Disease relevance of 5-Ddins

• The goal of this study was to compare the effects of the novel, selective endothelin-A receptor antagonist BMS-182874 in various models of hypertension [1].
• The reduction in pulmonary vascular response to hypoxia following BMS-182874 is at least partly independent of nitric oxide [2].
• In this study, we have investigated the effects of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary hypertension in pigs [2].
• There was no effect of BMS-182874 on glomerular filtration rate (0.5 +/- 0.05 ml/min/100 g body weight; vehicle: 0.7 +/- 0.06) [3].
• In the present study, BMS-182874 significantly improved the recovery of cardiac function and reduced the release of CK during reperfusion after ischemia and the content of tumor necrosis factor (TNF-alpha) in myocardial tissues [4].

High impact information on 5-Ddins

• To test this hypothesis, cholesterol-fed hamsters were treated with a selective endothelin subtype A (ETA) receptor antagonist BMS-182874 [5].
• METHODS: Four-week-old transgenic (mRen2)27 rat (TGRen2) received for four weeks a placebo, the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist irbesartan, the ET(A) endothelin receptor antagonist BMS-182874, and a combined treatment with irbesartan plus BMS-182874 [6].
• BMS-182874 reduced blood pressure in DOCA--salt hypertensive rats when administered at a dose of 30, 100, or 300 mumol/kg IV [1].
• METHODS: Four-week-old TGR were blood pressure (BP)-matched and allocated to receive a placebo (n=8), the calcium antagonist nifedipine (n=6), the AT-1 specific receptor antagonist irbesartan (n=6), the ET(A)/ET(B) antagonist bosentan (n=6) or the ET(A)-selective antagonist BMS-182874 (n=5) [7].
• RESULTS: The hypoxia-evoked increase in mean pulmonary artery pressure was reduced by administration of BMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05) [2].

Chemical compound and disease context of 5-Ddins

• Infusion (0.46 mumol/kg/min) of the endothelin (ET)-converting-enzyme inhibitor, phosphoramidon (P), protected function and structure after 30 min renal ischemia in rats more than treatment (5 mumol/kg/min) with the ETA receptor antagonist, BMS-182874 (B) [8].
• The observation that vasospasms were reversed by Y-27632 but not by BQ-123 or BMS-182874 suggests that Rho-kinase, rather than the ET(A) receptor, is the most promising pharmacological target for the treatment of ET-1-induced vasospasms, ischemic strokes, and sudden hearing loss [9].
• Pretreatment with an ETA receptor antagonist, BMS-182874 (50 micrograms/kg iv), blocked clonidine-induced hypotension and bradycardia [10].

Biological context of 5-Ddins

• In addition, BMS-182874 at 30 mg/kg reduced the pulmonary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1.1 mmHg.min.l-1 P < 0.05) [2].
• CONCLUSIONS: The non-peptide, selective ETA receptor antagonist, BMS-182874, reduces hypoxic pulmonary vasoconstriction in pigs [2].
• The apparent discrepancy between efficacy in cell and tissue models was likely related to the high degree of protein binding exhibited by BMS-182874 [11].
• Mutagenesis of Asp133 to alanine indicated that it was critical only for the binding of BMS-182874 [12].
• Administration of BMS-182874 (10 mumol/kg/min, i.v.) to anesthetized, male, spontaneously hypertensive rats decreased renal blood flow by approximately 50% (1.2 +/- 0.11 ml/min/100 g body weight) compared to vehicle (2.7 +/- 0.23) [3].

Anatomical context of 5-Ddins

• BMS-182874 was a competitive antagonist of force development elicited by stimulation of ETA, but not other, receptors in isolated blood vessels such as the rabbit carotid artery (KB = 520 nM) [11].
• 4. The treatment of ovariectomized rats with BMS-182874 (60 mg kg(-1) per day) did not reverse uterus atrophy [13].
• BMS-182874 competitively inhibited the binding of [125I]ET-1 to ETA receptors in rat vascular smooth muscle A10 (VSM-A10) cell membranes (Ki = 61 nM) and in CHO cells stably expressing the human ETA receptor (Ki = 48 nM), but was a weak inhibitor at ETB receptors (Ki > 50 microM) and non-ET receptors [11].
• The ET-receptor antagonist BMS-182874 selectively and competitively inhibits ET(A) receptors both on isolated myocytes and ventricular membranes with approximately 1,300 times greater affinity for ET(A) than ET(B) subtypes [14].
• Bile and urine were collected from bile-duct cannulated (BDC) rats and the in vivo metabolic pathways of BMS-182874 were evaluated [15].

Associations of 5-Ddins with other chemical compounds

• In addition, BMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effect of ET-1 in isolated porcine pulmonary arteries [2].
• These data indicate a role of aromatic interactions in the binding of these antagonists to ETA receptors an, in the case of BMS-182874, also suggested a hydrogen bond with the tyrosine hydroxyl [16].
• BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations [17].
• Blood pressure was significantly (P < 0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153 +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg) [18].
• Responses to ET-1 were resistant to the ETA antagonist FR 139317, and another, BMS 182874, inhibited responses only to high concentrations of ET-1 [19].

Gene context of 5-Ddins

• These data demonstrate that BMS-182874 is a competitive, selective and orally active ETA receptor antagonist that will be useful in understanding the role of ET in normal and disease states [11].
• 4. Responses to ET-1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ-788 [20].
• The addition of the selective ET(A) receptor antagonist BMS 182874 caused a rightward shift of the concentration-response curve to ET-1 in both sections of the colon [21].
• Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d) [22].
• BMS-182874 is a selective, nonpeptide endothelin ETA receptor antagonist [11].

Analytical, diagnostic and therapeutic context of 5-Ddins

• Despite in vivo clearance approached ca 50% of the total liver plasma flow, BMS-182874 was completely bioavailable after oral administration in rats [15].

References