Effects of clentiazem on cerebral ischemia induced by carotid artery occlusion in stroke-prone spontaneously hypertensive rats.
OBJECTIVE
We examined metabolic and functional changes when forebrain ischemia was induced in stroke-prone spontaneously hypertensive rats by bilateral carotid artery occlusion. In addition, the protective effect of clentiazem was evaluated in this model.


METHODS
Rats were anesthetized with urethane. Cerebral blood flow was measured with a laser Doppler flowmeter. Cerebral high-energy phosphates and intracellular pH were measured by phosphorus magnetic resonance spectroscopy. Electroencephalographic activity was evaluated as the summation of its amplitude. These parameters were monitored during a 30-minute period of ischemia and recirculation. Clentiazem was given orally as pretreatment (10 mg/kg twice a day for 3.5 days).


RESULTS
Bilateral carotid occlusion caused a decrease in cerebral blood flow to approximately 5% of the preischemic level and the disappearance of electroencephalographic activity. Occlusion also caused a decrease in ATP and phosphocreatine (to 48.7 +/- 4.3% and 23.7 +/- 2.2% of preischemic levels, respectively) as well as intracellular pH (from 7.3 +/- 0.1 to 6.0 +/- 0.1). During recirculation the reversal of these changes was variable: high-energy phosphates were partially restored, but electroencephalographic activity and intracellular pH showed little improvement. Hypoperfusion (55.7 +/- 11.5% of the preischemic flow) developed after reactive hyperemia. Pretreatment with clentiazem lessened the decrease in cerebral blood flow (control, 4.8 +/- 1.4%; clentiazem, 14.1 +/- 4.1% of the preischemic level; P < .05) and prevented the disappearance of electroencephalographic activity in some rats during ischemia. Clentiazem also prevented postischemic hypoperfusion and accelerated the restoration of high-energy phosphates, intracellular pH, and electroencephalographic activity during recirculation.


CONCLUSIONS
Carotid artery occlusion induced stable forebrain ischemia in stroke-prone spontaneously hypertensive rats. Clentiazem improved the metabolic and functional disturbances that occurred in this ischemic model, and its beneficial effect appeared to be due mainly to the relative preservation of cerebral blood flow during carotid occlusion.
Kikkawa
K
K
Pharmacological Research Laboratory, Tanabe Seiyaku Co, Ltd, Saitama, Japan.
Yamauchi
R
R
Suzuki
T
T
Banno
K
K
Murata
S
S
Tetsuka
T
T
Nagao
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001157:Arterial Occlusive Diseases / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D002245:Carbon Dioxide / Q000097:blood; D002340:Carotid Artery Diseases / Q000503:physiopathology*; D002536:Cerebral Arteries / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000235:genetics; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004198:Disease Susceptibility; D004569:Electroencephalography / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012039:Regional Blood Flow / Q000187:drug effects; D013997:Time Factors; D014018:Tissue Distribution
D000959:Antihypertensive Agents; D010725:Phosphocreatine; D002245:Carbon Dioxide; C056595:clentiazem; D000255:Adenosine Triphosphate; D004110:Diltiazem; D010100:Oxygen