Key result
IL-1beta-induced nitric oxide lowers rat myocardial contractility through direct mitochondrial inhibition rather than cGMP pathways.
Why the study?
It is uncertain whether nitric oxide produced by inducible nitric oxide synthase in cytokine-stimulated cardiac myocytes directly inhibits mitochondrial energy metabolism and impairs myocardial contractility.
Experimental study demonstrates that cytokine-induced nitric oxide impairs mitochondrial energy production and contractility in rat cardiac myocytes, indicating direct mitochondrial toxicity.
OBJECTIVES: The present study examined whether nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy metabolism and impair cell function in interleukin (IL)-1beta,-stimulated cardiac myocytes. BACKGROUND: Recent reports have indicated that excessive production of NO induced by cytokines can disrupt cellular energy balance through the inhibition of mitochondrial respiration in a variety of cells. However, it is still largely uncertain whether the NO-induced energy depletion affects myocardial contractility. METHODS: Primary cultures of rat neonatal cardiac myocytes were prepared, and NO2-/NO3- (NOx) in the culture media was measured using Griess reagent. RESULTS: Treatment with IL-1beta (10 ng/ml) increased myocyte production of NOx in a time-dependent manner. The myocytes showed a concomitant significant increase in glucose consumption, a marked increase in lactate production, and a significant decrease in cellular ATP (adenosine 5'-triphosphate). These metabolic changes were blocked by co-incubation with N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Sodium nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose-dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo-cGMP), a cGMP donor, had no effect on these parameters. The activities of the mitochondrial iron-sulfur enzymes, NADH-CoQreductase and succinate-CoQreductase, but not oligomycin-sensitive ATPase, were significantly inhibited in the IL-1beta, or SNP-treated myocytes. Both IL-1beta and SNP significantly elevated maximum diastolic potential, reduced peak calcium current (I(Ca)), and lowered contractility in the myocytes. KT5823, an inhibitor of cGMP-dependent protein kinase, did not block the electrophysiological and contractility effects. CONCLUSIONS: These data suggest that IL-1beta-induced NO production in cardiac myocytes lowers energy production and myocardial contractility through a direct attack on the mitochondria, rather than through cGMP-mediated pathways.
No takes yet. Share an insight, caveat, or question.
Tatsumi et al. (2000) studied Myocardial contractility and energy metabolism. Interleukin-1beta (IL-1beta) was evaluated on Cellular ATP, mitochondrial enzyme activities, and myocardial contractility. IL-1beta-induced nitric oxide production in rat cardiac myocytes lowered energy production and myocardial contractility through direct mitochondrial inhibition rather than cGMP-mediated pathways.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: