Abstract 852: Conditional Overexpression Of Neuronal Nitric Oxide Synthase Is Cardioprotective In Ischemia-reperfusion
Introduction: We previously demonstrated that conditional overexpression of the neuronal nitric oxide synthase (nNOS, NOS1) inhibited L-type Ca2+-channels. We now hypothesize that nNOS overexpression has an impact on myocardial contractility and acts cardioprotective after ischemia-reperfusion.
Methods and results: We assessed cardiac function in the newly established transgenic mouse model with conditional, myocardial nNOS overexpression. NOS-activity (22 ± 1.5 vs. 29 ± 1μM /sec, n=18, p<0.05) was significantly enhanced after nNOS overexpression. Co-immunoprecipitation experiments indicated interaction of nNOS with SR Ca2+ATPase and additionally with L-type Ca2+-channels in nNOS overexpressing animals. Ica,L (reduction of 40±6 rel. %, n=12, p<0.05) as well as intracellular Ca2+-transients and fractional shortening in cardiomyocytes were clearly impaired in nNOS overexpressing mice (3.0 ± 0.4F/F0 vs. 2.2 ± 0.2F/F0, n=13, p<0.005 and 7.7 ± 1.3% vs. 3.8 ± 0.5%, n=13, p<0.05). In vivo examinations of the nNOS overexpressing mice showed a decrease of +dp/dtmax (reduction for 52 ± 17%, n=12, p<0.05) as well as a reduced ejection fraction (43±5% vs. 63±9%, n=12, p<0.05). Ischemia-reperfusion experiments showed a cardio-protective effect of nNOS overexpression (30 min post-ischemia, LVDP 20±6 in non-induced animals vs. 60±11 mmHg in nNOS overexpressing animals, n=6, p<0.05).
Discussion: In summary, we demonstrated that under basline conditions, conditional transgenic overexpression of nNOS resulted in a mild reduction of myocardial contractility, mainly due to inhibition of the L-type Ca2+-channel. In contrast, under pathophysiological conditions (i.e. ischemia-reperfusion) nNOS overexpression acts cardioprotective. These effects might be caused by a reduction of myocardial Ca2+-overload after reperfusion.