J Kawasaki1, K Hirano, J Nishimura, M Fujishima, H Kanaide. 1. Division of Molecular Cardiology, Research Institute of Angiocardiology and Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Abstract
BACKGROUND: Troglitazone (TRO), a novel antidiabetic drug, has been reported to decrease blood pressure and relax vascular strips. The mechanism of relaxation induced by TRO was determined in terms of Ca2+ signaling in smooth muscle cells. METHODS AND RESULTS: Front-surface fluorometry and fura 2-loaded medial strips of porcine coronary artery were used to examine the effects of TRO on cytosolic Ca2+ concentrations ([Ca2+]i) and contractions. The sustained contraction induced by 100 nmol/L U46619 was similar to that induced by 60 mmol/L K+ depolarization (60K+). TRO concentration dependently decreased [Ca2+]i and the force of these contractions. The concentration of TRO required to induce 50% inhibition of U46619-induced force (2.9 micromol/L) was significantly lower than that required in the case of 60K+-induced force (7.3 micromol/L). Replacing extracellular Ca2+ with Mn2+ gradually quenched fluorescence at 360 nm excitation. This decline was accelerated by 100 nmol/L U46619 and 30K+ to a similar extent, indicating a similar activation of Ca2+ influx. TRO completely inhibited U46619-activated influx but partly inhibited depolarization-activated influx. Cumulative applications of extracellular Ca2+ during stimulations with U46619 or 118K+ induced stepwise increases in [Ca2+]i and force. TRO shifted the [Ca2+]i-force relation to the right during both stimulations. CONCLUSIONS: TRO relaxes coronary artery by decreasing [Ca2+]i and Ca2+ sensitivity of contractile apparatus. Inhibition of Ca2+ influx was important in decreasing [Ca2+]i. TRO more effectively inhibits receptor-operated Ca2+ influx than voltage-operated Ca2+ channels.
BACKGROUND:Troglitazone (TRO), a novel antidiabetic drug, has been reported to decrease blood pressure and relax vascular strips. The mechanism of relaxation induced by TRO was determined in terms of Ca2+ signaling in smooth muscle cells. METHODS AND RESULTS: Front-surface fluorometry and fura 2-loaded medial strips of porcine coronary artery were used to examine the effects of TRO on cytosolic Ca2+ concentrations ([Ca2+]i) and contractions. The sustained contraction induced by 100 nmol/L U46619 was similar to that induced by 60 mmol/L K+ depolarization (60K+). TRO concentration dependently decreased [Ca2+]i and the force of these contractions. The concentration of TRO required to induce 50% inhibition of U46619-induced force (2.9 micromol/L) was significantly lower than that required in the case of 60K+-induced force (7.3 micromol/L). Replacing extracellular Ca2+ with Mn2+ gradually quenched fluorescence at 360 nm excitation. This decline was accelerated by 100 nmol/L U46619 and 30K+ to a similar extent, indicating a similar activation of Ca2+ influx. TRO completely inhibited U46619-activated influx but partly inhibited depolarization-activated influx. Cumulative applications of extracellular Ca2+ during stimulations with U46619 or 118K+ induced stepwise increases in [Ca2+]i and force. TRO shifted the [Ca2+]i-force relation to the right during both stimulations. CONCLUSIONS:TRO relaxes coronary artery by decreasing [Ca2+]i and Ca2+ sensitivity of contractile apparatus. Inhibition of Ca2+ influx was important in decreasing [Ca2+]i. TRO more effectively inhibits receptor-operated Ca2+ influx than voltage-operated Ca2+ channels.