p38 MAP kinase inhibitor reverses stress-induced myocardial dysfunction in vivo

Abstract

Recent clinical reports strongly support the intriguing possibility that emotional stress alone is sufficient to cause reversible myocardial dysfunction in patients. We previously reported that a combination of prenatal stress followed by restraint stress (PS+R) results in echocardiographic evidence of myocardial dysfunction in anesthetized rats compared with control rats subjected to the same restraint stress (Control+R). We now report results of our catheter-based hemodynamic studies in both anesthetized and freely ambulatory awake rats, comparing PS+R vs. Control+R. Systolic function [positive rate of change in left ventricular pressure over time (+dP/d t)] was significantly depressed ( P < 0.01) in PS+R vs. Control+R both under anesthesia (6,287 ± 252 vs. 7,837 ± 453 mmHg/s) and awake (10,438 ± 741 vs. 12,111 ± 652 mmHg/s). Diastolic function (−dP/d t) was also significantly depressed ( P < 0.05) in PS+R vs. Control+R both under anesthesia (−5,686 ± 340 vs. −7,058 ± 458 mmHg/s) and awake (−8,287 ± 444 vs. 10,440 ± 364 mmHg/s). PS+R also demonstrated a significantly attenuated ( P < 0.05) hemodynamic response to increasing doses of the β-adrenergic agonist isoproterenol. Intraperitoneal injection of the p38 MAP kinase inhibitor SB-203580 reversed the baseline reduction in +dP/d t and −dP/d t as well as the blunted isoproterenol response. Intraperitoneal injection of SB-203580 also reversed p38 MAP kinase and troponin I phosphorylation in cardiac myocytes isolated from PS+R. Thus the combination of prenatal stress followed by restraint stress results in reversible depression in both systolic and diastolic function as well as defective β-adrenergic receptor signaling. Future studies in this animal model may provide insights into the basic mechanisms contributing to reversible myocardial dysfunction in patients with ischemic and nonischemic cardiomyopathies.