Cardiovascular pharmacologyPre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage
Introduction
Stroke is one of the leading causes of disability and death in the industrialized world, and post-stroke disabilities markedly impair quality of life. The renin angiotensin system is well known to play a role in the pathogenesis of ischemic brain damage, and has been evaluated in various studies such as in mouse models of brain infarction induced by middle cerebral artery (MCA) occlusion (Iwai et al., 2004, Saavedra et al., 2006, Walther et al., 2002). Angiotensin II type 1 (AT1) receptor blockers (ARBs) were shown to attenuate ischemic brain damage in these studies. Regarding the clinical relevance of the protective effects of ARBs against brain damage after stroke, Fuentes et al. reported that patients taking antihypertensive drugs at stroke onset had a lower rate of a poor outcome than those not on antihypertensive treatment, and those taking an ARB had better outcomes than those without an ARB, while analysis of other antihypertensive drugs showed no difference (Fuentes et al., 2010).
Inhibition of neutral endopeptidase (NEP) has been investigated as a potential novel therapeutic target, because of its ability to increase the plasma concentrations of natriuretic peptides (NPs), since NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and exert antiproliferative and antihypertrophic effects (Mangiafico et al., 2013). LCZ696 is a novel single molecule in which the molecular moieties of valsartan and the molecular moieties of an NEP inhibitor prodrug, AHU377, are present in a 1:1 M ratio (Gu et al., 2010). LCZ696 provides a complementary and fully additive reduction of BP compared with valsartan (Ruilope et al., 2010). In heart failure patients with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater degree than did valsartan alone, and LCZ696 showed beneficial effects on symptoms independent of its BP-lowering effect (Solomon et al., 2012), suggesting that LCZ696 leads to cardiovascular benefits over and above the effect on BP lowering (Bloch and Basile, 2010).
In the acute phase of ischemic stroke, NP level is frequently elevated and has been shown to be an independent predictor of mortality (Estrada et al., 1994, Iltumur et al., 2006, Nakagawa et al., 2005). These results suggest that NPs could play a role in the prevention of ischemic brain damage at least in part due to hemodynamic regulation during the acute phase of stroke. Accordingly, we tried to explore the beneficial effects of LCZ696 on focal brain ischemia induced by MCA occlusion in mice and its possible mechanisms in comparison with valsartan.
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Animals and treatment
All procedures were reviewed and approved by the Animal Studies Committee of Ehime University. An ARB, valsartan (VAL), was purchased from LKT Laboratories, Inc. (St. Paul, MN). LCZ696 was provided by Novartis Pharma AG (Basel, Switzerland). Mice were treated with VAL (3 mg/kg per day) or LCZ696 (6 mg/kg per day) orally as powder in gelatin mini-capsules (Torpac, Inc., Fairfield, NJ) daily for 2 weeks before MCA occlusion. Body weight was measured after VAL or LCZ696 pre-treatment for 2 weeks.
Focal ischemic injury of brain after MCA occlusion
Focal brain ischemia was induced by MCA occlusion using the intraluminal filament technique. VAL (3 mg/kg/day) or LCZ696 (6 mg/kg/day) was administered for 2 weeks before MCA occlusion. Systolic blood pressure, diastolic blood pressure and heart rate were not significantly different in each group (Fig. 1). Pre-treatment with VAL or LCZ attenuated the ischemic area, and quantitative analysis of the average ischemic ratio showed a significant reduction of approximately 41% and 55% in the VAL and
Discussion
In the present study, we demonstrated that both valsartan and LCZ696 pre-treatment significantly decreased the ischemic area after stroke, at least in part by increasing CBF in the penumbra and inhibiting oxidative stress. Moreover, we observed that LCZ696 pre-treatment was more effective than VAL pre-treatment in reducing the ischemic area, independent of BP.
In spite of their apparent similar effects to increase CBF and decrease superoxide anion production after stroke, LCZ696 was more
Sources of funding
This study was supported by JSPS KAKENHI Grant numbers 25293310 (M.H.) and 25462220 (M.M.), and research grants from pharmaceutical companies: Astellas Pharma Inc., Bayer Yakuhin, Ltd., Daiichi-Sankyo Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Shionogi & Co. Ltd., and Takeda Pharmaceutical Co. Ltd.
Disclosure
None.
Acknowledgment
This study was partially funded by Novartis Pharma K.K and the material was provided by Novartis Pharma AG.
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