION OF MUSCARINIC RECEPTORS IN CARDIAC VENTRICULAR MYOCYTES

Replacement of extracellular Na+ with tetramethylammonium (TMA) reduce s the magnitude of the Cl- current activated by beta-adrenergic recept or stimulation in guinea pig ventricular myocytes. However, the effect s of replacing Na+ appear to be associated with the presence of TMA, r ather than the absence of Na+. Direct addition of TMA to extracellular solutions, without changing the Na+ concentration, was able to inhibi t the Cl- current activated by isoproterenol (Iso) in a concentration- dependent manner. The concentration of TMA that caused half-maximal in hibition was 327 muM when the Cl- current was activated by 1 muM Iso a nd 29 muM when the Cl- current was activated by 0.03 muM Iso. The effe ct of TMA was also blocked by atropine, suggesting that TMA exerts its effect through stimulation of the muscarinic receptors. Furthermore, TMA inhibited the Iso-activated Ca2+ current, as would be expected for an effect involving muscarinic receptor stimulation. The response to complete Na+ replacement with TMA could not be overcome by increasing the concentration of Iso 1,000-fold, and direct addition of TMA was ab le to antagonize the Cl- current activated independently of the beta-a drenergic receptor, using forskolin and histamine. These results are c onsistent with the hypothesis that TMA does not exert its effects thro ugh a competitive mechanism at the beta-adrenergic receptor. It is con cluded that TMA is able to antagonize adenosine 3',5'-cyclic monophosp hate-dependent activation of ion channels in the heart through activat ion of muscarinic receptors.