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

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/dt)] 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/dt) 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 beta-adrenergic agonist isoproterenol. Intraperitoneal injection of the p38 MAP kinase inhibitor SB-203580 reversed the baseline reduction in +dP/dt and -dP/dt 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 beta-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.