0022-3asa/@S/2.513-117r)o2.00/0 TliB JOURNAL, O? PHARMACOLOGY AND BPERlYENTAL, ' h g R A P I V n C 8 M t Effects of Nicorandil on Cytosolic Calcium Concentrations in QuinBLoaded Rat Aortic Vascular Smooth Muscle Cells in Primary Culture1

ABSTRACT We made use of quin2 microfluorometry to observe the effects of nicorandil (2-nicotinarnidoethyl nitrate) on cytosolic Ca++ concentrations ([Ca++l,) in rat aortic vascular smooth muscle cells in primary culture. Regardless of whether cells were at rest, in a state of Ca++-depletion or at K+depolarization, nicorandil rapidly and dosedependently decreased [Ca++l, to the lower steadystate level. Nicorandil dose-dependently inhibited norepinephrine-induced Ca++ transients in physiological salt solution containing 1 mM Ca++. Nicorandil accelerated the reduction of [Ca++J observed when the cells were exposed to Ca++-free sdution. When the cells were treated with nicorandil in Ca++-free sdution, Ca++ transients induced by the first application of caffeine were little affected, but those induced by subsequent repetitive caffeine applications were reduced strongly and progressively. In contrast, pretreatment with nicorandil markedly inhibited Ca* transients induced by the first application of norepinephrine, in Ca++-free solution. These effects of nicorandil on [Ca++l, and Ca++ transients were similar to those seen with nitroglycerin. The denitrated compound of nicorandil, Nd2-hydroxyethyl)nicotinarnide, had no such effect. Thus, it is apparently the nitrate moiety of the chemical structure by which nicorandil actively and strongly reduces [Ca++]l in vascular smooth muscle cells. The reduction of [Ca++l, by nicorandil may result in a decrease in Ca* in the norepinephrine-sensitive store; hence, the reduction of [Ca++]l elevation by norepinephrine