Abstract 225: Treatment with LCZ696, an Orally Active Angiotensin Receptor Neprilysin Inhibitor Prevents Ischemic Brain Damage

Objective: Recent accumulating evidence suggests that an orally active angiotensin II receptor-neprilysin inhibitor, LCZ696, was supposed to be superior compared to angiotensin II receptor blocker (ARB), valsartan alone in treating cardiovascular disease. We previously reported that ARBs prevent ischemic brain damage using middle cerebral artery occlusion (MCAO) mouse model. Moreover, natriuretic peptides such as atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) increased by neprilysin inhibitor are also reported to protect brain damage. Therefore, we investigate the possible protective effects of valsartan (VAL) compared with LCZ696 (LCZ) (VAL+ neprilysin inhibitor; 1:1) on the prevention of ischemic damage after stroke. Methods: Focal brain ischemia was induced by MCAO with the intraluminal filament technique in 10-week male C57BL/6J mice. Mice were treated with VAL (3 mg/kg) or LCZ (6 mg/kg) orally as powder in gelatin mini-capsules daily for 2 weeks before MCAO. Ischemic area was evaluated by triphenyl tetrazolium chloride staining, cerebral blood flow (CBF) by laser-Doppler flowmetry, oxidative stress by dihydroethidium staining. Results: Telemetry method showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) did not change before and after treatments. Protective effect of LCZ treatment on ischemic brain damage in each brain section seemed to be more marked than that of VAL treatment. The average ischemic area ratio showed a significant reduction in VAL and LCZ groups compared with CON group. CBF in the peripheral region around ischemic core was significantly improved after treatments. Moreover, VAL and LCZ treatments significantly decreased the increase of superoxide anion production in the cortex of ischemic side. However, significant differences of CBF and superoxide anion production were not observed in VAL and LCZ. Conclusions: Both valsartan and LCZ696 treatments exerted preventive effects on ischemic stroke. The preventive effect of LCZ696 seemed more prominent than VAL. LCZ696 could be a novel powerful approach to protect brain after stroke. Further investigation has been performed to clarify the protective effect of LCZ696 on ischemic brain damage.

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Pre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage

European Journal of Pharmacology ◽

10.1016/j.ejphar.2015.05.059 ◽

2015 ◽

Vol 762 ◽

pp. 293-298 ◽

Cited By ~ 13

Author(s):

Hui-Yu Bai ◽

Masaki Mogi ◽

Hirotomo Nakaoka ◽

Harumi Kan-no ◽

Kana Tsukuda ◽

...

Keyword(s):

Brain Damage ◽

Angiotensin Receptor ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Neprilysin Inhibitor ◽

Angiotensin Receptor Neprilysin Inhibitor ◽

Pre Treatment ◽

Orally Active

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Circulating Catecholamines Modulate Ischemic Brain Damage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1986.102 ◽

1986 ◽

Vol 6 (5) ◽

pp. 559-565 ◽

Cited By ~ 84

Author(s):

Tohru Koide ◽

Tadeusz W. Wieloch ◽

Bo K. Siesjö

Keyword(s):

Blood Pressure ◽

Brain Damage ◽

Neuronal Damage ◽

Ischemic Insult ◽

Ischemic Brain Damage ◽

Neuronal Necrosis ◽

Ischemic Brain ◽

Bilateral Carotid ◽

Response To Stress ◽

Bilateral Carotid Artery

In search of factors influencing the outcome of an ischemic insult, we induced 10 min of forebrain ischemia in rats and assessed neuronal necrosis by quantitative histopathology after 1 week of recovery. Procedures for inducing ischemia included bilateral carotid artery clamping and reduction of blood pressure to 40–50 mm Hg by bleeding. To facilitate rapid lowering of blood pressure, a ganglionic blocker, trimethaphan (TMP), was administered at the onset of ischemia. Omission of the ganglionic blocker proved to markedly ameliorate neuronal damage. Similarly favorable effects were obtained when a mixture of adrenaline and noradrenaline (1 μg kg−1 min−1 each) was infused during the early recirculation period in animals previously given TMP. Infusion of noradrenaline alone also ameliorated the damage, though the efficacy was somewhat less. The results suggest that catecholamines, released as a response to stress, ameliorate ischemic brain damage.

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Salusin-β in Intermediate Dorsal Motor Nucleus of the Vagus Regulates Sympathetic-Parasympathetic Balance and Blood Pressure

Biomedicines ◽

10.3390/biomedicines9091118 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1118

Author(s):

Lu-Lu Wu ◽

Jin-Hua Bo ◽

Fen Zheng ◽

Feng Zhang ◽

Qi Chen ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Superoxide Anion ◽

Sympathetic Activity ◽

Motor Nucleus ◽

Vagal Activity ◽

Ros Production ◽

Superoxide Anion Production ◽

Dorsal Motor Nucleus ◽

Anion Production

The dorsal motor nucleus of the vagus (DMV) is known to control vagal activity. It is unknown whether the DMV regulates sympathetic activity and whether salusin-β in the DMV contributes to autonomic nervous activity. We investigated the roles of salusin-β in DMV in regulating sympathetic-parasympathetic balance and its underline mechanisms. Microinjections were carried out in the DMV and hypothalamic paraventricular nucleus (PVN) in male adult anesthetized rats. Renal sympathetic nerve activity (RSNA), blood pressure and heart rate were recorded. Immunohistochemistry for salusin-β and reactive oxidative species (ROS) production in the DMV were examined. Salusin-β was expressed in the intermediate DMV (iDMV). Salusin-β in the iDMV not only inhibited RSNA but also enhanced vagal activity and thereby reduced blood pressure and heart rate. The roles of salusin-β in causing vagal activation were mediated by NAD(P)H oxidase-dependent superoxide anion production in the iDMV. The roles of salusin-β in inhibiting RSNA were mediated by not only the NAD(P)H oxidase-originated superoxide anion production in the iDMV but also the γ-aminobutyric acid (GABA)A receptor activation in PVN. Moreover, endogenous salusin-β and ROS production in the iDMV play a tonic role in inhibiting RSNA. These results indicate that salusin-β in the iDMV inhibits sympathetic activity and enhances vagal activity, and thereby reduces blood pressure and heart rate, which are mediated by NAD(P)H oxidase-dependent ROS production in the iDMV. Moreover, GABAA receptor in the PVN mediates the effect of salusin-β on sympathetic inhibition. Endogenous salusin-β and ROS production in the iDMV play a tonic role in inhibiting sympathetic activity.

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