The effects of 2‐nicotinamidoethyl nitrate on smooth muscle cells of the dog mesenteric artery and trachea

Abstract

1 The effects of 2-nicotinamidoethyl nitrate (nicorandil; 2-NN), a synthesized coronary vasodilator, on smooth muscle cells of dog mesenteric artery or trachea were investigated using microelectrode, double sucrose gap and isometric tension recording methods. 2 Nicorandil hyperpolarized the smooth muscle membrane of the mesenteric artery (5 × 10⁻⁶m) and the trachea (5 × 10⁻⁵ m). 3 In both these smooth muscle cells, the nicorandil-induced hyperpolarization remained constant in various concentrations of [Cl⁻¹]_o, but changed with various concentrations of [K⁺]_o. This hyperpolarization was partly inhibited following pretreatment with tetraethylammonium (TEA > 1 mm) and was completely inhibited following pretreatment with procaine (1 mm or 5 mm), indicating that the nicorandyl-induced hyperpolarization is due to increase in the K-conductance, in both these membranes. 4 Following pretreatment with TEA (5 mm), outward current pulses evoked an action potential in tracheal smooth muscle cells. Nicorandil inhibited the generation of action potential due to the hyperpolarization of the membrane but not due to inhibition of the spike generating mechanism. 5 Nicorandil (10⁻⁶m) inhibited the contracture evoked by excess [K]_o, in both tissues. The contracture evoked by noradrenaline or repetitive field stimulation with short duration (50 μs) pulses was also inhibited in the mesenteric artery, while a higher dose of nicorandil (10⁻⁵m) was required to inhibit the contracture evoked by acetylcholine or repetitive field stimulation in the trachea. 6 Excitatory junction potentials (e.j.ps) evoked by field stimulation in the mesenteric artery due to the release of noradrenaline, or in the trachea due to release of acetylcholine, were suppressed by 10⁻⁵ m or 5 × 10⁻⁵ m nicorandil, respectively. The reduction in the amplitude of e.j.p. was mainly due to the hyperpolarization of the membrane with increase in the membrane conductance. 7 In the mesenteric artery, following pretreatment with TEA (1 mm) an action potential was generated on the e.j.p. Nicorandil suppressed the generation of the action potential by reduction in the amplitude of the e.j.p., below the threshold required for generation of the action potential. 8 These results indicate that nicorandil hyperpolarizes the membrane by increasing K-conductance and inhibits the generation of contraction, in both tissues. Higher concentrations of nicorandil are required to suppress the mechanical response in the trachea than in the mesenteric artery. Depression of the mechanical responses in both tissues is partly due to suppression of Ca-mobilization inside the muscle cells and partly to hyperpolarization of the membrane.