Characterizations of the α₁-adrenoceptor subtypes mediating contractions of the human internal anal sphincter.

Abstract

Human internal anal sphincter (IAS) is contracted by α₁-adrenoceptor stimulation and thus α₁-adrenoceptor agonists may be useful in treating fecal incontinence. This study characterizes the contribution of α₁-adrenoceptor subtypes in contraction of human IAS and to investigate the age-related risk of patients with fecal incontinence. IAS and inferior mesenteric artery (IMA), as a predictor of systemic arterial pressure, were obtained from 11 patients. Both muscle strips were assessed by isometric-contraction experiments using phenylephrine, further in IAS, in the presence of various subtype selective α₁-adrenoceptor antagonists. Immunohistochemistry and gene expression studies were performed in the same samples. The mean pEC₅₀ values with SEM of phenylephrine in IAS (6.30 ± 0.13) were higher than those of IMA (5.60 ± 0.10). Furthermore, the age-related pEC₅₀ change of IAS was observed between age <70 and ≥70 (6.58 ± 0.13 and 6.07 ± 0.16, respectively (P < 0.05)). In IAS, rightward shift of the concentration–response curves of phenylephrine was observed with three α₁-adrenoceptor antagonists. Each pKв value of silodosin, BMY-7378 and prazosin was 9.36 ± 0.53, 7.28 ± 0.20 and 8.89 ± 0.12, respectively. These pKв values and gene expression studies indicated that α₁ᴀ-adrenoceptor subtypes predominantly contributed to human IAS contraction.