Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility

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Abstract
The role of the neuronal NO synthase (nNOS or NOS1) enzyme in the control of cardiac function still remains unclear. Results from nNOS−/− mice or from pharmacological inhibition of nNOS are contradictory and do not pay tribute to the fact that probably spatial confinement of the nNOS enzyme is of major importance. We hypothesize that the close proximity of nNOS and certain effector molecules like L-type Ca2+-channels has an impact on myocardial contractility. To test this, we generated a new transgenic mouse model allowing conditional, myocardial specific nNOS overexpression. Western blot analysis of transgenic nNOS overexpression showed a 6-fold increase in nNOS protein expression compared with noninduced littermates (n=12; P3H]-l-arginine to [3H]-l-citrulline showed a 30% increase in nNOS overexpressing mice (n=18; Pmax compared with noninduced mice (PP2+ATPase and additionally with L-type Ca2+- channels in nNOS overexpressing animals. Accordingly, in adult isolated cardiac myocytes, ICa,L density was significantly decreased in the nNOS overexpressing cells. Intracellular Ca2+-transients and fractional shortening in cardiomyocytes were also clearly impaired in nNOS overexpressing mice versus noninduced littermates. In conclusion, conditional myocardial specific overexpression of nNOS in a transgenic animal model reduced myocardial contractility. We suggest that nNOS might suppress the function of L-type Ca2+-channels and in turn reduces Ca2+-transients which accounts for the negative inotropic effect.