Highly selective iNOS inhibition and sphincter of Oddi motility in the Australian possum

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Abstract

Aim

Inducible nitric oxide synthase (iNOS) plays a major role in acute pancreatitis. Selective inhibitors of iNOS are being developed as therapeutic agents. Sphincter of Oddi (SO) dysfunction may cause pancreatitis and nitric oxide is necessary for SO relaxation. A new highly selective iNOS inhibitor, AR-C102222AA (AR-C), is evaluated together with the established iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL), and the selective neuronal nitric oxide synthase (nNOS) blocker S-methyl-L-thiocitrulline (SMTC).

Methods

In anaesthetized Australian Brush-tailed possums, the effect of topical, i.v. or i.a. administration of these drugs was evaluated on spontaneous SO motility, blood pressure (BP) and pancreatic vascular perfusion. SO motility was recorded by manometry and pancreatic vascular perfusion by laser Doppler fluxmetry. Also, the effect of SMTC and AR-C on electrical field stimulation (EFS)-induced non-cholinergic non-adrenergic (NANC) SO relaxation in vitro was evaluated.

Results

Infusion of AR-C (0.1–30 μmol kg−1) increased SO contraction frequency (P = 0.026) only at the two highest doses. L-NIL infusion (0.15 to 14.7 μmol kg−1) also increased SO contraction frequency at 8.8 μmol kg−1 (P < 0.05) and reduced SO contraction amplitude at the two highest doses (P < 0.05). SMTC injections (0.5 nmol–2.4 μmol) produced a dose-dependent increase in SO contraction frequency (P = 0.009), but no effect was seen on the other parameters. In vitro SMTC (40–400 μM) inhibited EFS-induced NANC relaxation in a dose-dependent manner (P < 0.0005). In contrast AR-C (10–500 μM) had no effect on EFS-induced NANC relaxation (P > 0.05).

Conclusions

At low doses, AR-C does not effect SO motility or EFS-induced NO mediated relaxation. However, high doses of AR-C and L-NIL in vivo influenced SO motility by inhibiting nNOS activity and these effects need be considered in relation to therapeutic doses of this agent.

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