Background and purpose: The internal anal sphincter has been shown to contract in response to α 1-adrenoceptor stimulation and therefore α 1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α 1- 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 α 1A-adrenoceptor selective agonist A61603 (pEC 50=7.79±0.04) was 158-fold greater than that for noradrenaline (pEC 50=5.59±0.02). Phenylephrine (pEC 50=5.99±0.05) was 2.5-fold more potent than noradrenaline. The α 1D-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 α 1A-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 α 1A/L-adrenoceptor, most probably the α 1L-adrenoceptor form of this receptor.
Cyclophosphamide and ifosfamide: mechanisms of cytotoxic action and consequences for normal bladder functionAuthor: Mills, K., 10 Oct 2015
Student thesis: Doctoral ThesisFile