Lercanidipine rescues hippocampus pyramidal neurons from mild ischemia-induced delayed neuronal death in SHRSP.
Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipine, lisinopril, valsartan, and hydralazine on occlusion-induced DND in SHRSPs. Drugs were administered for 2 weeks, from 15 to 17 weeks of age. 0.1% Nicardipine and 0.01 or 0.03% lercanidipine were administered in the SP diet (about 61.3, 5.7, and 18.8 mg/kg/day, respectively), and the remaining drugs were administered at 10 mg/kg/day using the mini-osmotic pump. The animals were operated on at 16 weeks of age, and DND was analyzed by histological examination 1 week later. Systolic blood pressure was measured at 15, 16, and 17 weeks of age. For chronic treatment, Calcium-channel blockers were administered from 8 to 17 weeks of age. All antihypertensive drugs significantly lowered systolic blood pressure at 16 weeks of age. Hydralazine and lisinopril were associated with the greatest reduction; however, lercanidipine, nicardipine, and valsartan effectively reduced systolic blood pressure to within a medium range. DND was significantly inhibited only by 0.03% lercanidipine. Chronic treatment with 0.03% lercanidipine also protected pyramidal neurons. The results of this study demonstrate that the long-acting, lipophilic Calcium-channel blocker lercanidipine inhibits occlusion-induced DND in SHRSPs and that lercanidipine may effectively reduce dementia induced by small ischemic insults in patients with essential hypertension.
Department of Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. yasukosy@nagasaki-u.ac.jp
Yasuko
Y
Sakurai-Yamashita
Noboru
N
Harada
Masami
M
Niwa
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D006624:Hippocampus / Q000098:blood supply* / Q000473:pathology*; D007511:Ischemia / Q000150:complications / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000150:complications / Q000473:pathology*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C060343:lercanidipine
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