Novel therapy approach in primary stroke prevention: simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival

Abstract

Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.

Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme

“…The dual NEP/ECE inhibitor SLV338 reduced renal damage in chronically L-NAME-treated rats and preserved kidney function and reduced mortality in a rat model of severe acute renal failure . SLV338 also prevented interstitial and perivascular fibrosis in the heart of 2-kidney 1-clip rats and reduced the incidence of stroke (Wengenmayer et al, 2011) in a BP-independent manner. These data strengthen the concept presented in this paper that the effects of NEP/ECE inhibition may vary throughout the body.…”

“…In preclinical studies dual NEP/ECE inhibitors appear not as potent as ET A -antagonists in reducing elevated BP. Two recent studies Wengenmayer et al, 2011) suggest that their potential benefit may depend on their ability to alter the bioavailability of vasoactive peptides in an organ-specific manner rather than on their BP-lowering effect (Dhaun and Webb, 2011).…”

Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

“…ET-1 and its downstream effects are frequent targets of treatment for neurological diseases (Chang et al, 2004;Leonard et al, 2011;Wengenmayer et al, 2011). As such, the molecular mechanisms following ET-1 exposure in the brain are of great interest in developing strategies to address its specific consequences.…”

New Developments in the Pharmacological Treatment of Hypertension: Dead-End or a Glimmer at the Horizon?

“…For SLV338, only preclinical data are available. It significantly reduced the incidence of stroke and improved survival in stroke-prone spontaneously hypertensive rats (spSHR), however, in a blood pressure-independent manner [ 28 ]. On the other hand, besides having reduced proteinuria and glomerulosclerosis in streptozotocin-induced diabetic rats similarly to captopril [ 29 ], daglutril attenuated pulmonary and right atrial pressure in patients with congestive heart failure [ 30 ].…”