Effects of 2-nicotinamidoethyl nitrate (nicorandil; SG-75) and its derivative on smooth muscle cells of the canine mesenteric artery

Abstract

To clarify the mechanism of vasodilating actions of nicotinamidoethyl nitrate (nicorandil; SG-75) in relation to the chemical structure, we studied the effects of SG-75 and its derivatives [nitrate containing structure; 3,5-bis([2'- nitroxyethyl ] aminocarbonyl )pyridine (SG-114); nicotinamide derivatives: N-(2-hydroxyethyl)nicotinamide (SG-86) and N-(2- nicotinyloxyethyl )-nicotinamide; (SG-103)] on the electrical and mechanical properties of smooth muscle cells of the canine mesenteric artery. SG-75 significantly and SG-114 slightly hyperpolarized the membrane but SG-86 or SG-103 did not. The excitatory junction potential and spike potential evoked by perivascular nerve or direct muscle stimulation were markedly inhibited by SG-75 due to hyperpolarization of the membrane. SG-114 slightly inhibited but SG-86 or SG-103 did not inhibit the excitatory junction potential or spike potential. The K-induced contraction was inhibited by SG-75 (below 39.2 mM) or without hyperpolarization (over 39.2 mM) of the membrane, but SG-114 inhibited the contraction with no hyperpolarization. In concentrations over 39.2 mM K0, SG-114 inhibited the contraction more potently than did SG-75. On the other hand, the norepinephrine-induced contraction was inhibited by SG-75 or SG-114 to the same extent, due to additional hyperpolarization of the membrane, in the case of SG-75. Both agents inhibited but SG-86 or SG-103 did not inhibit the norepinephrine-induced contraction in the Ca-free 2 mM ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid containing solution. After the complete depletion of the stored Ca, application of Ca in the presence of SG-75 or SG-114 enabled estimation of the reduction in the amount of Ca stored in the cell, determined by the amplitude of the subsequently produced caffeine-induced contraction in Ca-free ethylene glycol bis(beta-aminoethyl ether)N,N'- tetraacetic acid containing solution. The effects of SG-75 or SG-114 on the norepinephrine-induced contraction in Ca-free solution also indicated a reduction in the Ca stored in the cell. It would appear that SG-75 hyperpolarizes the membrane due to the SG-75 moiety and not to the nitrate residue alone. The relaxation of the tissue induced by SG-75 or SG-114 is due to nitrate action, as observed in the case of nitroglycerin. SG-114 possesses a stronger potency with regard to relaxation of the tissue; however, in vivo, SG-75 may have a more potent vasodilating action than SG-114, as the former inhibits neuromuscular transmission mechanisms.