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

Nelissen, Jelly; Lemkens, Pieter; Sann, Holger; Bindl, M; Bassissi, Firas; Jasserand, Daniel; Mey, Jo G. R. De; Janssen, Ben J. A.

doi:10.1016/j.lfs.2012.01.015

Cited by 8 publications

(14 citation statements)

References 14 publications

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“…To evaluate this, we treated adult SHR with the dual NEP/ECE inhibitor SOL1, which effectively decreases big-ET-1 to ET-1 conversion, 34 and compared the effects with a 4-week treatment with an AT 1 receptor antagonist (losartan) and a 4-week treatment with a vasodilator (hydralazine). Decreasing ET-1 production might be helpful in conditions where either the intravascular levels of ET-1 and/or the vascular effects of the peptide are increased.…”

Section: Discussionmentioning

confidence: 99%

“…This means that both EDNO-and EDHF-type responses in the SOL1-treated group were improved by acute ET-receptor antagonism. Because SOL1 is easily removed from organs, 20 conversion of big-ET-1 to ET-1 may recommence before endothelial function is investigated. Subsequently, ET-1 might impair endothelium-derived relaxing responses through a similar myo-endothelial coupling mechanism, as proposed by Hilgers and De Mey.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] Thus, a dual NEP/ECE inhibitor, for example the novel compound SOL1, reduces ET-1 production by inhibiting all three pathways. 20 Recently, Kalk et al 21 reported that the dual NEP/ECE inhibitor daglutril (SLV338, an analog of SOL1) reduced cardiomyocyte hypertrophy, interstitial fibrosis and perivascular fibrosis in the 2-kidney 1-clip model of hypertension.…”

Section: Introductionmentioning

confidence: 99%

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Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

et al. 2017

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Endothelin 1 (ET-1), a potent vasoconstrictor, pro-mitogenic and pro-inflammatory peptide, may promote development of endothelial dysfunction and arterial remodeling. ET-1 can be formed through cleavage of big-ET-1 by endothelin-converting enzyme (ECE) or neutral endopeptidase (NEP). We investigated whether chronic treatment with the novel dual NEP/ECE inhibitor SOL1 improves functional and structural properties of resistance-sized arteries of 32-week-old male spontaneously hypertensive rats (SHR). SHR received a chronic 4-week treatment with SOL1, losartan or hydralazine. We then compared effects of inhibition of NO synthase (NOS) (100 μM L-NAME), blockade of ET A -and ET B -receptors (10 μM bosentan) and stimulation of the endothelium with 0.001-10 μM acetylcholine (ACh) in isolated third-order mesenteric resistance arteries. Losartan and hydralazine significantly lowered blood pressure. Losartan decreased the media-to-lumen ratio of resistance arteries. L-NAME (1) increased arterial contractile responses to K + (5.9-40 mM) in the losartan, SOL1 and vehicle group and (2) increased the sensitivity to phenylephrine (PHE; 0.16-20 μM) in the SOL1 group but not in the losartan, hydralazine and vehicle group. Relaxing responses to ACh in the absence or presence of L-NAME during contractions induced by either 10 μM PHE or 40 mM K + were not altered by any in vivo treatment. Acute treatment with bosentan did, however, significantly improve maximal relaxing responses involving endothelium-derived nitric oxide and -hyperpolarizing factors in the SOL1 group but not in the losartan, hydralazine or vehicle group. Thus, chronic inhibition of NEP/ECE improved basal endothelial function but did not alter blood pressure, resistance artery structure and stimulated endothelium-dependent relaxing responses in 32-week-old SHR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

et al. 2017

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“…Preliminary dose-finding experiments were carried out to identify appropriate doses of the dual NEP/ECE inhibitor SOL1 (2- 25 ). A dose of 50 mg kg À1 per day drastically decreased urinary ET1 content (from 32.89±3.91 to 1.35±0.25 pg ml À1 , Po0.001) in DOCA-salt hypertensive rats (n ¼ 3).…”

Section: Animals Model and Surgerymentioning

confidence: 99%

“…[22][23][24] Thus, a dual inhibitor of NEP and ECE reduces ET1 production by inhibiting all three pathways. 25 Recently Kalk et al 26 reported that the dual NEP/ECE inhibitor SLV338 reduces smooth muscle hypertrophy, interstitial fibrosis and perivascular fibrosis in the two kidney one clip model, partly by suppression of TGF-b1 expression.…”

Section: Introductionmentioning

confidence: 99%

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

et al. 2012

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Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased ( À90%) or increased ( þ 100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10 ± 1 Â 10 3 to 17 ± 2 Â 10 3 lm 2 ; 6 weeks: 13 ± 2 Â 10 3 to 24 ± 3 Â 10 3 lm 2 ). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (Ø: 385 ± 13 to 463±14 lm). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 Â 10 3 ±1 Â 10 3 lm 2 ). The diameter of the HF arteries of normotensive rats increased (Ø: 463 ± 22 lm) but no expansion occurred in the HF arteries of hypertensive rats (Ø: 471 ± 16 lm). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (Ø: 419 ± 13 to 475±16 lm). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean Ø between 235 and 290 lm), and infiltration of monocyte/macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition.

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Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

et al. 2012

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In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.

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

Cited by 8 publications

References 14 publications

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

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