Roles of hypertension in the rupture of intracranial aneurysms

Yoshiteru Tada, Kosuke Wada, Kenji Shimada, Hiroshi Makino, Elena I Liang, Shoko Murakami, Mari Kudo, Keiko T Kitazato, Shinji Nagahiro, Tomoki Hashimoto, Yoshiteru Tada, Kosuke Wada, Kenji Shimada, Hiroshi Makino, Elena I Liang, Shoko Murakami, Mari Kudo, Keiko T Kitazato, Shinji Nagahiro, Tomoki Hashimoto

Abstract

Background and purpose: Systemic hypertension has long been considered a risk factor of aneurysmal rupture. However, a causal link between systemic hypertension and the development of aneurysmal rupture has not been established. In this study, using a mouse model of intracranial aneurysm rupture, we examined the roles of systemic hypertension in the development of aneurysmal rupture.

Methods: Aneurysms were induced by a combination of deoxycorticosterone acetate (DOCA)-salt and a single injection of elastase into the cerebrospinal fluid in mice. Antihypertensive treatment was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage. Hydralazine (direct vasodilator) or discontinuation of DOCA-salt treatment was used to assess the roles of systemic hypertension. Captopril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin II type 1 receptor antagonist) was used to assess the roles of the local renin-angiotensin system in the vascular wall.

Results: Normalization of blood pressure by hydralazine significantly reduced the incidence of ruptured aneurysms and the rupture rate. There was a dose-dependent relationship between reduction of blood pressure and prevention of aneurysmal rupture. Captopril and losartan were able to reduce rupture rate without affecting systemic hypertension induced by DOCA-salt treatment.

Conclusions: Normalization of blood pressure after aneurysm formation prevented aneurysmal rupture in mice. In addition, we found that the inhibition of the local renin-angiotensin system independent from the reduction of blood pressure can prevent aneurysmal rupture.

Keywords: angiotensins; hypertension; intracranial aneurysm; models, animal; subarachnoid hemorrhage.

Figures

Figure 1. Representative intracranial aneurysms
Figure 1. Representative intracranial aneurysms
A: Normal cerebral arteries. B: Unruptured aneurysm in the posterior cerebral artery. C: Ruptured aneurysm with subarachnoid hemorrhage. Cerebral arteries were visualized by blue dyes dissolved in gelatin. Arrows indicate aneurysms.
Figure 2. Normalization of blood pressure by…
Figure 2. Normalization of blood pressure by hydralazine reduced the incidence of ruptured aneurysms and the rupture rates
A: Blood pressure. B: Incidence of ruptured and unruptured aneurysms. C: Rupture rate. D. Survival curve. Survival curves were constructed after excluding those mice that did not have aneurysms so that the curves mimic clinical settings.
Figure 3. Effects of the discontinuation of…
Figure 3. Effects of the discontinuation of DOCA-salt treatment one week after aneurysm induction
A: Blood pressure. B: Incidence of ruptured and unruptured aneurysms. C: Rupture rate. D. Survival curve.
Figure 4
Figure 4
Expression of angiotensin II and angiotensin II type 1 receptor.
Figure 5. Inhibition of the local renin-angiotensin…
Figure 5. Inhibition of the local renin-angiotensin system by captopril prevented aneurysmal rupture without affecting systemic hypertension
A: Blood pressure. B: Incidence of ruptured and unruptured aneurysms. C: Rupture rate. D. Survival curve.
Figure 6. Inhibition of the local renin-angiotensin…
Figure 6. Inhibition of the local renin-angiotensin system by losartan prevented aneurysmal rupture without affecting systemic hypertension
A: Blood pressure. B: Incidence of ruptured and unruptured aneurysms. C: Rupture rate. D. Survival curve.

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Source: PubMed

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