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077 THE EFFECT OF ZAPRINAST, A PHOSPHODIESTERASE TYPE 5 INHIBITOR, ON THE SHEEP ISOLATED INTERNAL ANAL SPHINCTER

N. Griffin1, A.G. Acheson1, J.H. Scholefield1, V.G. Wilson2.1Department of Surgery and 2School of Biomedical Sciences, Queen's Medical Centre, Nottingham NG7 2UH, UK

Introduction: Neurogenic relaxation of the internal anal sphincter is mediated by elevation of cyclic GMP, following activation of soluble guanylyl cyclase by nitric oxide. Since the activity of the cyclic nucleotide is also regulated by phosphodiesterase 5, we have examined the effect of zaprinast, an inhibitor of the enzyme, on the sheep isolated internal anal sphincter.

Method: Strips of isolated sheep internal anal sphincter were suspended in 5ml organ baths containing warmed and oxygenated Krebs and isometric tension recordings made. Preparations were exposed to a cumulative concentration of zaprinast (3x10–8M to 3x10–5M), firstly paired with time controls and then in the presence and absence of NG-nitro-L-arginine methyl ester (L-NAME, 100μM), a nitric oxide synthase inhibitor. In a separate series of experiments the effect of sodium nitroprusside, a direct activator of soluble guanylyl cyclase, was examined in the absence and presence of a sub-maximally effective concentration of zaprinast (3x10–6M).

Results: Zaprinast caused a concentration-related relaxation of the sheep anal sphincter with the highest concentration giving a mean effect of 92.3%±2.6 (n=7) compared to 11% ±3.2 loss in tone with time controls over the same period. In the presence of 100 μM L-NAME, the response to higher concentrations of zaprinast was significantly reduced (p<0.05, Student's t-test) but not abolished: 30 μM zaprinast (L-NAME) 72.4%±4.9 (n=7). SNP caused a concentration-related relaxation of the sphincter (EC50 3x10–7M) that was enhanced in the presence of zaprinast ((EC50 1x10–7M) (n=6)).

Conclusion: Zaprinast acts as a PDE 5 inhibitor to relax the sheep internal anal sphincter, however its actions are only partly …

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