Optimum AT1 receptor-neprilysin inhibition has superior cardioprotective effects compared with AT1 receptor blockade alone in hypertensive rats

Abstract

Neprilysin inhibitors prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. Here we studied the effects of a low and a high dose of the neprilysin inhibitor thiorphan on top of AT1 receptor blockade with irbesartan versus vehicle in TGR(mREN2)27 rats with high renin hypertension. Mean arterial blood pressure was unaffected by vehicle or thiorphan alone. Irbesartan lowered blood pressure, but after 7 days pressure started to increase again. Low- but not high-dose thiorphan prevented this rise. Only during exposure to low-dose thiorphan plus irbesartan did heart weight/body weight ratio, cardiac atrial natriuretic peptide expression, and myocyte size decrease significantly. Circulating endothelin-1 was not affected by low-dose thiorphan with or without irbesartan, but increased after treatment with high-dose thiorphan plus irbesartan. This endothelin-1 rise was accompanied by an increase in renal sodium-hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. Consequently, the endothelin type B receptor antagonist BQ788 no longer enhanced endothelin-1-induced vasoconstriction (indicative of endothelin type B receptor-mediated vasodilation), but prevented it. Thus, optimal neprilysin inhibitor dosing reveals additional cardioprotective effects on top of AT1 receptor blockade in renin-dependent hypertension.

Molecular regulation of the renin–angiotensin system by sodium–glucose cotransporter 2 inhibition in type 1 diabetes mellitus

“…In conclusion, this study provides the first evidence of systemic RAS activation and modulation by the SGLT-2 inhibitor empagliflozin in type 1 diabetes. Our results also show that empagliflozin plus selective RAS blockade upregulates the key alternative RAS component Ang (1)(2)(3)(4)(5)(6)(7). These outcomes provide a compelling incentive for further studies of the nephroprotective effects of SGLT-2 inhibitors in larger populations.…”

“…We subjected available serum samples from 37 type 1 diabetes patients treated for 8 weeks with empagliflozin (25 mg once daily) (NCT01392560) [5] to simultaneous quantification of individual molecular RAS components. Steady-state angiotensin peptide levels in the serum samples were quantified by liquid chromatographytandem mass spectrometry (LC-MS/MS) [7], as described in detail in the electronic supplementary material (ESM) methods. None of the patients received any form of therapeutic RAS blockade.…”

Dual Angiotensin Receptor and Neprilysin Inhibitor Ameliorates Portal Hypertension in Portal Hypertensive Rats

“…Our data showed that LCZ696 and valsartan significantly reduced MAP and SVR, which was in accordance to the previous studies in the hypertensive patients and experimental animal models [18,19]. Regarding portal hypertension, we found that LCZ696, but not valsartan, reduced PP and SMAR in portal hypertensive rats, implicating the superior portal hypotensive effects of LCZ696 compared to valsartan.…”

Angiotensin II Receptor–Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats

“…In addition to increasing several vasodilator substances, NEP inhibition may also elevate the level of a potent vasoconstrictor, ET-1. 19,20,39 In mice overexpressing human prepro-ET-1 restricted to the endothelium, an exaggerated production of ET-1 reduced endothelium-dependent, NOmediated relaxation through the generation of reactive oxygen species. 40 However, in the present study, ACh-induced, NOmediated relaxations in mesenteric arteries did not differ between LCZ696-and valsartan-treated SHR groups.…”