The calcium-channel blocker, azelnidipine, enhances the inhibitory action of AT1 receptor blockade on ischemic brain damage.

Abstract

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.

METHODS AND 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.

CONCLUSION:

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.

• Authors: Masaru Iwai, Rui Chen, Ayumi Ide, Jun Iwanami, Hirokazu Tomochika, Yumiko Tomono, Masaki Mogi, Masatsugu Horiuchi
• Journal: Journal of hypertension (J Hypertens) Vol. 24 Issue 10 Pg. 2023-31 (Oct 2006) ISSN: 0263-6352 [Print] Netherlands
• PMID: 16957563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Calcium Channel Blockers
• Dihydropyridines
• Imidazoles
• Tetrazoles
• Azetidinecarboxylic Acid
• olmesartan
• azelnidipine

Topics

• Angiotensin II Type 1 Receptor Blockers (administration & dosage, therapeutic use)
• Animals
• Azetidinecarboxylic Acid (administration & dosage, analogs & derivatives, therapeutic use)
• Brain Ischemia (drug therapy, pathology, physiopathology)
• Calcium Channel Blockers (administration & dosage, therapeutic use)
• Cerebrovascular Circulation (drug effects)
• Dihydropyridines (administration & dosage, therapeutic use)
• Disease Models, Animal
• Drug Therapy, Combination
• Imidazoles (administration & dosage, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Tetrazoles (administration & dosage, therapeutic use)