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.
Parekh
A B
AB
University Department of Pharmacology, Oxford.
Brading
A F
AF
D000818:Animals; D001704:Biopolymers; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology*; D011343:Procaine / Q000494:pharmacology; D013270:Stomach
D001704:Biopolymers; D007295:Inositol Phosphates; D002110:Caffeine; D011343:Procaine; D002217:Carbachol; D009543:Nifedipine; D002118:Calcium