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Kidney Int. 2015 Jul;88(1):109-20. doi: 10.1038/ki.2015.107. Epub 2015 Apr 1.

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

Author information

1
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
2
Attoquant Diagnostics, Medical University of Vienna, Vienna, Austria.
3
1] Attoquant Diagnostics, Medical University of Vienna, Vienna, Austria [2] Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
4
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
5
Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

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.

PMID:
25830765
DOI:
10.1038/ki.2015.107
[Indexed for MEDLINE]

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