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The guinea pig ileum lacks the direct, high-potency, M(2)-muscarinic, contractile mechanism characteristic of the mouse ileum.

Griffin MT, Matsui M, Ostrom RS, Ehlert FJ - Naunyn Schmiedebergs Arch. Pharmacol. (2009)

Bottom Line: Following 4-DAMP mustard treatment, the concentration-response curve of oxotremorine-M in wild-type ileum resembled that of the M(3) knockout mouse in terms of its pEC (50), E (max), and inhibition by selective muscarinic antagonists.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 M(3) response.The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Chapman University, Orange, CA, USA.

ABSTRACT
We explored whether the M(2) muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M(3) 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 M(3) selectivity. Then, we used 4-DAMP mustard to inactivate M(3) responses in the guinea pig ileum to attempt to reveal direct, M(2) receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M(2) receptor knockout, and M(3) receptor knockout mice characterized by negative log EC(50) (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 M(2) receptor knockout mice were approximately the same, but that in the M(3) 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 M(3) knockout mouse in terms of its pEC (50), E (max), and inhibition by selective muscarinic antagonists. Thus, 4-DAMP mustard treatment appears to inactivate M(3) responses selectively and renders the muscarinic contractile behavior of the wild-type ileum similar to that of the M(3) 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 M(3) response. The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component.

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Contractile activity of oxotremorine-M in ilea from the guinea pig and from wild type, M2 KO, and M3 KO mice. The data represent the mean values ± SEM from experiments on 13 guinea pigs, 39 wild-type mice, 25 M2 KO mice, and 25 M3 KO mice. The responses in the guinea-pig ileum have been normalized relative to Emax and those in mice to the Emax in wild type
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Fig1: Contractile activity of oxotremorine-M in ilea from the guinea pig and from wild type, M2 KO, and M3 KO mice. The data represent the mean values ± SEM from experiments on 13 guinea pigs, 39 wild-type mice, 25 M2 KO mice, and 25 M3 KO mice. The responses in the guinea-pig ileum have been normalized relative to Emax and those in mice to the Emax in wild type

Mentions: Contractile activity of oxotremorine-M in guinea pig and mouse ileum Oxotremorine-M potently elicited contractions in ilea from both the mouse and guinea pig. The average negative log EC50 (pEC50) ± SEM and Emax ± SEM values of oxotremorine-M were both greater in guinea pig (7.48 ± 0.05 and 58.2 ± 4.5 mN) than in wild-type mouse (6.75 ± 0.03 and 12.2 ± 0.5 mN). The average responses and their associated SEM values in guinea pig and wild-type mouse were normalized relative to the average Emax value of its respective group (i.e., guinea pig or wild-type mouse), and the normalized data are plotted in Fig. 1. The higher potency of oxotremorine-M in the guinea pig is readily apparent from the figure. The contractile activity of oxotremorine-M was also investigated in ilea from M2 and M3 KO mice. The responses in each mouse ileum were first normalized relative to the contraction elicited by KCl (50 mM) as described under “Methods.” The mean contractile responses and their respective SEM values were then normalized relative to the Emax value of the wild-type mouse. The average Emax value ± SEM of oxotremorine-M in the M2 KO mouse ileum (101.2 ± 7.5%) was similar to that of wild type, whereas that measured in the M3 KO mouse was substantially smaller (35.7 ± 3.5%). Normalization of the muscarinic responses in the mouse to that of KCl did not significantly change the relationship among the Emax values in the M2 KO and M3 KO strains relative to wild type but did cause a modest reduction in the variance of the mean estimates in wild-type and M2 KO mice. The potency of oxotremorine-M in the M2 KO mouse (pEC50 = 6.26 ± 0.05) was about one third that of the wild-type mouse, whereas that in the M3 KO mouse (pEC50, 6.99 ± 0.08) was 1.7-fold greater than wild type. These differences in pEC50 were significant as indicated in the summary of these data in the legend to Table 2. Since prior reports have shown that the ileum from the M2/M3 double KO mouse lacks a muscarinic contractile response, the data in Fig. 1 are consistent with the postulate that the muscarinic contractile response in the wild-type mouse ileum includes a major M3-receptor component as well as a minor, but more potent, M2-receptor component. Matsui et al. (2000; 2002) have reached a similar conclusion .Fig. 1


The guinea pig ileum lacks the direct, high-potency, M(2)-muscarinic, contractile mechanism characteristic of the mouse ileum.

Griffin MT, Matsui M, Ostrom RS, Ehlert FJ - Naunyn Schmiedebergs Arch. Pharmacol. (2009)

Contractile activity of oxotremorine-M in ilea from the guinea pig and from wild type, M2 KO, and M3 KO mice. The data represent the mean values ± SEM from experiments on 13 guinea pigs, 39 wild-type mice, 25 M2 KO mice, and 25 M3 KO mice. The responses in the guinea-pig ileum have been normalized relative to Emax and those in mice to the Emax in wild type
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2749929&req=5

Fig1: Contractile activity of oxotremorine-M in ilea from the guinea pig and from wild type, M2 KO, and M3 KO mice. The data represent the mean values ± SEM from experiments on 13 guinea pigs, 39 wild-type mice, 25 M2 KO mice, and 25 M3 KO mice. The responses in the guinea-pig ileum have been normalized relative to Emax and those in mice to the Emax in wild type
Mentions: Contractile activity of oxotremorine-M in guinea pig and mouse ileum Oxotremorine-M potently elicited contractions in ilea from both the mouse and guinea pig. The average negative log EC50 (pEC50) ± SEM and Emax ± SEM values of oxotremorine-M were both greater in guinea pig (7.48 ± 0.05 and 58.2 ± 4.5 mN) than in wild-type mouse (6.75 ± 0.03 and 12.2 ± 0.5 mN). The average responses and their associated SEM values in guinea pig and wild-type mouse were normalized relative to the average Emax value of its respective group (i.e., guinea pig or wild-type mouse), and the normalized data are plotted in Fig. 1. The higher potency of oxotremorine-M in the guinea pig is readily apparent from the figure. The contractile activity of oxotremorine-M was also investigated in ilea from M2 and M3 KO mice. The responses in each mouse ileum were first normalized relative to the contraction elicited by KCl (50 mM) as described under “Methods.” The mean contractile responses and their respective SEM values were then normalized relative to the Emax value of the wild-type mouse. The average Emax value ± SEM of oxotremorine-M in the M2 KO mouse ileum (101.2 ± 7.5%) was similar to that of wild type, whereas that measured in the M3 KO mouse was substantially smaller (35.7 ± 3.5%). Normalization of the muscarinic responses in the mouse to that of KCl did not significantly change the relationship among the Emax values in the M2 KO and M3 KO strains relative to wild type but did cause a modest reduction in the variance of the mean estimates in wild-type and M2 KO mice. The potency of oxotremorine-M in the M2 KO mouse (pEC50 = 6.26 ± 0.05) was about one third that of the wild-type mouse, whereas that in the M3 KO mouse (pEC50, 6.99 ± 0.08) was 1.7-fold greater than wild type. These differences in pEC50 were significant as indicated in the summary of these data in the legend to Table 2. Since prior reports have shown that the ileum from the M2/M3 double KO mouse lacks a muscarinic contractile response, the data in Fig. 1 are consistent with the postulate that the muscarinic contractile response in the wild-type mouse ileum includes a major M3-receptor component as well as a minor, but more potent, M2-receptor component. Matsui et al. (2000; 2002) have reached a similar conclusion .Fig. 1

Bottom Line: Following 4-DAMP mustard treatment, the concentration-response curve of oxotremorine-M in wild-type ileum resembled that of the M(3) knockout mouse in terms of its pEC (50), E (max), and inhibition by selective muscarinic antagonists.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 M(3) response.The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Chapman University, Orange, CA, USA.

ABSTRACT
We explored whether the M(2) muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M(3) 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 M(3) selectivity. Then, we used 4-DAMP mustard to inactivate M(3) responses in the guinea pig ileum to attempt to reveal direct, M(2) receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M(2) receptor knockout, and M(3) receptor knockout mice characterized by negative log EC(50) (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 M(2) receptor knockout mice were approximately the same, but that in the M(3) 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 M(3) knockout mouse in terms of its pEC (50), E (max), and inhibition by selective muscarinic antagonists. Thus, 4-DAMP mustard treatment appears to inactivate M(3) responses selectively and renders the muscarinic contractile behavior of the wild-type ileum similar to that of the M(3) 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 M(3) response. The guinea pig ileum, therefore, lacks a direct, highly potent, M(2)-contractile component but may have a direct, lower potency M(2) component.

Show MeSH
Related in: MedlinePlus