Disease relevance of Bosentan

• Bosentan in essential hypertension [1].
• METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks [2].
• METHODS: We report a case of a 42-year-old patient with PPHTN and alcoholic cirrhosis treated with the mixed endothelin receptor antagonist bosentan [3].
• Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14 [4].
• CONCLUSIONS: In the present study, a mixed ET(A) and ET(B) receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction [5].
• In the present series of patients with well-preserved liver function and severe portopulmonary hypertension, treatment with both inhaled iloprost and bosentan appeared to be safe [6].
• Bosentan administration does not seem to induce clinically relevant gas exchange abnormalities in idiopathic pulmonary fibrosis patients [7].

High impact information on Bosentan

• CONCLUSIONS: An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients [8].
• The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation [8].
• In separate experiments, the stimulatory effect of L-NAME on collagen I gene activation was abolished when animals were treated with bosentan, an endothelin receptor antagonist [9].
• Similarly, bosentan reduced the increased extracellular matrix deposition in afferent arterioles and glomeruli during NO inhibition [9].
• Finally, in vivo administration of bosentan, an endothelin receptor antagonist, totally prevented lethality in Vim-/- mice [10].

Chemical compound and disease context of Bosentan

• Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05) [11].
• METHODS: Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan [12].
• The covariates body weight, gender, age, and the use of epoprostenol had no significant effect on the pharmacokinetics of bosentan [13].
• Although bosentan alone did not affect SAP, the development of Ang II-induced hypertension was entirely prevented by the endothelin antagonist [14].
• Albuminuria in diabetic rats rose further with bosentan but was reduced with valsartan [15].

Biological context of Bosentan

• Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002) [2].
• CONCLUSIONS: Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ETA/ETB endothelin-receptor antagonist bosentan under acute conditions [16].
• Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate [17].
• In rats with secondary biliary cirrhosis, bosentan (30 mg/kg) significantly reduced portal pressure from 14.6 +/- 1.2 to 12.1 +/- 0.6 mm Hg, while portal blood flow and cardiac output increased by 45% and 57%, respectively [18].
• Finally, the mixed endothelin-A (ETA) and ETB receptor antagonist, bosentan, reduced portal pressure in portal hypertensive animals, consistent with its inhibitory effect on stellate cell contraction [19].

Anatomical context of Bosentan

• Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]) [4].
• METHODS AND RESULTS: Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)) [17].
• Chronic bosentan treatment also decreased ET-1 levels (390+/-33 versus 475+/-22 pg/g tissue, P<.05) and density of ET-1 receptors (262+/-24 versus 346+/-31 fmol/mg protein, P<.05) in left ventricular myocardium [5].
• In contrast, reperfusion in the presence of the endothelinA+B receptor antagonist bosentan (2 x 10(-4) mol/L) restored functional sinusoid density and surface PO2 to baseline values, resulted in a small reduction in the number of propidium iodide-positive hepatocytes, and caused similar increases in enzyme release as compared with vehicle [20].
• Improved blood flow was not mediated by nitric oxide production, because bosentan had no effect on cerebrospinal fluid or plasma nitrite/nitrate concentrations at 6, 12, or 18 hours [21].

Associations of Bosentan with other chemical compounds

• BQ-123, an ET-A receptor antagonist, and bosentan, a nonselective ET receptor antagonist, significantly blocked the hypertrophic response of MCs induced by treatment with NMC-conditioned media [22].
• To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) [23].
• After 6 months of follow-up, diabetes and galactose feeding induced basement membrane thickening, which was partially prevented by bosentan treatment [24].
• Oral bosentan, an endothelin A/B receptor antagonist, decreased distal nephron H+ secretion in HiPro rats as a result of reduced Na+/H+ exchange and H+-ATPase activity as shown previously by the authors' laboratory [25].
• Similarly, pretreatment with the endothelin antagonist bosentan abolished the effects of AP6A on both urine flow and Na+ excretion, whereas suramin had no effects on the AP6A-induced increase in urine flow [26].
• At steady state, concomitant rifampin significantly decreased exposure to bosentan by 58% [27].

Gene context of Bosentan

• Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease [16].
• The ETA/ETB receptor antagonist bosentan caused a parallel shift of the concentration-contraction curve to the right at all concentrations of endothelin [28].
• For determination of whether endothelin-1-mediated effects were crucial in the transition from benign to malignant phase hypertension, an oral nonspecific combined endothelin-A and endothelin-B receptor antagonist (bosentan) was given to hypertensive rats susceptible to malignant hypertension [29].
• Furthermore, bosentan, a pharmacological inhibitor of Endothelin-1 signaling caused a loss of I56i-lacZ expression in the most distal aspects of the expression domain, corresponding to the area of Dlx-6 expression previously shown to be under the control of Endothelin-1 [30].
• Acute inhibition of both ETA and ETB receptors with bosentan dramatically prolonged 125I-ET-1 plasma half-life and shifted tissue uptake from lung to liver and kidneys [31].

Analytical, diagnostic and therapeutic context of Bosentan

• 24 patients with chronic heart failure received randomly and double blind two intravenous infusions of either placebo or bosentan (100 mg followed after 60 min by 200 mg) [32].
• CONCLUSIONS--Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evidenced by the significant reduction in mean arterial pressure after oral administration of bosentan [33].
• METHODS AND RESULTS: Three hours after coronary ligation or sham operation, bosentan (100 mg x kg body wt(-1) x d(-1)) or placebo was given by gavage [5].
• Role of endogenous endothelin in the development of graft arteriosclerosis in rat cardiac allografts: antiproliferative effects of bosentan, a nonselective endothelin receptor antagonist [34].
• METHODS AND RESULTS: Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days [34].

References