The goal of the study is to examine the possible mechanisms of impaired cutaneous microvascular function through local heating along with administration of vasoconstrictors.

Start Date01 Oct 2018

Sponsor / Collaborator

The University of Texas at Arlington

NCT04907838

/ Unknown statusNot Applicable

Insulin Stimulated Vasodilation in Patients With Type 2 Diabetes

This study evaluates the role of endothelin in insulin stimulated vasodilation and glucose uptake. The subjects will complete an hyperinsulinemic euglycemic clamp with and without blockade of the endothelin receptors.

Start Date01 May 2018

Sponsor / Collaborator

University of Southern Denmark

[+1]

NCT02062346

/ CompletedNot ApplicableIIT

The Vascular Effects of Endothelin Receptor Antagonism in Systemic Vasculitis

Patients with vasculitis commonly develop cardiovascular disease. The reasons for this are not clear and is not adequately treated with current drugs. It is thus understand the reasons why patients with vasculitis develop cardiovascular disease in order to develop new drugs to reduced this risk.
Endothelin is a chemical produced by blood vessels that contributes to the development of hypertension and cardiovascular disease Higher than normal levels of endothelin are seen in patients with vasculitis but how this contributes to cardiovascular disease in patients with vasculitis is not clear. By using drugs that block the effects of endothelin ('endothelin receptor antagonists') the investigators can hopefully reduce the risk of cardiovascular disease in patients with vasculitis. The purpose of the study is to ascertain if endothelin receptor antagonists improve blood vessel function in patients with vasculitis.

Start Date01 Aug 2016

Sponsor / Collaborator

The University of Edinburgh

[+1]

100 Clinical Results associated with BQ-788

100 Translational Medicine associated with BQ-788

100 Patents (Medical) associated with BQ-788

1,005

Literatures (Medical) associated with BQ-788

01 Feb 2025·Hypertension

Ang-(1-7) and ET-1 Interplay Through Mas and ET _B Receptor Interaction Defines a Novel Vasoprotective Mechanism

Article

Author: Montezano, Augusto C. ; Alves-Lopes, Rheure ; Findlay, Jane E. ; Awan, Fazli R. ; Namkung, Yoon ; Gallen, Emily ; Basheer, Sehrish ; Santos, Robson A. ; MacLean, Margaret R. ; Camargo, Livia L. ; Touyz, Rhian M. ; Laporte, Stéphane A. ; Passaglia, Patricia ; Kuriakose, Jithin ; Hood, Katie Y. ; Tejeda, Gonzalo ; Sin, Yuan Yan ; Castro, Carlos H. ; Baillie, George S.

BACKGROUND: Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ET B R (endothelin receptor type B). METHODS:To address this, we studied multiple models: in vivo, in a mouse model of ET-1–associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells.RESULTS: Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1–induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ET B R. In human endothelial cells, Ang-(1-7)–induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ET B R antagonist). A779 inhibited ET-1–induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ET B R. Binding sites for ET B R were mapped to MasR (amino acids 290–314). Binding sites for MasR on ET B R were identified (amino acids 176–200). Peptides that disrupt MasR:ET B R prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ET B R interaction, which we termed enhancers. Enhancers increased Ang-(1-7)–induced eNOS activity, NO production, and Ang-(1-7)–mediated vasorelaxation, and reduced contractile responses. CONCLUSIONS: We identify cross talk between Ang-(1-7) and ET-1 through MasR:ET B R interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ET B R-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ET B R signaling may have therapeutic potential in conditions associated with vascular damage.

31 Dec 2024·Blood Pressure

Endothelin-1- and acetylcholine-mediated effects in human and rat vessels: impact of perivascular adipose tissue, diabetes, angiotensin II, and chemerin

Article

Author: Danser, A. H. Jan ; Tan, Lunbo ; Cruz-López, Edwyn O. ; Verdonk, Koen ; Stolk, Daniël G. ; van den Bogaerdt, Antoon J.

OBJECTIVETo study the role of perivascular adipose tissue (PVAT) in the reactivity of rat and human vessels.METHODSIliac and mesenteric arteries were obtained from normotensive Sprague-Dawley rats, hypertensive transgenic (mRen2)27 rats overexpressing mouse renin, and (mRen2)27 rats made diabetic with streptozotocin. Human coronary arteries were obtained from donors. Concentration-response curves were constructed to endothelin-1 and acetylcholine with and without PVAT. The contribution of NO and endothelium-dependent hyperpolarization (EDH) were determined making use of the NO synthase inhibitor L-NAME and the EDH inhibitors apamin + TRAM-34. The endothelin type A and type B (ET_A, ET_B) receptor blockers BQ123 and BQ788, the chemerin inhibitors α-NETA and pravastatin, and the angiotensin receptor blocker losartan were also used.RESULTSIn rat iliac arteries, PVAT diminished endothelin-induced constriction, while the opposite was true in human coronaries. Coronary effects were unaltered by α-NETA, pravastatin, or losartan. ET_B receptor-mediated relaxation in iliac arteries occurred only with PVAT, and BQ123 blocked endothelin-1-induced constriction. Diabetes upregulated the anticontractile effects of PVAT. In rat mesenteric arteries, acetylcholine-induced relaxation with PVAT relied on NO, and on NO + EDH without PVAT. Diabetes upregulated the EDH component exclusively with PVAT.CONCLUSIONPVAT modulates ET-1-induced constriction in a vessel type-dependent manner. Its enhancing effects in coronaries involved neither chemerin nor angiotensin II. Its anticontractile effects in rat iliac arteries involved ET_B receptor-mediated relaxation. Diabetes upregulated PVAT's anticontractile effects. In mesenteric arteries, PVAT counterbalanced the EDH component of the relaxant effect of acetylcholine. Diabetes reversed this effect by upregulating the EDH component.

01 Dec 2024·Glia

Endothelin‐1 increases Na⁺‐K⁺‐2Cl⁻ cotransporter‐1 expression in cultured astrocytes and in traumatic brain injury model: An involvement of HIF1α activation

Article

Author: Fukui, Yura ; Izumi, Yasuhiko ; Fujimoto, Rina ; Hosogi, Nami ; Michinaga, Shotaro ; Hishinuma, Shigeru ; Ogawa, Yasuhiro ; Koyama, Yutaka ; Takahashi, Kenta ; Hamada, Yasuhiro

AbstractNa+‐K+‐2Cl− cotransporter‐1 (NKCC1) is present in brain cells, including astrocytes. The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin‐1 (ET‐1) is a factor that induces brain edema and regulates the expression of several pathology‐related genes in astrocytes. In the present study, we investigated the effect of ET‐1 on NKCC1 expression in astrocytes. ET‐1 (100 nM)‐treated cultured astrocytes showed increased NKCC1 mRNA and protein levels. The effect of ET‐1 on NKCC1 expression in cultured astrocytes was reduced by BQ788 (1 μM), an ETB antagonist, but not by FR139317 (1 μM), an ETA antagonist. The involvement of ET‐1 in NKCC1 expression in TBI was examined using a fluid percussion injury (FPI) mouse model that replicates the pathology of TBI with high reproducibility. Administration of BQ788 (15 nmol/day) decreased FPI‐induced expressions of NKCC1 mRNA and protein, accompanied with a reduction of astrocytic activation. FPI‐induced brain edema was attenuated by BQ788 and NKCC1 inhibitors (azosemide and bumetanide). ET‐1‐treated cultured astrocytes showed increased mRNA and protein expression of hypoxia‐inducible factor‐1α (HIF1α). Immunohistochemical observations of mouse cerebrum after FPI showed co‐localization of HIF1α with GFAP‐positive astrocytes. Increased HIF1α expression in the TBI model was reversed by BQ788. FM19G11 (an HIF inhibitor, 1 μM) and HIF1α siRNA suppressed ET‐induced increase in NKCC1 expression in cultured astrocytes. These results indicate that ET‐1 increases NKCC1 expression in astrocytes through the activation of HIF1α.

100 Deals associated with BQ-788

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Phase 2	-	MelCure	01 May 2011
Hypertension	Phase 2	-	Merck Serono SA	-

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01395329 (NETS, CTgov)	Phase 4	Hypertension \| Prehypertension	42	FBF response to Sodium Nitroprusside+Nebivolol+ACh+BQ-788+BQ-123 (Nebivolol)	nwspdmqytv(jlwejfpjfp) = tznjrhcppn dvxtsepskj (yyqfuirlnh, rfmswwtwty - ublynmfugy) View more	-	06 Dec 2018
NCT01395329 (NETS, CTgov)	Phase 4	Hypertension \| Prehypertension	42	FBF response to Sodium Nitroprusside+Metoprolol+ACh+BQ-788+BQ-123 (Metoprolol)	nwspdmqytv(jlwejfpjfp) = kgacwtdaqk dvxtsepskj (yyqfuirlnh, yomwgvzphj - nwqkdtpuml) View more	-	06 Dec 2018
NCT02442466 (Pubmed \| Oncologist) Manual	Phase 1	Melanoma	5	BQ788	(zgbgrvvaze) = mepqcdorci sseuunmzsm (qnkzdwnuhi )	Positive	01 Oct 2015

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