Selected issues from an overview on nicorandil: tolerance, duration of action, and long-term efficacy

Nicorandil exerts its pharmacodynamic effects through two different modes of action: increase of cyclic GMP and activation of K+ channels of smooth muscle cells. The latter mechanism could explain the lack of development of tolerance that had been demonstrated clearly in various animal experiments. Therefore, it was attempted to elucidate this mechanism in humans. In 16 healthy subjects, the acute hemodynamic effects of a single oral dose of 40 mg nicorandil were compared with those of a single sublingual dose of 0.8 mg nitroglycerin. Thereafter, the subjects were treated with 30 mg isosorbide-5-mononitrate (IS-5-MN) slow release t.i.d. for 7 days to induce nitrate tolerance. Two hours after the last dose of IS-5-MN, hemodynamic measurements were repeated before and after administration of nicorandil and nitroglycerin, respectively. Recordings obtained from impedance cardiography and finger plethysmography as well as measurements of systolic time intervals provided evidence that nicorandil in the state of IS-5-MN tolerance continued to exert hemodynamic effects similar to those exerted after the first dose. The hemodynamic actions of nitroglycerin were no longer observed after chronic treatment with IS-5-MN. The duration of action of nicorandil was investigated in 22 patients with coronary artery disease (CAD). After a 2-week run-in period on placebo, patients had to perform a symptom-limited bicycle exercise tolerance test (ETT) on two separate days in which the reproducible anginal threshold had to be proven. After qualification, patients were allocated randomly to receive double-blind 10 or 20 mg nicorandil b.i.d. for 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)