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Saturday 01 November 2003

Peroxynitrite-induced cardiac depression: role of myofilament desensitization and cGMP pathway.

By: Brunner F, Wolkart G.

Cardiovasc Res 2003 Nov 1;60(2):355-64

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 Ca(2+) ([Ca(2+)](i)). METHODS: Rat hearts were perfused retrogradely and left ventricular function (balloon method) and [Ca(2+)](i) transients were recorded on a beat-to-beat basis using the aequorin bioluminescence method. Peroxynitrite was infused at 10.8+/-0.93 microM 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 [Ca(2+)](i) (1.3- and 2.3-fold, respectively; n=12). When Ca(2+) entry through Ca(2+) channels or Na(+)/Ca(2+) exchange transport was blocked using nicardipine (1 microM, n=3) or dichlorobenzamil (30 microM, n=5), respectively, cells showed lower [Ca(2+)](i) and accentuated negative inotropic action in response to peroxynitrite. Peroxynitrite slowed left ventricular relaxation and [Ca(2+)](i) transients, both of which were not affected by extracellular Ca(2+) restriction. Importantly, the oxidant greatly depressed myofilament responsiveness to Ca(2+), 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 Ca(2+) to trigger contraction, and this effect is partly mediated by the cGMP/cGMP-dependent protein kinase pathway.

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