The sources of calcium for carbachol-induced contraction in the circular smooth muscle of guinea-pig stomach.

1. The action of carbachol on the mechanical activity of circular muscle from guinea-pig upper stomach was studied. High concentrations of carbachol (e.g. 10(-4) M) produced a rapid phasic contraction followed by a smaller, sustained tonic contraction. Low concentrations (e.g. 10(-7) M) caused a contraction which did not generally show marked distinction between phasic and tonic components. 2. The response to 10(-7) M carbachol was very sensitive to 10(-5) M nifedipine as was the phasic response to 10(-4) M carbachol. The tonic contraction to the latter, however, was only slightly reduced by nifedipine. 3. The carbachol-induced contractions remaining in the presence of nifedipine were dose-related and very dependent on the presence of external calcium. 4. Carbachol, 10(-7) M, did not produce a contraction after 4 min exposure to calcium-free solution whereas 10(-4) M carbachol did and this was phasic in nature but much reduced relative to the control in normal Ca. 5. A phasic followed by a small tonic contraction to 10(-4) M carbachol was seen superimposed on the K contracture in tissues depolarized with 100 mM K, whereas only a small tonic response occurred for 10(-7) M carbachol. 6. In the absence of a functional carbachol-sensitive intracellular store, 10(-4) M carbachol was unable to trigger a contraction in calcium-free solution. However, when calcium was simultaneously readmitted with carbachol after exposure to calcium-free solution, a contraction occurred. 7. Carbachol, 10(-7) M, did not significantly increase inositol polyphosphate levels, whereas 10(-4) M carbachol did. The increase with 10-4M occurred rapidly peaking within 2min and was undetectable after 5 min, in the absence of lithium. 8. It is concluded that low concentrations of muscarinic agonist trigger a contraction predominantly through a nifedipine-sensitive route whereas higher concentrations further utilize intracellular calcium release and a receptor-operated extracellular calcium-dependent pathway. The former is probably associated with the phasic component and the latter with the tonic one.