Troglitazone Improves Recovery of Left Ventricular Function After Regional Ischemia in Pigs

Abstract

Background-This study determined whether treatment of normal (nondiabetic) pigs with the insulin-sensitizing agent troglitazone improves recovery of left ventricular (LV) function after acute ischemia and whether such effects are associated with altered myocardial substrate metabolism. Methods and Results-Juvenile pigs (nϭ6) were treated with troglitazone (75 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 PO) for 8 weeks. Untreated pigs (nϭ8) served as controls. Under anesthetized, open-chest conditions, pigs underwent 90 minutes of moderate regional LV ischemia and 90 minutes of reperfusion. Regional LV function was assessed with subendocardial sonomicrometry crystals. Fasting plasma insulin and free fatty acid levels were lower in troglitazone-treated pigs than in untreated pigs, whereas blood glucose did not differ between groups. These findings suggest that treatment enhanced systemic insulin sensitivity. Baseline hemodynamics and regional LV function did not differ between groups. After ischemia and reperfusion, systolic function (external work) of the ischemic region recovered to 44Ϯ6% of baseline in troglitazone-treated pigs versus 18Ϯ6% of baseline in untreated pigs (PϽ0.05). Regional diastolic function (maximum rate of wall expansion) recovered to 78Ϯ7% of baseline in treated pigs versus 52Ϯ7% of baseline in untreated pigs (PϽ0.05). Recovery of global LV systolic and diastolic function was also significantly greater in treated pigs. Myocardial glucose uptake did not differ between groups under any condition; however, net myocardial lactate uptake after reperfusion was 7 times greater in troglitazone-treated pigs than in untreated pigs, suggesting that treatment enhanced myocardial carbohydrate oxidation after reperfusion. Conclusions-In nondiabetic pigs, chronic troglitazone treatment improves recovery of LV systolic and diastolic function after acute ischemia.

Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ Activator in Myocardial Ischemia and Reperfusion in Pigs

“…These results are in direct contrast to the beneficial effects on contractile function and energy metabolism and the absence of pro-arrhythmic effects observed after chronic pretreatment with troglitazone in the same model (10). The present findings also contrast with protective effects of either acute or chronic rosiglitazone treatment in myocardial ischemia/reperfusion in rats.…”

“…We found that pretreated pigs had significantly greater recovery of myocardial mechanical function and carbohydrate metabolism after ischemia and reperfusion than untreated pigs (10). There were no sustained ventricular arrhythmias among treated pigs.…”

“…Altogether 22 domestic farm pigs weighing 28 Ϯ 1 kg were studied. Techniques of anesthesia, surgical instrumentation, and physiologic measurements conformed to the Guide for the Care and Use of Laboratory Animals of the U.S. National Institutes of Health and were similar to those used in our previous study of chronic troglitazone pretreatment (10). After an overnight fast, pigs were sedated with ketamine HCl (25 mg/kg i.m.…”

“…This measure is sensitive to changes in preload (end-diastolic wall area), which generally increases during the course of an experiment. 3) Therefore, a load-insensitive measure of regional systolic function, preload-adjusted regional external work was calculated as follows: Regional Frank-Starling relations were derived from recordings of LV pressure versus wall area loops were during brief occlusion of the inferior vena cava (10). Under each experimental condition, preload-adjusted regional external work was calculated from the Frank-Starling relation for that condition with end-diastolic wall area set to its baseline, steady-state value.…”

Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-γ, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury

“…Our present data on cardiac energetics, however, are limited, and it is not clear whether acute rosiglitazone perfusion of isolated hearts reduces glycolysis or rapidly enhances uptake of accumulated lactate early in reperfusion. The latter may be more likely in view of the demonstration that treatment of pigs with troglitazone, another PPAR-␥ ligand, enhances uptake of lactate during reperfusion (27).…”