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 AT 1 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 AT 1 receptor blockade in renin-dependent hypertension.

AT<inf>1</inf> receptor antagonist, Cardiac hypertrophy, Hypertension, Neprilysin inhibition, Renin, Sodium-hydrogen exchanger 3
dx.doi.org/10.1038/ki.2015.107, hdl.handle.net/1765/88771
Kidney International
Erasmus MC: University Medical Center Rotterdam

Roksnoer, L.C.W, van Veghel, R, de Vries, R.R.P, Garrelds, I.M, Bhaggoe, U.M, Friesema, E.C.H, … Batenburg, W.W. (2015). Optimum at 1 receptor-neprilysin inhibition has superior cardioprotective effects compared with at 1 receptor blockade alone in hypertensive rats. Kidney International, 88(1), 109–120. doi:10.1038/ki.2015.107