© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Peroxynitrite-induced cardiac depression: role of myofilament desensitization and cGMP pathway
Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
*Corresponding author. Tel.: +43-316-380-5559; fax: +43-316-380-9890. Email address: friedrich.brunner{at}kfunigraz.ac.at
Objective: The oxidant species peroxynitrite, the reaction product of nitric oxide (NO·) and superoxide, has been implicated in several pathophysiological conditions of the heart. Here, we studied the mechanism of peroxynitrite-induced cardiac depression using specific drugs and simultaneous analyses of myocardial function and intracellular Ca2+ ([Ca2+]i). Methods: Rat hearts were perfused retrogradely and left ventricular function (balloon method) and [Ca2+]i transients were recorded on a beat-to-beat basis using the aequorin bioluminescence method. Peroxynitrite was infused at 10.8±0.93 µM via sideline for 10 min, followed by a 15-min recovery period to monitor irreversible effects. Test drugs were infused prior to and during peroxynitrite application. Results: Peroxynitrite depressed left ventricular developed pressure (LVDevP; –40%), yet increased systolic and diastolic [Ca2+]i (1.3– and 2.3–fold, respectively; n = 12). When Ca2+ entry through Ca2+ channels or Na+/Ca2+ exchange transport was blocked using nicardipine (1 µM, n = 3) or dichlorobenzamil (30 µM, n = 5), respectively, cells showed lower [Ca2+]i and accentuated negative inotropic action in response to peroxynitrite. Peroxynitrite slowed left ventricular relaxation and [Ca2+]i transients, both of which were not affected by extracellular Ca2+ restriction. Importantly, the oxidant greatly depressed myofilament responsiveness to Ca2+, which was partly antagonized by Rp-8-(4-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate (Rp-cGMPS), an inhibitor of cGMP-dependent protein kinase. Also, the inhibitor partially restored left ventricular contractility (n = 6). Peroxynitrite stimulated cardiac cGMP production and coronary cGMP efflux (n = 6). Decomposed peroxynitrite had no effect in any of the tests. Conclusions: Peroxynitrite depresses myocardial contractility by decreasing the ability of Ca2+ to trigger contraction, and this effect is partly mediated by the cGMP/cGMP-dependent protein kinase pathway.
KEYWORDS Peroxynitrite; Contractility; Free radicals; Calcium
Time for primary review 16 days
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