A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis.

Abstract

SUMMARY1. 31P nuclear magnetic resonance was used to measure the relative concentrations of phosphorus-containing metabolites in Langendorff-perfused ferret hearts. Intracellular concentrations of inorganic phosphate ([Pi]i), phosphocreatine ([PCr]i), ATP ([ATP]i) and H+ (pHi) were monitored under control conditions and while oxidative phosphorylation and/or glycolysis were prevented. Mechanical performance was assessed by recording the pressure developed in a balloon placed in the left ventricle.2. Oxidative phosphorylation was prevented either by replacement of 02 with N2 or by addition of cyanide. When the rate of oxidative phosphorylation was reduced by either method, developed pressure fell to a stable level of about 35 % of control after 5 min. The pHi (control value 6 98) first increased to a peak of 7 07 after 2 min but then decreased to give a stable acidosis (pH 6 85).[PCr]i decreased rapidly to about 15 % of the control value after 5 min whereas [ATP]i declined very slowly, reaching about 90 % of the control value after 10 min.3. Reduction in the rate of glycolysis was achieved either (i) by removal of external glucose and depletion of glycogen stores by a long (1-2 h) period of stimulation or (ii) by removal of glucose and application of 2-deoxyglucose (1 mM) for 30-60 min.These procedures had only a small effect on pressure development, [ATP]i, [PCr]i and pHi. Measurements of lactate production showed that these procedures reduced the rate of glycolysis by a factor of about 10.4. When oxidative phosphorylation was prevented during periods when the rate ofglycolysis was reduced, developed pressure fell to less than 5 % of control after 5 min and there was a subsequent increase in resting pressure hypoxicc contracture). pHi (control value 7 03) first increased to a peak of 7-12 and then declined to about pH 7 00, but there was no subsequent acidosis. [PCr]i fell rapidly to about 10 % of control after about 5 min while [ATP]i declined to about half of its control value over 10 min.5. It is concluded that (i) when oxidative phosphorylation alone is prevented, the

Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death

“…the peak level of PAR, Figure 1Ed) was seen as early as after 5-10 min exposure to H 2 O 2 , before caspase 3 activation, which started at 15 min and peaked at 30-40 min (Figure 4c). Since the resting level of the [ATP] i is B4-7 mM in the heart, 43 it may take time (B40 min exposure, Figure 4c) for it to be completely depleted by activated PARP. It should be noted that PARP/PAR activity starts to slowly decrease after 30 min exposure (Figure 1Ed), at the time when caspase 3 activity peaked (B30-40 min exposure, Figure 4c).…”

ATP‐sensitive K+ channels in heart muscle cells first open and subsequently close at maintained anoxia

“…The main objections against a relevant contribution of KATp-channels are: (i) half maximum inhibition of the channel activity is reached at tens to hundreds of/aM ATP [16,17] whereas measured ATP levels in the ischaemic myocardium are in the range of several mM [18][19][20] which would allow only a few channels to open. In turn this would not be sufficient to explain the large K ÷ efflux; (ii) glibenclamide, a specific blocker of KgTa-Channels, blocks the K ÷ efflux in the ischaemic myocardium only during the first steep phase [4].…”

On the mechanism of nucleotide diphosphate activation of the ATP‐sensitive K+ channel in ventricular cell of guinea‐pig.

“…With altered metabolic states during ischaemia, it has been reported that intracellular ADP may rise to 180 fM from the physiological value of 10-20 /M (Allen, Morris, Orchard & Pirolo, 1985), although alterations in other NDPs have not been well studied yet. Thus, openings of the dephosphorylated KATP channel induced by increased ADP might be involved in the shortening of the cardiac action potential during ischaemia.…”