EFFECTS OF 2-NICOTINAMIDOETHYL NITRATE (NICORANDIL - SG-75) AND ITS DERIVATIVES ON SMOOTH-MUSCLE CELLS OF THE CANINE MESENTERIC-ARTERY

  • 1 January 1984
    • journal article
    • research article
    • Vol. 229  (3) , 793-802
Abstract
To clarify the mechanism of vasodilating actions of nicotinamidoethyl nitrate (nicorandil; SG-75) in relation to the chemical structure, 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 were studied. SG-75 significantly and SG-114 slightly hyperpolarized the membrane but SG-86 or SG-103 did not. The excitator 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 Ko, SG-114 inhibited the contraction more potently than did SG-75. 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''-tetracetic acid containing solution. The effects of SG-75 or SG-114 on the norepinephrine-induced contraction of Ca-free solution also indicated a reduction in the Ca stored in the cell. Apparently, 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. In vivo, SG-75 may have a more potent vasodilating action than SG-114, as the former inhibits neuromuscular transmission mechanisms.

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