The Effect of Nimodipine on High-Energy Phosphates and Intracellular pH During Cerebral Ischemia

Abstract

Experimental and clinical studies suggest that the calcium channel blocker nimodipine may reduce cerebral ischemic injury. Using rapid acquisition phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy, we examined the effect of nimodipine on cerebral energy metabolism during severe ischemia in gerbils. High-energy phosphates and intracellular pH were characterized at baseline and at 2-min intervals following bilateral common carotid artery (CCA) ligation. Serial forebrain spectroscopy was continued until phosphocreatine (PCr) and adenosine triphosphate (ATP) resonances disappeared. Controls (n = 10) were compared to gerbils receiving intraperitoneal nimodipine 30 min prior to carotid ligation, at the following doses: 0.5 mg/kg (n = 8), 1.0 mg/kg (n = 10), 2.0 mg/kg (n = 8), or 4.0 mg/kg (n = 4). In the control group, PCr and ATP peaks were undetectable after a mean of 5.4 +/- 0.47 min following CCA ligation. Compared with controls, the mean time for depletion of high-energy phosphates following carotid ligation was prolonged at nimodipine doses of 0.5 mg/kg and 1.0 mg/kg, but the differences did not reach statistical significance. In the 2.0 mg/kg group, however, ATP was preserved until 9.8 +/- 1.0 min following the onset of ischemia, significantly longer than the control group (p = 0.005, Mann-Whitney test). Nimodipine had no effect on the time course or severity of intracellular acidosis. In this model of severe ischemia, relatively high doses of nimodipine slowed the depletion of high-energy phosphates without altering intracellular acidosis. This suggests that nimodipine may provide cerebral protection by directly altering ischemic cellular metabolism.

Effect of calcium-channel blockers on calcium--phosphate metabolism in patients with end-stage renal disease

“…Under pathological conditions there is some evidence for direct interactions between CCB and phosphorus metabolism, but they are scarce. For instance, the protective effect of CCB against ischaemic damage has been associated with delayed cellular depletion of high-energy phosphate, be it in the brain with nimodipine [16], in the myocardium with nifedipine [17] and verapamil [ 18] or in the kidney with verapamil [19]. Such intracellular accumulations of phosphorus could not account for increments in plasma levels as observed with diltiazem, but could theoretically be invoked to decrements in plasma phosphorus levels * Data on phosphorus were not reported in the paper.…”

Ischemia and Reperfusion Injury of the Rat Liver: The Role of Nimodipine

“…During liver ischemia, the deficit of metabolic subAlthough extensive studies on calcium channel strates induces important biochemical changes such as blockers agree that there is a beneficial effect on ischdegradation of ATP and other energetic metabolites: emia and reperfusion, the literature is rather contraactivation of enzyme systems, phospholipases, and prodictory concerning the explanation of mechanisms of teases that may lead to damage of the cell membrane action of these drugs. In central nervous system ischthrough production of oxygen-reactive species, hydrolyemia, Lemons et al [36] showed that, in gerbils, nimodsis of phospholipids, membrane blebbing, and cell lysis ipine in high doses slowed the depletion of high-energy [1]. Lack of oxygen and cellular energy depletion lead phosphates (measured by phosphorus 31 nuclear magto abnormal balance of intracellular metabolites and netic resonance).…”