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Nitric oxide synthase inhibition and elevated endothelin increase oxygen consumption but do not affect glucose and palmitate oxidation in the isolated rat heart

100%

Kurzelewski M., Duda M., Stanley W. C., Baresewicz A.

Journal of Physiology and Pharmacology

2004

tom 55

nr 1,1

Evidence indicates that nitric oxide (NO) suppresses myocardial oxygen consumption (MVO2) and regulates myocardial substrate oxidation, however data from in vivo and isolated heart preparations are conflicting. In addition, cardiac endothelin (ET-1) release has been shown to increase with inhibition of NO synthase (NOS), however the effects of ET-1 on myocardial energetics is not clear. We employed the isolated rat heart model to assess the role of NO and ET-1 on myocardial function and metabolism. Oxidation of glucose and FFA was measured using [U-14C]glucose and [9,10-3H]palmitate. NOS inhibition with NG-methyl-L-arginine acetate salt (L-NMMA, 50 µM), resulted in an increase in MVO2 at a given rate of myocardial external workload, and no change in myocardial glucose or FFA oxidation. ET-1 (25 pM), which caused coronary vasoconstriction similar to that produced by L-NMMA, also increased MVO2 without an effect on cardiac workload, or substrate oxidation, suggesting a role for ET-I in the regulation of myocardial energetics. We assessed also the effect of ETA/ETB receptor blockade (tezosentan; 5 nM) on MVO2 and glucose and FFA oxidation and observed no effect, suggesting that basal ET-1 production does not play a role in regulating MVO2 or substrate selection. In conclusion, inhibition of NOS or the addition of ET-1 resulted in an increase in MVO2, but did not affect glucose or FFA oxidation.

Step and ramp induction of myocardial ischemia: comparison of in vivo and in silico results

76%

Salem J. E., Cabrera M. E., Chandler M. P., McElfresh T. A., Huang H., Sterk J. P., Stanley W. C.

Journal of Physiology and Pharmacology

2004

tom 55

nr 3

This study tested the robustness of our computational model of myocardial metabolism by comparing responses to two different inputs with experimental data obtained in pigs under similar conditions. Accordingly, an abrupt and a gradual reduction in coronary flow of similar magnitude were implemented and used as model input. After flow reductions reached 60% from control values, ischemia was kept constant for 60 min in both groups. Our hypotheses were that: (1) these two flow-reduction profiles would result in different transients (concentrations and flux rates) while having similar steady-state values and (2) our model-simulated responses would predict the experimental results in an anesthetized swine model of myocardial ischemia. The two different ischemia-induction patterns resulted in the same decrease in steady-state MVO2 and in similar steady-state values for metabolite concentrations and flux rates at 60 min of ischemia. While both the simulated and experimental results showed decreased glycogen concentration, accumulation of lactate, and net lactate release with ischemia, the onset of glycogen depletion and the switch to lactate efflux were more rapid in the experiments than in the simulations. This study demonstrates the utility of computer models for predicting experimental outcomes in studies of metabolic regulation under physiological and pathological conditions.

Ograniczanie wyników

2 Journal of Physiology and Pharmacology

2 Stanley W. C.

1 Baresewicz A.

1 Cabrera M. E.

1 Chandler M. P.

1 Duda M.

1 Huang H.

1 Kurzelewski M.

1 McElfresh T. A.

1 Salem J. E.

1 Sterk J. P.

2 2004

Wyniki wyszukiwania

Nitric oxide synthase inhibition and elevated endothelin increase oxygen consumption but do not affect glucose and palmitate oxidation in the isolated rat heart

Step and ramp induction of myocardial ischemia: comparison of in vivo and in silico results