Carbon monoxide mediates vasoactive intestinal polypeptide-associated nonadrenergic/noncholinergic neurotransmission.

Carbon monoxide (CO) synthesized by heme oxygenase 2 (HO2) and nitric oxide (NO) produced by neuronal NO synthase (nNOS) mediate nonadrenergic/noncholinergic (NANC) intestinal relaxation. In many areas of the gastrointestinal tract, NO and CO function as coneurotransmitters. In the internal anal sphincter (IAS), NANC relaxation is mediated primarily by CO. Vasoactive intestinal polypeptide (VIP) has also been shown to participate in NANC relaxation throughout the intestine, including the IAS. By using a combination of pharmacology and genetic knockout of the biosynthetic enzymes for CO and NO, we show that the physiologic effects of exogenous and endogenous VIP in the IAS are mediated by HO2-synthesized CO.