title: 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/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.
authors.affiliation: Department of Medicine, West Virginia University, Morgantown, WV 26506-9157, USA.
authors.forename: Fangping
authors.initials: F
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Kan
authors.forename: Gerry
authors.initials: G
authors.lastname: Hobbs
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Finkel
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D047468:Immunoprecipitation; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000150:complications*; D014335:Tropomyosin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014335:Tropomyosin; D048051:p38 Mitogen-Activated Protein Kinases; D007545:Isoproterenol; C093642:SB 203580