Vol. 290, Issue 2, 641-648, August 1999

Lack of Effect of McN-A-343 on Membrane Current and Contraction in Guinea Pig Ventricular Myocytes¹

Jian-Bing Shen, Bin Jiang and Achilles J. Pappano

Department of Pharmacology, University of Connecticut Health Center, Farmington, Connecticut

We asked whether agonist occupancy of M₁ muscarinic receptor (mAChR) causes increased L-type Ca²⁺ [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°C). The mAChR agonists carbachol (Cch, nonselective), McN-A-343 (McN, M₁-selective), and oxotremorine (Oxo, M₂-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 µM) 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°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 M₁-selective agonist McN had a negligible role to regulate I_Ca(L). The antiadrenergic effect of mAChR agonists is attributable to M₂ receptor occupancy. That Cch, but not McN, increased cell shortening excludes participation of M₁ mAChR in the stimulant effect of Cch on guinea pig ventricular myocyte contractions.