Moderation of anal sphincter tone with nitric oxide agonists and antagonists

To test the thesis that agonists and antagonists of nitric oxide, when applied topically to the anal and rectal mucosa, could moderate rectal pressure.

In vitro studies of muscle strips have suggested that tension of the internal anal sphincter is controlled by nitric oxide.

Gently restrained, unanesthetized rats were used. The experimental drug in a volume of 0.1 mL was introduced into the rectal lumen with a fine syringe. Thereafter a soft catheter-tipped balloon was inserted and inflated with 1 mL of water, and, after 1 minute when the reflex muscle spasm had abated, pressure was measured with a strain gauge transducer. The catheter was reinserted at 10- to 30-minute intervals for pressure measurements.

Tumor necrosis factor alpha led to a dose-dependent reduction in pressure, reaching a nadir at 30 minutes and returning toward baseline at 60 minutes. At a concentration of 0.1 microgram per 0.1 mL of saline, pressure fell from 63 to 47 mm Hg, while pressure fell from 72 to 23 mm Hg at 10 micrograms. The precursor of nitric oxide, L-arginine, in concentrations of 0.01 mg but not 0.0001 mg, also led to declines in sphincter pressure (P < .05). The higher concentrations appeared to cause a more rapid fall in pressure; however, in all cases the nadir was reached at 30 minutes. Sphincter pressure remained low at 60 minutes but could be restored to baseline 30 minutes after the topical application of 1 mg of the L-arginine antagonist, N-omega-nitro-L-arginine methyl ester (L-NAME) but not with saline. In animals treated with L-arginine mixed in a water-soluble jelly, sphincter pressure continued to fall during the 60 minutes of monitoring. At a concentration of 1 mg, pressure fell from 56 +/- 3 to 33 +/- 2 (mean +/- SEM) mm Hg (P < .05); at 10 mg, pressure fell from 63 +/- 4 to 36 +/- 3 mm Hg (P < .05). When L-NAME was admixed with L-arginine in the water-soluble jelly, there was no fall in pressure during the 60-minute observation period.

These data indicate that the action of agonists and antagonists of nitric oxide synthesis carries across the anorectal mucosa and rapidly modifies sphincter tone.