Mechanisms of vasorelaxation induced by troglitazone, a novel antidiabeticdrug, in the porcine coronary artery

Background-Troglitazone (TRO), a novel antidiabetic drug, has been reported to decrease blood pressure and relax vascular strips. The mechanism of rel axation 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 stri ps of porcine coronary artery were used to examine the effects of TRO on cy tosolic Ca2+ concentrations ([Ca2+](i)) and contractions. The sustained con traction induced by 100 nmol/L U46619 was similar to that induced by 60 mmo l/L K+ depolarization (60K(+)). TRO concentration dependently decreased [Ca 2+](i) and the force of these contractions. The concentration of TRO requir ed to induce 50% inhibition of U46619-induced force (2.9 mu mol/L) was sign ificantly lower than that required in the case of 60K(+)-induced force (7.3 mu mol/L). Replacing extracellular Ca2+ with Mn2+ gradually quenched fluor escence at 360 Mm excitation. This decline was accelerated by 100 nmol/L U4 6619 and 30K(+) to a similar extent, indicating a similar activation of Ca2 + influx. TRO completely inhibited U46619-activated influx but partly inhib ited depolarization-activated influx. Cumulative applications of extracellu lar Ca2+ during stimulations with U46619 or 118K(+) induced stepwise increa ses 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+ se nsitivity of contractile apparatus. inhibition of Ca2+ influx was important in decreasing [Ca2+](i). TRO more effectively inhibits receptor-operated C a2+ influx than voltage-operated Ca2+ channels.