Nonvasoactive concentrations of NO synthase inhibitors protect the heart against ischemic damage; this relates to a stimulation of glycolysis from exogenous glucose.

The creatine kinase reaction has been studied by 31P NMR in exercising human calf muscle. Quantitative analysis of high energy phosphates and saturation transfer study of the creatine kinase flux in the direction of ATP synthesis (Vfor) were performed at rest and during exercise. As expected, exercise induced a [PCr] decrease (from 28.5 +/- 0.9 to 21.9 +/- 1.5 mM, P < 0.01) matched by a Pi increase (from 4.5 +/- 0.2 to 8.9 +/- 1.8 mM, P = 0.06). pHi and [ATP] remained unchanged. Vfor did not change from rest (12.4 +/- 0.9 mM s(-1)) to moderate exercise and decreased at the highest exercise level (8.4 +/- 1.4 mM s(-1), P = 0.006). This observation differs from the prediction of the creatine kinase rate equation, showing an increase in the flux with exercise intensity. Computations suggest that this discrepancy arises from metabolite compartmentalization and/or from the reaction kinetics of a dead end complex stabilized by planar anions.

To investigate the dynamic control of cardiac ATP synthesis, we simultaneously determined the time course of mitochondrial oxygen consumption with the time course of changes in high-energy phosphates following steps in cardiac energy demand. Isolated isovolumically contracting rabbit hearts were perfused with Tyrode's solution at 28°C (n=7) or at 37°C (n=7). Coronary arterial and venous oxygen tensions were monitored with fast-responding oxygen electrodes. A cyclic pacing protocol in which we applied 64 step changes between two different heart rates was used. This enabled nuclear magnetic resonance measurement of the phosphate metabolites with a time resolution of =2 seconds. Oxygen consumption changed after heart-rate steps with time constants of 14±1 (mean±SEM) seconds at 28°C and 11±1 seconds at 37°C, which are already corrected for diffusion and vascular transport delays. Doubling of the heart rate resulted in a significant decrease in phosphocreatine (PCr) in inorganic phosphate (Pi) content, although oxygen supply was shown to be nonlimiting. The time constants for the change of both Pi and PCr content, =5 seconds at 28°C and 2.5 seconds at 37°C, are significantly smaller than the respective time constants for oxygen consumption. The changes in phosphate metabolites during changes in oxygen consumption suggest that regulation of oxidative phosphorylation could occur partly via products of ATP hydrolysis, but the unequal time constants of PCr and oxygen consumption suggest that other regulatory mechanisms also play a role. These dissimilar time constants further suggest that there might be an appreciable transient contribution of nonaerobic, presumably glycolytic, ATP synthesis to buffer the high-energy phosphates during fast transitions in cardiac work. (Circ Res. 1994;75: 751-759.) Key Words * myocardial energy metabolism * rabbit hearts * mitochondrial control * 31P nuclear magnetic resonance spectroscopy * oxidative phosphorylation changes in high-energy phosphates and Pi despite increases in myocardial oxygen consumption suggested that the phosphate metabolites may not be the primary regulators of cardiac mitochondrial respiration.The absence of a change in ATP or phosphocreatine (PCr) after a change in metabolic demand would also mean that mitochondrial ATP production and hence oxygen consumption must adapt immediately to a change in cytosolic ATP hydrolysis. In the isolated perfused rabbit heart, this is not the case, because oxygen consumption adapts to a new work load with a mean response time of at least 6 seconds.

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The aim of this study was to investigate the effects of riluzole on the lesion induced by a permanent middle cerebral artery occlusion (MCAO) in rats. Riluzole at 4 or 8 mg/kg i.v. significantly reduced the cortical ischemic brain damage. With the most effective dose of 8 mg/kg, the time evolution of the lesion was assessed by T2-weighted magnetic resonance imaging (MRI) repeated on the same animals after MCAO. MRI obtained at 24, 48, and 72 hours after MCAO showed a progressive increase of the ischemic lesion, except in the cortex of the riluzole-treated rats (8 mg/kg i.v.). Furthermore, there was no difference between lesion volumes as measured by MRI or by histology. This study indicates that MRI may be a valuable method to quantify in vivo the neuroprotective profile of a drug.