Tetramethylammonium activation of muscarinic receptors in cardiac ventricular myocytes.
Replacement of extracellular Na+ with tetramethylammonium (TMA) reduces the magnitude of the Cl- current activated by beta-adrenergic receptor stimulation in guinea pig ventricular myocytes. However, the effects of replacing Na+ appear to be associated with the presence of TMA, rather than the absence of Na+. Direct addition of TMA to extracellular solutions, without changing the Na+ concentration, was able to inhibit the Cl- current activated by isoproterenol (Iso) in a concentration-dependent manner. The concentration of TMA that caused half-maximal inhibition was 327 microM when the Cl- current was activated by 1 microM Iso and 29 microM when the Cl- current was activated by 0.03 microM Iso. The effect 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 able to antagonize the Cl- current activated independently of the beta-adrenergic receptor, using forskolin and histamine. These results are consistent with the hypothesis that TMA does not exert its effects through a competitive mechanism at the beta-adrenergic receptor. It is concluded that TMA is able to antagonize adenosine 3',5'-cyclic monophosphate-dependent activation of ion channels in the heart through activation of muscarinic receptors.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970.
S I
SI
Zakharov
J L
JL
Overholt
R A
RA
Wagner
R D
RD
Harvey
D000818:Animals; D002712:Chlorides / Q000502:physiology; D004553:Electric Conductivity; D005110:Extracellular Space / Q000378:metabolism; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
D002712:Chlorides; D000644:Quaternary Ammonium Compounds; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D012964:Sodium; C027917:tetramethylammonium; D007545:Isoproterenol