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NEUROREGULATION AND MOTILITY

Role of nitric oxide in ₃-adrenoceptor activation on basal tone of internal anal sphincter

Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Submitted 27 December 2002 ; accepted in final form 30 April 2003

Effects of activation of ₃-adrenoceptor (₃-AR) have not been determined in the spontaneously tonic smooth muscle of the internal anal sphincter (IAS). The effects of disodium (R,R)-5-[2-[2-3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243), a selective ₃-AR agonist, on the basal smooth muscle tone and direct release of nitric oxide (NO) by circular smooth muscle strips of the opossum IAS were determined. We also examined the presence of endothelial nitric oxide synthase (eNOS) protein by Western blot studies. CL 316243 produced a concentration-dependent relaxation of the smooth muscle that remained unmodified by different neurohumoral antagonists. The smooth muscle relaxation by CL 316243 was selectively antagonized by L 748337, a ₃-AR antagonist. Such relaxation was several times longer than by isoproterenol. The effect of CL 316243 was significantly attenuated by a nonselective NOS inhibitor N-nitro-L-arginine (L-NNA) and by putative inhibitor of eNOS L-N⁵-(1-iminoethyl)-ornithine dihydrochloride (L-NIO). Inhibitors of iNOS [N-(3-aminomethyl)benzyl acetamide 2HCl] and nNOS {1-[2-(trifluoromethylphenyl)imidazole]} had no effect on this relaxation. Relaxation of the IAS smooth muscle induced by CL 316243 was accompanied by an increased release of NO; this was attenuated by L-NNA and L-NIO. In addition, Western blot studies revealed the presence of eNOS in the circular smooth muscle of the IAS. These data demonstrate potent and protracted IAS smooth muscle relaxation by ₃-AR activation, which is partly transduced via NOS, possibly smooth muscle eNOS. Multiple signal-transduction pathways including NOS activation may explain the characteristic IAS relaxation by ₃-AR activation. The studies may have therapeutic implications in anorectal motility disorders.

internal anal sphincter smooth muscle; nitric oxide synthase; nitric oxide synthase inhibitors; nonadrenergic noncholinergic relaxation; Hirschsprung's disease

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