title: The oxygen radical generator pyrogallol impairs cardiomyocyte contractile function via a superoxide and p38 MAP kinase-dependent pathway: protection by anisodamine and tetramethylpyrazine.
abstract: Oxygen-derived free radicals have been demonstrated to contribute to the pathogenesis of myocardial dysfunction, although the underlying mechanism remains not fully understood. This study was designed to examine the role of the superoxide generator pyrogallol on cardiac contractile function and possible intervention with herbal medicines anisodamine and tetramethylpyrazine (TMP) on pyrogallol-induced cardiac contractile response. Adult rat ventricular myocytes were isolated and stimulated to contract at 0.5 Hz. Mechanical properties were evaluated using an IonOptix system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), and maximal velocity of shortening/relengthening (+/-dL/dt). A 10-min exposure of pyrogallol (0 to 10(-2) M) did not affect cardiac contractile mechanics. However, longer duration of pyrogallol exposure (1, 3, and 6 h) significantly shortened resting cell length, reduced PS and +/-dL/dt, and prolonged TPS and TR90 in time- and concentration-dependent manners. The pyrogallol (10(-4) M with 6-h incubation)-induced mechanical defects were prevented by the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (1 microM) and superoxide dismutase (SOD, 500 U/mL) with the exception that pyrogallol-induced PS depression was unaffected by SOD. Interestingly, incubation of herbal antioxidants anisodamine (10(-7) M) and TMP (10(-7) M) effectively attenuated the pyrogallol-induced cardiac mechanical defects with the exception of PS unaffected by TMP. Our data demonstrate a direct inhibitory effect of pyrogallol on cardiac contraction, probably in a superoxide- and p38 MAP kinase-dependent manner. The antioxidant medicines anisodamine and TMP may be useful in the treatment of oxygen free radical-induced myocardial dysfunction.
authors.affiliation: Creighton University School of Medicine, Omaha, NE, USA.
authors.forename: Lucy B
authors.initials: LB
authors.lastname: Esberg
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011748:Pyrogallol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012991:Solanaceous Alkaloids / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D011719:Pyrazines; D011725:Pyridines; D012991:Solanaceous Alkaloids; C003922:anisodamine; D011748:Pyrogallol; D013481:Superoxides; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C017953:tetramethylpyrazine