Nicorandil metabolism in rat myocardial mitochondria

The in vitro study using rats was carried out to clarify the hypothesis tha t nicorandil is denitrated and then may produce nitric oxide (NO) in myocar dial mitochondria. In the presence of a NADPH-generating system, [C-14]nico randil, which was incubated in mitochondrial and microsomal fractions of th e lung, heart, or liver, was converted to its main denitrated metabolite, S G-86 and other metabolites. Apparent K-m and V-max for nicorandil in mitoch ondrial and microsomal fractions of the heart were considerably similar to those of the lung, bur completely different from those of the liver. It see ms that glutathione-S-transferases (GSTs) are not primarily involved in the conversion of nicorandil to SG-86, because a known GST inhibitor, indometh acin, did not affect the nicorandil degradation in the mitochondrial fracti on. Nitrite. the stable metabolite of NO, was measured by the Griess reacti on. In the presence of an NADPH-generating system, nicorandil significantly increased nitrite production in myocardial mitochondria, but SG-86 did not . These data strongly indicate that nicorandil is metabolized to SG-86 in m yocardial mitochondria, then releasing NO, and that GSTs are not primarily responsible for the conversion of nicorandil to SC-86.