BACKGROUND AND PURPOSE: The internal anal sphincter has been shown to contract in response to alpha1-adrenoceptor stimulation and therefore alpha1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the alpha1-adrenoceptor subtype responsible for mediating contraction of the internal anal sphincter of the pig. EXPERIMENTAL APPROACH: The potency of agonists and the affinities of several receptor subtype selective antagonists were determined on smooth muscle strips for the pig internal anal sphincter. Cumulative concentration-response curves were performed using phenylephrine and noradrenaline. KEY RESULTS: The potency of the alpha1A-adrenoceptor selective agonist A61603 (pEC50=7.79+/-0.04) was 158-fold greater than that for noradrenaline (pEC50=5.59+/-0.02). Phenylephrine (pEC50=5.99+/-0.05) was 2.5-fold more potent than noradrenaline. The alpha1D-adrenoceptor selective antagonist BMY7378 caused rightward shifts of the concentration-response curves to phenylephrine and noradrenaline, yielding low affinity estimates of 6.59+/-0.15 and 6.33+/-0.13, respectively. Relatively high affinity estimates were obtained for the alpha1A-adrenoceptor selective antagonists, RS100329 (9.01+/-0.14 and 9.06+/-0.22 with phenylephrine and noradrenaline, respectively) and 5-methylurapidil (8.51+/-0.10 and 8.31+/-0.10, respectively). Prazosin antagonized responses of the sphincter to phenylephrine and noradrenaline, yielding mean affinity estimates of 8.58+/-0.10 and 8.15+/-0.08, respectively. The Schild slope for prazosin with phenylephrine was equal to unity (1.01+/-0.24), however the Schild slope using noradrenaline was significantly less than unity (0.50+/-0.11, P<0.05). CONCLUSION AND IMPLICATIONS: The results suggest that contraction of circular smooth muscle from the pig internal anal sphincter is mediated via a population of adrenoceptors with the pharmacological characteristics of the alpha1A/L-adrenoceptor, most probably the alpha1L-adrenoceptor form of this receptor.
BACKGROUND AND PURPOSE: The internal anal sphincter has been shown to contract in response to alpha1-adrenoceptor stimulation and therefore alpha1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the alpha1-adrenoceptor subtype responsible for mediating contraction of the internal anal sphincter of the pig. EXPERIMENTAL APPROACH: The potency of agonists and the affinities of several receptor subtype selective antagonists were determined on smooth muscle strips for the pig internal anal sphincter. Cumulative concentration-response curves were performed using phenylephrine and noradrenaline. KEY RESULTS: The potency of the alpha1A-adrenoceptor selective agonist A61603 (pEC50=7.79+/-0.04) was 158-fold greater than that for noradrenaline (pEC50=5.59+/-0.02). Phenylephrine (pEC50=5.99+/-0.05) was 2.5-fold more potent than noradrenaline. The alpha1D-adrenoceptor selective antagonist BMY7378 caused rightward shifts of the concentration-response curves to phenylephrine and noradrenaline, yielding low affinity estimates of 6.59+/-0.15 and 6.33+/-0.13, respectively. Relatively high affinity estimates were obtained for the alpha1A-adrenoceptor selective antagonists, RS100329 (9.01+/-0.14 and 9.06+/-0.22 with phenylephrine and noradrenaline, respectively) and 5-methylurapidil (8.51+/-0.10 and 8.31+/-0.10, respectively). Prazosin antagonized responses of the sphincter to phenylephrine and noradrenaline, yielding mean affinity estimates of 8.58+/-0.10 and 8.15+/-0.08, respectively. The Schild slope for prazosin with phenylephrine was equal to unity (1.01+/-0.24), however the Schild slope using noradrenaline was significantly less than unity (0.50+/-0.11, P<0.05). CONCLUSION AND IMPLICATIONS: The results suggest that contraction of circular smooth muscle from the pig internal anal sphincter is mediated via a population of adrenoceptors with the pharmacological characteristics of the alpha1A/L-adrenoceptor, most probably the alpha1L-adrenoceptor form of this receptor.
Authors: A P Ford; N F Arredondo; D R Blue; D W Bonhaus; J Jasper; M S Kava; J Lesnick; J R Pfister; I A Shieh; R L Vimont; T J Williams; J E McNeal; T A Stamey; D E Clarke Journal: Mol Pharmacol Date: 1996-02 Impact factor: 4.436
Authors: A J Noble; R Chess-Williams; C Couldwell; K Furukawa; T Uchyiuma; C Korstanje; C R Chapple Journal: Br J Pharmacol Date: 1997-01 Impact factor: 8.739
Authors: S J Rayment; T Eames; J A D Simpson; M R Dashwood; Y Henry; H Gruss; A G Acheson; J H Scholefield; V G Wilson Journal: Br J Pharmacol Date: 2010-08 Impact factor: 8.739