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Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies.
J Hypertens. 2008 Jul; 26(7):1435-45.JH

Abstract

BACKGROUND

Angiotensin II type 1 (AT1) receptor blockers decrease ischemia by mechanisms dependent on and independent of arterial blood pressure in hypertensive rats and AT1-R knockout mice, respectively. However, the detailed mechanisms underlying the effects of AT1 receptor blockers remain unclear.

AIMS

To elucidate the systemic and focal effects of AT1 receptor blockers against cerebral ischemia in in-vivo and in-vitro studies.

METHODS

Normotensive Wistar rats were treated for 2 weeks with 0.5 or 1 mg/kg candesartan cilexetil and then subjected to 2-h middle cerebral artery occlusion-reperfusion. Human umbilical endothelial cells were stimulated with the active form of candesartan and angiotensin II in the absence and presence of an angiotensin II type 2 (AT2) receptor antagonist.

RESULTS

In candesartan-pretreated hypotensive and nonhypotensive rats, blood pressure was moderately increased during middle cerebral artery occlusion and fell gradually to the baseline after the reperfusion; it remained elevated in the control even after the reperfusion occlusion. Candesartan treatment resulted in a decrease in the cortical infarct volume and oxidative damage, the hypoxic status was improved, and the expression of repair-associated and growth-associated proteins in the cortical penumbra was augmented. Candesartan also increased the eNOS mRNA level and the lumen size of the middle cerebral artery. In human umbilical endothelial cells, candesartan increased the eNOS protein level AT2-R dependently, inhibited the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and angiotensin II-induced intracellular reactive oxygen species and nitric oxide, and promoted the extracellular release of nitric oxide, suggesting that it augmented the bioavailability of nitric oxide.

CONCLUSION

Among the mechanisms candesartan exerts in its protection against cerebral ischemia, restoration of endothelial function may represent an attractive therapeutic goal to address cerebral ischemia.

Authors+Show Affiliations

Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18551021

Citation

Liu, Hao, et al. "Protective Mechanisms of the Angiotensin II Type 1 Receptor Blocker Candesartan Against Cerebral Ischemia: In-vivo and In-vitro Studies." Journal of Hypertension, vol. 26, no. 7, 2008, pp. 1435-45.
Liu H, Kitazato KT, Uno M, et al. Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens. 2008;26(7):1435-45.
Liu, H., Kitazato, K. T., Uno, M., Yagi, K., Kanematsu, Y., Tamura, T., Tada, Y., Kinouchi, T., & Nagahiro, S. (2008). Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. Journal of Hypertension, 26(7), 1435-45. https://doi.org/10.1097/HJH.0b013e3283013b6e
Liu H, et al. Protective Mechanisms of the Angiotensin II Type 1 Receptor Blocker Candesartan Against Cerebral Ischemia: In-vivo and In-vitro Studies. J Hypertens. 2008;26(7):1435-45. PubMed PMID: 18551021.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. AU - Liu,Hao, AU - Kitazato,Keiko T, AU - Uno,Masaaki, AU - Yagi,Kenji, AU - Kanematsu,Yasuhisa, AU - Tamura,Tetsuya, AU - Tada,Yoshiteru, AU - Kinouchi,Tomoya, AU - Nagahiro,Shinji, PY - 2008/6/14/pubmed PY - 2008/10/24/medline PY - 2008/6/14/entrez SP - 1435 EP - 45 JF - Journal of hypertension JO - J Hypertens VL - 26 IS - 7 N2 - BACKGROUND: Angiotensin II type 1 (AT1) receptor blockers decrease ischemia by mechanisms dependent on and independent of arterial blood pressure in hypertensive rats and AT1-R knockout mice, respectively. However, the detailed mechanisms underlying the effects of AT1 receptor blockers remain unclear. AIMS: To elucidate the systemic and focal effects of AT1 receptor blockers against cerebral ischemia in in-vivo and in-vitro studies. METHODS: Normotensive Wistar rats were treated for 2 weeks with 0.5 or 1 mg/kg candesartan cilexetil and then subjected to 2-h middle cerebral artery occlusion-reperfusion. Human umbilical endothelial cells were stimulated with the active form of candesartan and angiotensin II in the absence and presence of an angiotensin II type 2 (AT2) receptor antagonist. RESULTS: In candesartan-pretreated hypotensive and nonhypotensive rats, blood pressure was moderately increased during middle cerebral artery occlusion and fell gradually to the baseline after the reperfusion; it remained elevated in the control even after the reperfusion occlusion. Candesartan treatment resulted in a decrease in the cortical infarct volume and oxidative damage, the hypoxic status was improved, and the expression of repair-associated and growth-associated proteins in the cortical penumbra was augmented. Candesartan also increased the eNOS mRNA level and the lumen size of the middle cerebral artery. In human umbilical endothelial cells, candesartan increased the eNOS protein level AT2-R dependently, inhibited the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and angiotensin II-induced intracellular reactive oxygen species and nitric oxide, and promoted the extracellular release of nitric oxide, suggesting that it augmented the bioavailability of nitric oxide. CONCLUSION: Among the mechanisms candesartan exerts in its protection against cerebral ischemia, restoration of endothelial function may represent an attractive therapeutic goal to address cerebral ischemia. SN - 0263-6352 UR - https://www.unboundmedicine.com/medline/citation/18551021/Protective_mechanisms_of_the_angiotensin_II_type_1_receptor_blocker_candesartan_against_cerebral_ischemia:_in_vivo_and_in_vitro_studies_ DB - PRIME DP - Unbound Medicine ER -