title: Tetramethylpyrazine elicits disparate responses in cardiac contraction and intracellular Ca(2+) transients in isolated adult rat ventricular myocytes.
abstract: Tetramethylpyrazine (TMP) is the biologically active ingredient isolated from a popular Chinese medicinal plant, Ligusticum wallichil franchat, which has been used effectively since the 1970s to treat ischemic heart disease, cerebrovascular and thrombotic vascular diseases. The direct action of TMP on cardiac contractile function, however, is largely unclear. This study was designed to examine the effect of TMP on ventricular contractile function at the single cardiac myocyte level. Adult rat ventricular myocytes were isolated and stimulated to contract at 0.5 Hz, and mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix Myocam system. Contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS), time-to-90% relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dl/dt), resting intracellular Ca(2+) level, Ca(2+)-induced Ca(2+) release (CICR) and decay. TMP (10(-10)-10(-5) M) exhibited an increase in PS with a maximal increase of 30.9%. TMP had no effect on +/-dl/dt, TPS/TR(90) or CICR but lowered resting intracellular Ca(2+) level and slowed intracellular Ca(2+) decay. Pretreatment with either the nonspecific nitric oxide synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 100 microM) or inducible NOS inhibitor W1400 effectively abolished the positive effect of TMP on myocyte shortening. Our data demonstrate a direct positive inotropic effect of TMP in cardiac myocytes, which may be related, at least in part, to NO production.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Science, University of North Dakota, Grand Forks, ND 58203, USA.
authors.forename: Kadon K
authors.initials: KK
authors.lastname: Hintz
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D003374:Coumarins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000578:Amidines; D003374:Coumarins; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; C470914:N-(6-bromo-7-hydroxycoumarin-4-yl)methoxycarbonyl-N-(3-(aminomethyl)benzyl)acetamide; D011719:Pyrazines; D014665:Vasodilator Agents; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D016257:Fura-2; D019331:NG-Nitroarginine Methyl Ester; C017953:tetramethylpyrazine