Mechanisms of vasorelaxation induced by troglitazone, a novel antidiabetic drug, 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 relaxation induced by TRO was determined in terms of Ca2+ signaling in smooth muscle cells.


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.
Kawasaki
J
J
Division of Molecular Cardiology, Research Institute of Angiocardiology and Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Hirano
K
K
Nishimura
J
J
Fujishima
M
M
Kanaide
H
H
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006632:Histamine; D000077288:Troglitazone; D011188:Potassium; D002118:Calcium