Disease relevance of EDNRA

• Effects of a specific endothelin-converting enzyme inhibitor on cardiac, renal, and neurohumoral functions in congestive heart failure: comparison of effects with those of endothelin A receptor antagonism [1].
• This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR [2].
• METHODS: We administered either the ETA receptor antagonist FR139317 (FR [n = 8], 1 and 10 mg/kg body weight) or the ETB receptor antagonist RES-701-1 (RES [n = 8], 0.2 and 1.5 mg/kg) to dogs with CHF induced by rapid ventricular pacing [3].
• CONCLUSIONS: The results suggest that ET plays a significant role in the development of delayed cerebral vasospasm via an interaction with ETA receptors [4].
• Furthermore, ETA receptor antagonists may represent a novel therapeutic approach to the treatment of subarachnoid hemorrhage [4].

High impact information on EDNRA

• Acute endothelin A receptor blockade with FR-139317 resulted in significant decreases in mean arterial pressure and systemic vascular resistance in TIVCC [5].
• Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF [1].
• BACKGROUND: Endothelin (ET), a coronary vasoconstrictor, mediates its activity through the specific receptors ET-A and ET-B, which may demonstrate different activity under pathophysiological conditions [6].
• Endothelin at pathophysiological concentrations mediates coronary vasoconstriction via the endothelin-A receptor [7].
• Three binding sites were apparent in the left circumflex coronary artery: an ETA receptor, a high-affinity ETB receptor, and a lower-affinity ETB receptor [8].

Chemical compound and disease context of EDNRA

• We conclude that treatment of lung allografts with the mixed endothelin A/endothelin B (ETA/ETB) receptor antagonist SB209670 can ameliorate ischemia-reperfusion injury, resulting in improved graft function and survival after lung transplantation [9].
• Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model [10].
• We examined the preventive effect of a novel ETA receptor antagonist, BQ-485, on experimental vasospasm using canine two-hemorrhage model of subarachnoid hemorrhage [11].
• The aim of this study was to test the antiarrhythmic and anti-ischemic efficacy of the mixed endothelin-A- and -B- (ETA/B) receptor antagonist bosentan (BOS) on ET-1-induced arrhythmias on six mongrel dogs [12].
• The hemodynamic effects of enalapril, an angiotensin-converting enzyme inhibitor, BQ-123, a selective ETA receptor antagonist, and bosentan, a nonselective ETA and ETB receptor antagonist, were studied in dogs 4 weeks after myocardial infarction (MI) produced by ligation of the left anterior descending coronary artery [13].

Biological context of EDNRA

• Our findings suggest that selective ETA receptor antagonists have potential therapeutic benefits affecting both hemodynamic variables and diuresis, whereas ETB receptor antagonists have adverse hemodynamic effects, with the possibility of preventing fluid retention through suppression of aldosterone secretion in dogs with CHF [3].
• In conclusion, selective ETA receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated [14].
• CONCLUSIONS: ET-A receptor activation mediates microvascular dysfunction through precapillary blockades and leukocyte-endothelial cell interactions after cold ischemia and reperfusion in the canine small bowel [15].
• Independent of ET-A receptor inhibition, cardiac output during haemorrhage was maintained within the control range [16].
• Endothelin-1 (0.1 ml, 100 nM), which has high affinity for ETA endothelin receptors, when administered to a population of right atrial neurons via their regional arterial blood supply increased neuronal activity (+173%), heart rate (+18%), as well as right (62%) and left ventricular (14%) intramyocardial systolic pressures in 12 dogs so tested [17].

Anatomical context of EDNRA

• CONCLUSIONS: Endogenous ETs increase cardiac pressures and the retention of body fluid through ETA receptors in CHF [3].
• BQ-123, an ETA receptor antagonist, had a high affinity to block the ET-1-induced IP accumulation and tracheal smooth muscle contraction with pKB values of 7.3 and 7.4, respectively [18].
• Dynamic in vivo observation of villus microcirculation during small bowel autotransplantation: effects of endothelin-A receptor inhibition [15].
• PURPOSE: Endothelin-1 (ET-1), a peptide produced by the vascular endothelium, causes profound renal vasoconstriction by binding to ET-A receptors [19].
• We conclude that ischemic myocardium releases transferable vasomotor signals that produce coronary microvascular constriction during the blockade of NO production and the constrictor signal is mediated by ETA receptors [20].

Associations of EDNRA with chemical compounds

• Endothelin-a receptor blockade does not debilitate the cardiovascular and hormonal adaptation to xenon or isoflurane anesthesia in dogs [21].
• To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ETA receptor antagonist BQ-123, and sarafotoxin S6c were performed [8].
• The nonselective ETA/ETB receptor antagonist TAK-044 inhibited the specific binding of ET-1 to the receptors in a concentration-dependent manner [22].
• In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of Nomega-nitro-L-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ETA/ETB receptor blocker [23].
• METHODS: Six dogs were studied in four protocols: (1) control experiments (controls); (2) ETA blockade using ABT-627 (ETAB); (3) AT1 blockade using losartan (AT1B); and (4) combined AT1B and ETAB (AT1B + ETAB) [24].

Regulatory relationships of EDNRA

• The selective endothelin-A-receptor antagonist LU 135.252 inhibits the direct arrhythmogenic action of endothelin-1 [25].

Analytical, diagnostic and therapeutic context of EDNRA

• Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion [2].
• Endothelin-A receptor antagonism improves small bowel graft perfusion and structure after ischemia and reperfusion [26].
• Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA [27].
• INTERVENTIONS: Anesthetized mongrel dogs (ET-receptor antagonist group; n = 6) received a bolus injection of 1 mg of the nonselective ET-A/ET-B-receptor antagonist PD 145065 (Sigma Chemical; St. Louis, MO), and dogs in the control group (n = 6) received saline solution [28].
• We investigated the expression and influence of endothelin-1, and the effects of an ETA and ETB nonselective endothelin receptor antagonist, TAK-044, at reperfusion after cold preservation in a canine lung transplantation model [29].

References