The relaxant action of nicorandil in guinea‐pig isolated trachealis

Abstract

1 Nicorandil (1–1000 μmol 1–¹) caused concentration-dependent relaxation of guinea-pig isolated trachealis. 2 Propranolol (1 μmol 1⁻¹) did not modify the relaxant action of nicorandil but antagonized isoprenaline. 3 Among K⁺-channel inhibitors tested, apamin (0.1 μmol 1⁻¹) and procaine (5 mmol 1⁻¹) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol 1⁻¹) caused five fold antagonism. 4 Trachealis exposed to K⁺-rich (120 mmol 1⁻¹) Krebs solution developed near-maximal tension. Nicorandil relaxed the K⁺-depolarized tissue though its concentration-effect curve was shifted markedly to the right. 5 In tissues in which tone was induced by histamine, methylene blue (100 μmol 1⁻¹) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline. 6 Intracellular electrophysiological recording showed that nicorandil (1 μmol 1⁻¹) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10–1000 μmol 1⁻¹) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration-dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished. 7 TEA (8 mmol 1⁻¹) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge. 8 Procaine (5 mmol 1⁻¹) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential. Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves. 9 In studies of the efflux of ⁸⁶Rb⁺ from muscle-rich strips of trachea, nicorandil (1000 μmol 1⁻¹) increased the efflux rate constant, whereas isoprenaline (1 μmol 1⁻¹) was without effect. 10 It is concluded that nicorandil-induced relaxation does not involve the activation of β-adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K⁺ conductance and thereby evokes hyperpolarization of trachealis cells. The K⁺ channels opened by nicorandil are permeable to ⁸⁶Rb, insensitive to apamin and TEA but may be inhibited by procaine.