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Abstract

Angiotensin II (AII) has a protective effect against acute cerebral ischemia, mediated through non-AT1 receptors and independent of its pressive action (Fernandez L et al, J Cardiovasc Pharmacol 1994; 24: 937-40). The pentapeptide angiotensin IV is no longer regarded as an inactive breakdown product of AII, since its specific receptor (AT4) has been described. AT4 receptors are expressed in the brain and the vessels, are vasodilators and are involved in cerebral blood flow regulation (Wright JW, et al. Brain Res 1996; 717: 1-11). To examine the contribution of AT4 in the adaptation to acute cerebral ischemia, unilateral carotid ligation was performed in penthobarbital anesthetized 80 grams male gerbils pretreated 30 min prior with lisinopril (3mg/kg), candesartan (1mg/kg) or saline intraperitoneously (ip). In each group of animals, post-treatment with AIV or saline as control was administrated ip as a bolus (0.25 mg/kg) followed by a six hours continuous infusion (0.1 mg/kg/h). Mortality was examined at 24, 48 and 72 hours and Kaplan-Meier survival curves were analysed by a logrank test.

Survival rate (%) at day 3 were:

Survival was markedly reduced in L pretreated animals compared to S and C groups in the absence of AIV rescue, confirming that AII contributes to protective adaptation to cerebral ischemia through non-AT1 receptors. Rescue treatment with AIV significantly improved the survival in the L group, and to a less and non significant extent in the S and C groups. Global analysis of the mortality irrespective to the pretreatment further demonstrated the protective effect of rescue treatment with AIV. In saline pretreated animals, AIV lowered systolic BP measured at the tail (68.9 ±2.9 vs 85.4 ± 2.4 mmHg, in saline post-treated, p = .0002) similarly to C and L in gerbils post-treated with saline (resp 68.6 ± 3.1 and 69.4 ± 3.9 mmHg) but did not further lower blood pressure in C and L pretreated animals (67.1 ± 4 and 70.2 ± 4.6 mmHg). Conclusion: angiotensin IV reverses the deleterious effect of ACE inhibition on acute ischemic stroke mortality in the gerbil. These results suggest that AIV is involved in the BP independent, non AT1-mediated renin-angiotensin system protective effect against cerebral ischemia. (See Table)

post-treatment
pre-treatmentsalineangio IVsal vs angio IV
saline (S)42.4 (n= 33)52.8 (n= 36)ns
lisinopril (L)11.8 (n=34)36.4 (n= 33)p = 0.008
candesartan (C)43.3 (n= 30)56.7 (n= 30)ns
all treatments31.9 (n= 97)48.5 (n=99)p = 0.012
post-treatment
pre-treatmentsalineangio IVsal vs angio IV
saline (S)42.4 (n= 33)52.8 (n= 36)ns
lisinopril (L)11.8 (n=34)36.4 (n= 33)p = 0.008
candesartan (C)43.3 (n= 30)56.7 (n= 30)ns
all treatments31.9 (n= 97)48.5 (n=99)p = 0.012
post-treatment
pre-treatmentsalineangio IVsal vs angio IV
saline (S)42.4 (n= 33)52.8 (n= 36)ns
lisinopril (L)11.8 (n=34)36.4 (n= 33)p = 0.008
candesartan (C)43.3 (n= 30)56.7 (n= 30)ns
all treatments31.9 (n= 97)48.5 (n=99)p = 0.012
post-treatment
pre-treatmentsalineangio IVsal vs angio IV
saline (S)42.4 (n= 33)52.8 (n= 36)ns
lisinopril (L)11.8 (n=34)36.4 (n= 33)p = 0.008
candesartan (C)43.3 (n= 30)56.7 (n= 30)ns
all treatments31.9 (n= 97)48.5 (n=99)p = 0.012

stroke, AT1 receptors, angiotensin IV
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© American Journal of Hypertension, Ltd. 2001
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