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

• Published in: Circulation (New York, N.Y.) N.Y.), 1998-12, Vol.98 (22), p.2446-2452
• Main Authors: KAWASAKI, J, HIRANO, K, NISHIMURA, J, FUJISHIMA, M, KANAIDE, H
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Animals; Arteries - drug effects; Arteries - metabolism; Biological and medical sciences; Calcium - analysis; Calcium - metabolism; Chromans - pharmacology; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Cytosol - chemistry; Cytosol - drug effects; Histamine - pharmacology; Hormones. Endocrine system; Hypoglycemic Agents - pharmacology; In Vitro Techniques; Isometric Contraction - drug effects; Medical sciences; Pharmacology. Drug treatments; Potassium - pharmacology; Swine; Thiazoles - pharmacology; Thiazolidinediones; Troglitazone; Vasodilation - physiology; Vasodilator Agents - pharmacology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.98.22.2446

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. 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. 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.