The calcium-channel blocker, azelnidipine, enhances the inhibitory action of AT1 receptor blockade on ischemic brain damage.
OBJECTIVE
The combined effects of a calcium-channel blocker (CCB) with an angiotensin (Ang) II type 1 (AT1) receptor blocker were investigated in focal brain ischemia induced by middle cerebral artery (MCA) occlusion.


RESULTS
In male C57BL/6J mice, permanent occlusion of the MCA-induced focal cerebral ischemia and neurological deficit after 24 h, accompanied by a reduction of cerebral blood flow and an increase in superoxide production in the ischemic area. Administration of azelnidipine, a CCB, at 1.0 mg/kg per day for 10 days significantly suppressed these changes after MCA without affecting systolic blood pressure. Such inhibitory effects of azelnidipine on brain ischemia could be observed in AT1a receptor-deficient mice. In addition, olmesartan, an AT1 receptor blocker, at 3.0 mg/kg per day also diminished the ischemic brain area and neurological score, as well as superoxide production and the reduction of cerebral surface blood flow in C57BL/6 mice. The combination of lower doses of azelnidipine (0.1 mg/kg per day) and olmesartan (0.5 mg/kg per day) significantly attenuated the ischemic brain area, neurological score, superoxide production and the reduction of cerebral surface blood flow after MCA occlusion in C57BL/6 mice, whereas either of these agents alone at these doses did not affect brain ischemia.


CONCLUSIONS
These results indicate that azelnidipine inhibited ischemic brain damage induced by MCA occlusion, at least in part, through suppression of blood flow change and oxidative stress via a signaling mechanism independent of AT1 receptor stimulation. Moreover, azelnidipine synergistically enhanced the inhibitory action of olmesartan on brain ischemia, suggesting beneficial combined effects of a CCB with an AT1 receptor blocker on ischemic brain damage.
Iwai
Masaru
M
Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
Chen
Rui
R
Ide
Ayumi
A
Iwanami
Jun
J
Tomochika
Hirokazu
H
Tomono
Yumiko
Y
Mogi
Masaki
M
Horiuchi
Masatsugu
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004095:Dihydropyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D013777:Tetrazoles; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; C061679:azelnidipine