The M3 muscarinic receptor links to three different transduction mechanisms with different efficacies in circular muscle of guinea-pig stomach.
1. In a previous publication, we showed that 10 microM carbachol induced contraction by activating three independent transduction mechanisms in circular smooth muscle of guinea-pig gastric fundus (Parekh & Brading, 1991). These were: inositol trisphosphate-mediated intracellular Ca2+ release, Ca2+ influx through a nifedipine-sensitive route and Ca2+ influx through a receptor operated nifedipine-insensitive pathway. The former two processes contribute to the phasic contraction and the latter two to the tonic contraction. In this paper, we have studied the effects of muscarinic receptor antagonists with known selectivity for different muscarinic receptor subtypes, on the contraction evoked by 10 microM carbachol. 2. Low concentrations of pirenzepine (M1 selective) had little effect on the contraction initiated by carbachol. Higher concentrations (greater than 1 microM) reduced only the phasic component. This concentration of pirenzepine greatly reduced the contraction evoked by 10 microM carbachol in Ca(2+)-free solution, indicating inhibition of intracellular Ca2+ release. 3. In the presence of 10 microM nifedipine, the tonic contraction evoked by 10 microM carbachol (reflecting the receptor-operated nifedipine-insensitive route) was abolished by 10 microM pirenzepine. In the absence of nifedipine pretreatment, however, 10 microM pirenzepine did not abolish the contraction to 10 microM carbachol. This contraction was subsequently abolished by nifedipine. 4. Only high concentrations (greater than 10 microM) of the M2-selective antagonist, gallamine, inhibited the contraction to 10 microM carbachol. Like pirenzepine, gallamine preferentially inhibited the phasic component of the contraction, indicating an effect on intracellular Ca2+ release. 5. The non-selective muscarinic receptor antagonist, atropine, abolished all components of the contraction. At low concentrations, atropine also reduced the phasic component without affecting the tonic one, indicating preferential inhibition of intracellular Ca2+ release.6. It is concluded that (i) the different transduction mechanisms have different sensitivities to the antagonists used and (ii) an M3 receptor activates the three transduction mechanisms with different efficacies.
Parekh
A B
AB
University Department of Pharmacology, Oxford.
Brading
A F
AF
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D005703:Gallamine Triethiodide / Q000494:pharmacology; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010890:Pirenzepine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction
D011976:Receptors, Muscarinic; D010890:Pirenzepine; D002217:Carbachol; D005703:Gallamine Triethiodide