Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle
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Published on: August 18, 2014
1Research Centre Sanofi Midy, Via GB Piranesi 38, 20137 Milan, Italy. luciano.manara@sanofi-synthelabo.com
Background And Aims:
The subtype and species related heterogeneity of beta adrenoceptors prompted a functional reappraisal of these molecular targets of motility inhibition in the human colon.
Methods:
Relaxation of muscle strips was measured in vitro.
Results:
The following agonists had decreasing relaxing potency (effective concentration range 10(-8)-10(-4) mol/l): (-)isoprenaline (non-selective), terbutaline (beta(2) selective), CGP 12177 (beta(3) selective, also beta(1), beta(2) antagonist), and SR 58611A (beta(3) selective). Isoprenaline and terbutaline were more potent on circular than taenia strips; CGP 12177 and SR 58611A weakly and partially relaxed taenia but had little effect on circular strips. The potency of isoprenaline on circular strips was greatly reduced by the beta(1) selective antagonist CGP 20712 (10(-7) mol/l), and less so by ICI 118551 (10(-7) mol/l, beta(2) selective). CGP 20712 and ICI 118551 together (both 3 x 10(-6) mol/l) had no effect on taenia relaxation by SR 58611A and rendered isoprenaline and terbutaline virtually inactive on circular strips, although not on taenia, which was relaxed at higher than control concentrations and maximally by isoprenaline. Propranolol, a beta(1), beta(2) non-selective antagonist, at high concentrations (10(-5) mol/l) prevented taenia relaxation by CGP 12177 and SR 58611A; its quantitative antagonism of isoprenaline (in common with that of CGP 12177 used as an antagonist) was competitive in circular strips but not on taenia.
Conclusions:
beta(1), beta(2), and beta(3) adrenoceptors are functionally detectable in the human colon; agonist stimulation of any one type relaxed taenia but only isoprenaline was fully effective at the beta(3) subtype.
Insights
Human colon smooth muscle relaxation involves beta-1, beta-2, and beta-3 adrenoceptors. Different subtypes show varying potencies and effects on circular and taenia muscle strips, impacting motility inhibition.
Area of Science:
- Pharmacology
- Gastroenterology
- Molecular Biology
Background:
- Beta adrenoceptors exhibit heterogeneity across subtypes and species, necessitating a functional re-evaluation in the human colon.
- Understanding these molecular targets is crucial for addressing motility inhibition in the human colon.
Purpose of the Study:
- To functionally reappraise beta adrenoceptors as molecular targets of motility inhibition in the human colon.
- To investigate the subtype-specific roles of beta adrenoceptors in human colon smooth muscle relaxation.
Main Methods:
- In vitro measurement of muscle strip relaxation.
- Utilized selective and non-selective agonists and antagonists for beta adrenoceptor subtypes (beta(1), beta(2), beta(3)).
- Compared agonist potency and antagonist effects on circular and taenia muscle strips.
Main Results:
- Agonist potency for relaxation decreased in the order: (-)isoprenaline (non-selective) > terbutaline (beta(2) selective) > CGP 12177 (beta(3) selective) > SR 58611A (beta(3) selective).
- Isoprenaline and terbutaline were more potent on circular strips, while CGP 12177 and SR 58611A showed weak relaxation on taenia strips.
- Beta(1), beta(2), and beta(3) adrenoceptors were functionally detected; all subtypes relaxed taenia, but only isoprenaline fully activated beta(3) receptors for taenia relaxation.
Conclusions:
- Beta(1), beta(2), and beta(3) adrenoceptors are functionally present in the human colon.
- Agonist stimulation of any beta adrenoceptor subtype can relax taenia muscle.
- Isoprenaline demonstrated full efficacy at the beta(3) subtype for taenia relaxation, highlighting subtype-specific functional roles.
