Lack of effect of McN-A-343 on membrane current and contraction in guinea pig ventricular myocytes.
We asked whether agonist occupancy of M(1) muscarinic receptor (mAChR) causes increased L-type Ca(2+) [I(Ca(L))] and contractions in ventricular myocytes. Voltage-clamp pulses evoked I(Ca(L)) in guinea pig ventricular myocytes superfused with Tyrode's solution (22-24 degrees C). The mAChR agonists carbachol (Cch, nonselective), McN-A-343 (McN, M(1)-selective), and oxotremorine (Oxo, M(2)-selective) were tested at 0.1 mM. None of these agonists affected basal I(Ca(L)). McN did not change isoproterenol-stimulated I(Ca(L)) in 13 of 15 cells. The slight decrease in two cells was not muscarinic because atropine (1 microM) did not antagonize it. Carbachol or Oxo decreased isoproterenol-stimulated I(Ca(L)) by 87 +/- 6.7 (n = 8 cells) and 49 +/- 9.0% (n = 4 cells), respectively. Atropine blocked inhibition by Cch or Oxo. External stimulation evoked contractions of single myocytes (35 degrees C). McN increased contraction in 1 of 22 cells stimulated at 0.2 Hz and in 0 of 16 cells stimulated at 1.0 Hz. Carbachol significantly increased contraction in 10 of 15 cells at 0.2 Hz and in 8 of 10 cells at 1.0 Hz stimulus frequency. Summarily, the M(1)-selective agonist McN had a negligible role to regulate I(Ca(L)). The antiadrenergic effect of mAChR agonists is attributable to M(2) receptor occupancy. That Cch, but not McN, increased cell shortening excludes participation of M(1) mAChR in the stimulant effect of Cch on guinea pig ventricular myocyte contractions.
Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut, USA.
J B
JB
Shen
B
B
Jiang
A J
AJ
Pappano
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D010095:Oxotremorine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D018721:Muscarinic Agonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D010095:Oxotremorine; D002217:Carbachol; D000242:Cyclic AMP; D007545:Isoproterenol