The guinea pig ileum lacks the direct, high-potency, M2-muscarinic, contractile mechanism characteristic of the mouse ileum

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Griffin, Michael T. ; Matsui, Minoru ; Ostrom, Rennolds S. ; Ehlert, Frederick J. (2009)
  • Publisher: Springer Nature
  • Journal: Naunyn-Schmiedeberg's Archives of Pharmacology, volume 380, issue 4, pages 327-335 (issn: 0028-1298, eissn: 1432-1912)
  • Related identifiers: pmc: PMC2749929, doi: 10.1007/s00210-009-0434-8
  • Subject: Ileum | Guinea pig | Original Article | Neurosciences | M3 muscarinic receptor | Muscarinic receptor knockout mice | 4-DAMP mustard | Pharmacology | Biomedicine | Pharmacology/Toxicology | M2 muscarinic receptor

We explored whether the M2 muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M3 muscarinic receptor knockout mouse. First, we characterized the irreversible receptor-blocking activity of 4-DAMP mustard in ileum from muscarinic receptor knockout mice to verify its M3 selectivity. Then, we used 4-DAMP mustard to inactivate M3 responses in the guinea pig ileum to attempt to reveal direct, M2 receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M2 receptor knockout, and M3 receptor knockout mice characterized by negative log EC50 (pEC 50 ) values ± SEM of 6.75 ± 0.03, 6.26 ± 0.05, and 6.99 ± 0.08, respectively. The corresponding E max values in wild-type and M2 receptor knockout mice were approximately the same, but that in the M3 receptor knockout mouse was only 36% of wild type. Following 4-DAMP mustard treatment, the concentration–response curve of oxotremorine-M in wild-type ileum resembled that of the M3 knockout mouse in terms of its pEC 50 , E max, and inhibition by selective muscarinic antagonists. Thus, 4-DAMP mustard treatment appears to inactivate M3 responses selectively and renders the muscarinic contractile behavior of the wild-type ileum similar to that of the M3 knockout mouse. Following 4-DAMP mustard treatment, the contractile response of the guinea pig ileum to oxotremorine-M exhibited low potency and a competitive-antagonism profile consistent with an M3 response. The guinea pig ileum, therefore, lacks a direct, highly potent, M2-contractile component but may have a direct, lower potency M2 component.
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