Pharmacology of the Endothelin<sub>A</sub> Receptor Antagonist: LU 135252

Rohmeiss, Peter; Birck, Rainer; Braun, Claude; Münter, Klaus; Woude, Fokko J. van der; Kirchengast, Michael

doi:10.1111/j.1527-3466.1998.tb00365.x

Cited by 12 publications

(5 citation statements)

References 64 publications

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“…Although use of a mixed ET receptor antagonist successfully lowered BP, selective ET A receptor antagonists may be as effective. Darusentan, an ET receptor antagonist that has an ET A :ET B receptor affinity of ∼130:1 ( Rohmeiss et al, 1998 ) was administered to ∼400 patients with stage 2 primary hypertension ( Nakov et al, 2002 ). Within 1 week of a daily administration of 10, 30, or 100 mg darusentan, a significant dose-dependent reduction in systolic BP (10 mg: −6 mmHg; 30 mg: −7 mmHg; 100 mg: −11 mmHg) and diastolic BP (10 mg: −4 mmHg; 30 mg: −5 mmHg; 100 mg: −8 mmHg) relative to placebo was observed.…”

Section: Role Of Endothelin In Human Pharmacology Deduced From Ementioning

confidence: 99%

Endothelin

et al. 2016

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The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

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Section: Role Of Endothelin In Human Pharmacology Deduced From Ementioning

confidence: 99%

Endothelin

et al. 2016

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“…A second TGR group received losartan, a specific AT 1 receptor antagonist (10 mg/kg body wt, MSD; Haar). A third TGR group received LU 135252, 8 a specific ET A receptor antagonist (30 mg/kg body wt; Knoll AG;). A fourth TGR group received the combination of both compounds at these doses in their drinking water during a period of 4 weeks.…”

Section: Experimental Protocolmentioning

confidence: 99%

Synergistic Effects of AT ₁ and ET _A Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model

et al. 2000

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Abstract-Angiotensin II and endothelin may participate in increasing blood pressure and inducing end-organ damage, but the evidence is conflicting. We tested the hypothesis that endothelin A receptor blockade would ameliorate blood pressure and end-organ damage in a rat model of human renin-dependent hypertension. We studied rats that were transgenic for both the human renin and angiotensinogen genes. Experimental groups (nϭ12 each) of untreated transgenic rats, transgenic rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic peptide, collagen III, and ACE was measured. The mortality rate in untreated transgenic rats was 42%, which is consistent with previous observations in this line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat per group (8%), without significantly lowering blood pressure. In the combination group, blood pressure was normalized and all rats survived. The drug combination also decreased elevated water intake in transgenic rats to normal levels and significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III gene expression. We suggest that endothelin participates in this model of angiotensin II-induced hypertension and end-organ damage. Key Words: endothelin Ⅲ angiotensin Ⅲ rats, transgenic Ⅲ hypertrophy, cardiac Ⅲ thirst Ⅲ hypertension, arterial N umerous cellular events are triggered by angiotensin (Ang) II via its Ang II type 1 (AT 1 ) receptor, which can directly stimulate cellular hypertrophy and hyperplasia. Ang II is capable of inducing severe end-organ damage, independent of its blood pressure (BP)-raising effects. 1 ACE inhibitors, AT 1 receptor blockers, and possibly the combination of these agents have proved to be effective treatment for much of Ang II-induced cardiovascular injury. However, complete amelioration is not generally achieved. One possible explanation includes the participation of other pathogenic factors in end-organ damage that are elicited by Ang II or facilitate Ang II-dependent effects. A strong candidate for such secondary effects is the endothelin (ET) system. Ang II was shown to be a powerful stimulator of ET synthesis and release in vascular smooth muscle and endothelial cells. 2,3 Furthermore, Ang II promotes the ability of ET to produce vascular hypertrophy. The importance of ET in these interactions and for cardiovascular damage was recently reviewed. 4,5 The availability of specific antagonists to the two ET receptors (ET A and ET B ) permits the direct testing of such an interaction. We studied the possible pathophysiological role of ET in a unique, high human renin form of hypertension in the transgenic rat (TGR). Rats were made transgenic for the human renin (hREN) gene and c...

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“…Importantly, we applied a low dose of darusentan in order to achieve a selective ET A receptor blockade. Administration of a high dose of the drug may lead to a loss of subtype selectivity and, hence, blockade of the endothelial ET B receptor, resulting in decreased NO release, followed by reduced vasodilation [16,17]. This could possibly counteract an antihypertensive effect of darusentan treatment mediated by ET A receptor inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore we investigated whether prolonged, selective ET A receptor blockade was able to reduce blood pressure in SHR and to restore the vascular NO-cGMP pathway. Darusentan ((+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-proprionic acid, CAS 171714-84-4) was used in this study as a potent, orally available, selective ET A receptor antagonist, with a K i value of 1.4 nmol/l at ET A -and 184 nmol/l at ET B -receptors [16]. An oral target dose of 10 mg kg -1 d -1 was chosen, as this was previously shown to lower mean arterial pressure over 24 hours in SHR at the end of a 2 week treatment period [17].…”

Section: Introductionmentioning

confidence: 99%

Effects of Chronic Endothelin ETA Receptor Blockade on Blood Pressure and Vascular Formation of Cyclic Guanosine-3’,5’-monophosphate in Spontaneously Hypertensive Rats

Kirchengast

Witte

Stolpe

et al. 2011

Arzneimittelforschung

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Endothelin (ET) mediates vasoconstriction in intact arterial blood vessels with functional endothelium via stimulation of ET(A) receptors, while ET(B) receptor stimulation leads to vasodilation via nitric oxide (NO) release and formation of cyclic guanosine-3',5'-monophosphate (cGMP). In spontaneously hypertensive rats (SHR) the cGMP-forming NO-receptor guanylyl cyclase (sGC) is downregulated. It is unclear whether ET contributes to the hypertensive phenotype of SHR, and whether this involves the disturbed cGMP signaling. The selective ETA receptor antagonist darusentan (CAS 171714-84-4), given orally via drinking water (10 mg kg(-1) d(-1)) for 12 weeks, significantly lowered systolic blood pressure of SHR as determined by radiotelemetry. Neither impaired endothelium-dependent relaxation to acetylcholine was restored nor sGC expression and activity affected when compared to control SHR. While these findings show a role for ETA receptors in blood pressure regulation in genetically elevated blood pressure, downregulation of sGC expression and cGMP-mediated vasorelaxant response in SHR were shown to be independent of ETA receptors. The findings suggest distinct mechanisms of gene expression affecting ET and cGMP mediated vasomotor functions.

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Pharmacology of the Endothelin_A Receptor Antagonist: LU 135252

Cited by 12 publications

References 64 publications

Endothelin

Endothelin

Synergistic Effects of AT ₁ and ET _A Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model

Effects of Chronic Endothelin ETA Receptor Blockade on Blood Pressure and Vascular Formation of Cyclic Guanosine-3’,5’-monophosphate in Spontaneously Hypertensive Rats

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Pharmacology of the EndothelinA Receptor Antagonist: LU 135252

Cited by 12 publications

References 64 publications

Endothelin

Endothelin

Synergistic Effects of AT 1 and ET A Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model

Effects of Chronic Endothelin ETA Receptor Blockade on Blood Pressure and Vascular Formation of Cyclic Guanosine-3’,5’-monophosphate in Spontaneously Hypertensive Rats

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Pharmacology of the Endothelin_A Receptor Antagonist: LU 135252

Synergistic Effects of AT ₁ and ET _A Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model