Methoctramine and gallamine inhibit PI hydrolysis in guinea-pig gallbladder.

The present study aimed to determine the effect of two M2/M4-selective muscarinic receptor antagonists on blocking the hydrolysis of carbachol (CCh) stimulated phospho-inositide (PI) breakdown in order to address the possibility that a muscarinic receptor other than the M(3) receptor is involved in PI hydrolysis in this tissue. Gallbladder tissue slices labeled with myo-[2-3H] inositol were incubated with increasing concentrations of antagonists and agonist. After the reactions were terminated by the addition of chloroform/methanol, labeled inositol phosphates were separated using anion exchange chromatography. Muscarinic M2 antagonists methoctramine and gallamine both inhibited carbachol-induced PI breakdown at high concentrations, with log IC50 values of -5.145 and -6.049, respectively. Gallamine at 10(-5)M concentration failed to displace the dose-response curve for carbachol-induced accumulation of inositol triphosphate (IP3). Our data suggest that M(3) receptors play a major role in stimulation of PI hydrolysis in the guinea-pig gallbladder.