Dihydropyridine calcium antagonists reduce the consumption of high-energy phosphates in the rat brain. A study using combined 31P/1H magnetic resonance spectroscopy and 31P saturation transfer.
The disappearance of high-energy phosphates (HEPs) in the rat brain during global ischemia induced by cardiac arrest is slowed down significantly by dihydropyridine Ca antagonists (DCAs) compared to controls. Two mechanisms might account for this effect: increased HEP production via anaerobic glycolysis or decreased HEP consumption. In order to obtain more insight into the underlying mechanisms of ATP preservation we have studied in the rat the effect of the DCAs isradipine, darodipine and nimodipine on the cerebral steady-state levels of HEPs and lactate as well as the intracellular pH value during global ischemia using combined 31P/1H magnetic resonance spectroscopy. We have found that the ATP preservation in DCA-treated animals is not associated with significantly higher postischemic lactate levels (lactate/N-acetylaspartate 0.97 +/- 0.08 for isradipine at a dose of 2.5 mg/kg i.p.) or lower pH values (6.40 +/- 0.03) as compared to control rats (lactate/N-acetylaspartate 0.94 +/- 0.13, pH = 6.49 +/- 0.03). This is in contrast to hyperglycemic rats, in which similar preservation of ATP levels during ischemia was observed; however, at the expense of a larger drop in brain pH (6.22 +/- 0.09) and a concomitant increase in cerebral lactate (lactate/N-acetylaspartate = 1.40 +/- 0.09). These results strongly favor reduced ATP consumption to be the cause for the protective effect of DCAs.(ABSTRACT TRUNCATED AT 250 WORDS)
Rudin
M
M
Preclinical Research, Sandoz Ltd., Basle, Switzerland.
Sauter
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D001786:Blood Glucose; D002121:Calcium Channel Blockers; D007773:Lactates; D019344:Lactic Acid; D000255:Adenosine Triphosphate