Abstract 24: Normalization of Blood Pressure and the Inhibition of Local Angiotensin II Prevent Aneurysm Rupture in Mice

Abstract

Background and Purpose Hypertension is generally considered as a major risk factor for aneurysmal subarachnoid hemorrhage. The renin-angiotensin system plays a crucial role in the regulation of blood pressure. Angiotensin II type 2 receptor (AT2R) counters most effects of angiotensin II type 1 receptor (AT1R). In our recently established mouse model of intracranial aneurysms, aneurysmal rupture occurs at a high incidence and results in neurological symptoms. We hypothesized that either normalization of blood pressure or inhibition of local renin angiotensin system alone can prevent aneurysmal subarachnoid hemorrhage. Furthermore, we tested relative contributions of AT1R and AT2R. Methods Intracranial aneurysms were induced in male mice using a combination of a single injection of elastase into the cerebrospinal fluid and deoxycorticosterone acetate (DOCA) salt hypertension. Six days after aneurysm induction, we started treatments with vehicle control (VC; n=87), hydralazine (direct vasodilator, 250mg/L in drinking water; n=15), angiotensin-converting enzyme inhibitor (captopril; 6mg/kg/day; n=17), an AT1R antagonist (losartan 30mg/kg/day; n=37), the same AT1R antagonist and an AT2R antagonist (PD123319; 10mg/kg/day; n=16), and an AT2R agonist ( CGP42112 ; 1ug/kg/min; n=16), and continued for 15 days. Mice were sacrificed when the mice developed neurological symptoms, or at day 21 if mice did not develop any symptoms. Symptom-free survival curves were analyzed using Kaplan-Meier analysis. Results Normalization of blood pressure by hydralazine significantly reduced the rate of symptomatic ruptured aneurysms (mice with symptomatic ruptured aneurysms / mice with any aneurysms), and improved symptom free survival curve compared to the vehicle control group (P < 0.05). As expected, losartan or captopril did not affect DOCA salt induced hypertension. However, these treatments reduced the rate of symptomatic ruptured aneurysms (P < 0.05). Whereas the AT2R antagonist abolished the protective effect of losartan ( Figure ), the AT2R agonist alone reduced the rate of aneurysmal rupture (P < 0.05). Conclusions Either normalization of blood pressure or inhibition of local renin-angiotensin system was protective against aneurysmal rupture. Moreover, our data suggested potentially protective effects of AT2R activation against aneurysmal rupture. These data may be useful in choosing anti-hypertensive agents for patients with unruptured aneurysms.