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Endothelin Receptor Antagonist (endothelin + receptor_antagonist)
Selected AbstractsREVIEW: Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension: An OverviewCARDIOVASCULAR THERAPEUTICS, Issue 5 2010Shahzad G. Raja The last decade has seen major advances in the pharmacotherapy of pulmonary arterial hypertension (PAH). One of these advances has been the discovery of endothelin receptor antagonists (ERAs). ERAs are a class of potent vasodilators and antimitotic substances, which could specifically dilate and remodel pulmonary arterial system, and have been proposed as an alternative to traditional therapies for PAH. Current available evidence suggests that ERAs improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening for patients with PAH. This review attempts to provide an overview of the pharmacology, therapeutic benefits, and safety profile of ERAs in patients with PAH. [source] Carbazolothiophene-2-carboxylic Acid Derivatives as Endothelin Receptor Antagonists.CHEMINFORM, Issue 25 2004Govindarajulu Babu Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Structural Similarity and Its Surprises: Endothelin Receptor Antagonists , Process Research and Development Report.CHEMINFORM, Issue 23 2001R. Jansen Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Spasmogenic action of endothelin-1 on isolated equine pulmonary artery and bronchusEQUINE VETERINARY JOURNAL, Issue 2 2003A. E. M. BENAMOU Summary Reasons for performing study: There is currently little published information about the effects of endothelin-1 (ET-1), a potent endogenous spasmogen of vascular and airway smooth muscle, on pulmonary vasculature and airways or which ET receptor subtypes mediate ET-1-induced vasoconstrictive and bronchoconstrictive action in the horse. Objectives: To investigate the effect of endothelin-1 (ET-1) on smooth muscle from isolated equine pulmonary artery and bronchus. In addition, the roles of ETA and ETB receptors in ET-1 mediated contraction in these tissues were assessed. Methods: The force generation of ring segments from pulmonary arteries or third-generation airways (obtained from horses subjected to euthanasia fororthopaedic reasons) were studied in an organ bath at 37°C in response to exogenous endothelin and selective endothelin A (BQ123) or B receptor (BQ788) antagonists. Results: ET-1 produced concentration-dependent contractions of the equine pulmonary artery and bronchus. The threshold for contraction was 10,10 and 10,9 mol/l ET-1 for pulmonary artery and bronchus, respectively. The maximal contraction induced by the highest ET-1 concentration (10,7 mol/l) was 173 and 194% of the contraction obtained with 100 mmol/l KCl in pulmonary artery and bronchus, respectively. ET-1 potency was 25 times greater in equine pulmonary artery than in equine bronchus (concentration of ET-1 producing 50% of maximal contraction [EC50] = 5.6 10,9 mol/l and 2.2 10,8 mol/l, respectively). In pulmonary artery, ET-1 induced contractions were significantly inhibited by the ETA receptor antagonist BQ123 (1 ,mol/l; dose-response curve to ET-1 was shifted to the right by 5.4-fold), but not by the ETB antagonist BQ788. In bronchus, dose-responses curves to ET-1 were shifted to the right by BQ123 (1 ,mol/l; 2.5-fold), but not by BQ788 (1 ,mol/l). In the presence of both antagonists, the dose-response curve to ET-1 was shifted to the right by 4.5-fold. Conclusions: These functional studies demonstrate that ET-1 is a potent spasmogen of equine third generation pulmonary artery and bronchus, and that contractions are mediated via ETA receptors in the former and both ETA and ETB receptors in the latter. Potential clinical relevance: Endothelin receptor antagonists may have potential for treating equine pulmonary hypertension or bronchoconstriction. [source] Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome,,HEPATOLOGY, Issue 1 2008Florence Wong Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 ± 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at ,4 days because of concerns about worsening renal function (serum creatinine increased from 180 ± 21 to 222 ± 58 ,mol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 ± 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 ± 0.3 pg/mL at the baseline to 19.1 ± 7.3 pg/mL (P < 0.05). Conclusion: An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients. (HEPATOLOGY 2007.) [source] Current treatment strategies for pulmonary arterial hypertensionJOURNAL OF INTERNAL MEDICINE, Issue 3 2005S. H. LEE Abstract., Lee SH, Rubin LJ (University of California, San Diego, La Jolla, CA, USA). Current treatment strategies for pulmonary arterial hypertension (Review). J Intern Med 2005; 258: 199,215. Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, exercise tolerance, functional class, haemodynamics, echocardiographic parameters and quality of life measures. Since the introduction of continuous intravenous prostacyclin, the treatment armamentarium of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Selective endothelin-A receptor antagonists have shown promise in clinical trials and are likely to be added to the list of options. As the number of medications available for PAH continues to increase, treatment decisions regarding first-line therapy, combination treatments, and add-on strategies are becoming more complex. This article reviews the current treatments strategies for PAH and provides guidelines for its management. [source] Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis,ARTHRITIS & RHEUMATISM, Issue 7 2010J. R. Seibold Objective Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). Method Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150,500 meters or a 6-minute walk distance of ,500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. Results Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). Conclusion No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc. [source] Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: Impact of interstitial lung diseaseARTHRITIS & RHEUMATISM, Issue 2 2009Stephen C. Mathai Objective Pulmonary hypertension (PH) is an important cause of mortality in systemic sclerosis (SSc), where it can be isolated (pulmonary arterial hypertension [PAH]) or associated with interstitial lung disease (ILD). This study was undertaken to characterize determinants of survival among SSc patients with either type of PH who received PAH-specific therapy. Methods Consecutive SSc patients with PAH or ILD-associated PH confirmed by right heart catheterization were included in the study. Kaplan-Meier and Cox proportional hazards models were used to compare survival between SSc patients with PAH and those with ILD-associated PH and to identify predictors of survival. Results Fifty-nine patients (39 with PAH and 20 with ILD-associated PH) were identified. The majority (15 of 20 with ILD-associated PH and 27 of 39 with PAH) received an endothelin receptor antagonist as initial therapy. Median followup time was 4.4 years (range 2.7,7.4 years). Survival was significantly worse in SSc patients with ILD-associated PH than in those with PAH (1-, 2-, and 3-year survival rates 82%, 46%, and 39% versus 87%, 79%, and 64%, respectively; P < 0.01 by log rank test). In a multivariable analysis, ILD-associated PH was associated with a 5-fold increase in risk of death compared with PAH. Pulmonary vascular resistance index was also an independent predictor of mortality in the overall cohort (hazard ratio 1.05, P < 0.01) and was a significant univariable risk factor in each group separately. Type of initial PAH therapy and the use of warfarin were not related to survival. Conclusion Survival in SSc complicated by PH remains poor despite currently available treatment options. While therapy may be associated with improved survival in PAH compared with historical controls, the prognosis for patients with ILD-associated PH is particularly grim. Early diagnosis and treatment may improve outcomes since worsening hemodynamic factors were associated with reduced survival. [source] Role of Humoral Mediators in, and Influence of a Liposomal Formulation on, Acute Amphotericin B NephrotoxicityBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2001Ramzi Sabra Both direct effects of amphotericin B on contractile vascular cells, and indirect effects, due to humoural mediators, have been proposed. This study examines the role of nitric oxide, endothelin and angiotensin II in the acute nephrotoxic effects of amphotericin B in rats, and compares the antifungal and nephrotoxic effects of liposomal amphotericin B and amphotericin B-deoxycholate. Anaesthetized rats were given infusions of amphotericin B-deoxycholate in the presence or absence of N-nitro-L-arginine, PD 145065, a non-specific endothelin receptor antagonist, and L-158809, an angiotensin II type I receptor antagonist, or increasing doses of liposomal amphotericin B. Amphotericin B-deoxycholate (0.03 mg/kg/min intravenously) caused a significant 44% reduction in glomerular filtration rate and 65% maximal fall in renal blood flow. N-Nitro-L-arginine-treated rats had a lower renal blood flow and glomerular filtration rate at baseline, but sustained similar reduction of 53% and 75% in these parameters, respectively. PD145065 and L-158809 did not modify these effects either. Increasing doses of liposomal amphotericin B (from 0.01 up to 0.50 mg/kg/min.) induced no change in either glomerular filtration rate or renal blood flow. In vitro susceptibility tests revealed similar potency for liposomal amphotericin B and amphotericin B-deoxycholate in their fungistatic effects and slightly higher potency for amphotericin B-deoxycholate in their fungicidal effect. These results suggest that endogenous endothelin, angiotensin II or nitric oxide systems are not involved in the nephrotoxic effects of amphotericin B. The liposomal amphotericin B results suggest that amphotericin B nephrotoxicity is due to a direct interaction of amphotericin B with renal cells that is prevented by its encapsulation in liposomes. [source] Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance,associated protein 2BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2007Yuji Mano Abstract The bile salt export pump (BSEP/Bsep/ABCB11) and multidrug resistance-associated protein 2 (MRP2/Mrp2/ABCC2) are involved in bile acid-dependent and -independent bile secretion, respectively. It has been reported that bosentan, an endothelin receptor antagonist, inhibits Bsep, which may lead to cholestatic liver injury due to the intracellular accumulation of bile salts, while increasing bile salt-independent bile flow. Thus, in this study, the effects of bosentan on BSEP/Bsep and MRP2/Mrp2 were evaluated using membrane vesicles derived from Spodoptera frugiperda (Sf) 9 cells, which express these transporters. The adenosine 5,-triphosphate (ATP)-dependent uptake of 3H-taurocholic acid into membrane vesicles for BSEP/Bsep was inhibited by bosentan, and its IC50 values were 76.8 and 101 µM for BSEP and Bsep, respectively. In contrast, bosentan stimulated the MRP2/Mrp2-mediated ATP-dependent vesicular transport of 3H-estradiol 17,-glucuronide by shifting the sigmoidal dependence of transport rate on substrate concentration to a more hyperbolic one. Collectively, these results suggest that bosentan inhibits BSEP in humans with a similar potency to rats, and that increased bile salt-independent flow in rats by bosentan is at least partly attributable to the activation of Mrp2. Copyright © 2006 John Wiley & Sons, Ltd. [source] Evaluation of choroidal blood flow after treatment of retinal diseasesACTA OPHTHALMOLOGICA, Issue 2009C CHIQUET Purpose this review aims to summarize studies which assessed the effect of treatment on choroidal blood flow. Methods this presentation will focus on studies using the laser Doppler flowmeter for the analysis of choroidal blood flow parameters (velocity, volume and flow) before and after treatment. Therapies have been assessed in different ocular disease, such as age-related macular degeneration (laser photocoagulation therapy, photodynamic therapy, transpupillary thermotherapy, sildenafil citrate, niacin, pentoxifylline), diabetes mellitus (panretinal photocoagulation, intravenous C-peptide infusion), retinal vein occlusions (isovolemic hemodilution), macular edema (diclofenac), inflammation (corticosteroid), retinal detachment (surgery) or glaucoma (nimodipine, endothelin receptor antagonist, bimatoprost, timolol, trabeculectomy). Results this paper will give insight to the effects of laser treatment (laser photocoagulation, photodynamic therapy), surgery (scleral buckling, trabeculectomy, ocular anesthesia) or systemic drugs on the choroidal blood flow. Methodological considerations will be analyzed, such as the calculation of the sensitivity of the experiments, the comparisons of different groups with or without randomization. Conclusion laser Doppler flowmetry is a useful and a non invasive technique to study the effect of treatment on choroidal blood flow. In ocular disease, investigators should be aware of the tissue scattering changes associated with a retinal or choroidal disease and the necessity of a controlled foveal fixation. [source] The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009N. J. Davie Abstract Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ETA or nonselective ETA/ETB blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease. [source] Dual ETA/ETB vs. selective ETA endothelin receptor antagonism in patients with pulmonary hypertensionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2006C. F. Opitz Abstract Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ETA/ETB and selective ETA receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ETA receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ETB receptors has been more complex. It has been shown that there is a subpopulation of ETB receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ETB receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ETA receptor antagonism. [source] Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome,,HEPATOLOGY, Issue 1 2008Florence Wong Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 ± 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at ,4 days because of concerns about worsening renal function (serum creatinine increased from 180 ± 21 to 222 ± 58 ,mol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 ± 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 ± 0.3 pg/mL at the baseline to 19.1 ± 7.3 pg/mL (P < 0.05). Conclusion: An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients. (HEPATOLOGY 2007.) [source] The role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the ratHEPATOLOGY, Issue 6 2004Yiqun Ling Endothelin-1 (ET-1) stimulation of endothelial nitric oxide synthase (eNOS) via pulmonary endothelial endothelin B (ETB) receptors and pulmonary intravascular macrophage accumulation with expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) are implicated in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Our aim was to evaluate the role of ET-1 in the development of experimental HPS. The time course of molecular and physiological changes of HPS and the effects of selective endothelin receptor antagonists in vivo were assessed after CBDL. Effects of ET-1 on intralobar pulmonary vascular segment reactivity and on eNOS expression and activity in rat pulmonary microvascular endothelial cells (RPMVECs) were also evaluated. Hepatic and plasma ET-1 levels increased 1 week after CBDL in association with a subsequent increase in pulmonary microvascular eNOS and ETB receptor levels and the onset of HPS. Selective ETB receptor inhibition in vivo significantly decreased pulmonary eNOS and ETB receptor levels and ameliorated HPS. CBDL pulmonary artery segments had markedly increased ETB receptor mediated, nitric oxide dependent vasodilatory responses to ET-1 compared with controls and ET-1 triggered an ETB receptor dependent stimulation of eNOS in RPMVECs. Pulmonary intravascular macrophages also accumulated after CBDL and expressed HO-1 and iNOS at 3 weeks. Selective ETB receptor blockade also decreased macrophage accumulation and iNOS production. In conclusion, ET-1 plays a central role in modulating pulmonary micovascular tone in experimental HPS. (HEPATOLOGY 2004;39:1593,1602.) [source] Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis,ARTHRITIS & RHEUMATISM, Issue 7 2010J. R. Seibold Objective Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). Method Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150,500 meters or a 6-minute walk distance of ,500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. Results Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). Conclusion No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc. [source] Repeatability of local forearm vasoconstriction to endothelin-1 measured by venous occlusion plethysmographyBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2002Fiona E. Strachan Aims ,We ,investigated ,the ,repeatability ,of ,the ,forearm ,blood ,flow ,response ,to intra-arterial infusion of endothelin-1 (ET-1), assessed by venous occlusion plethysmography. Methods In eight healthy men (aged 18,50 years), on four separate occasions, ET-1 (2.5 or 10 pmol min,1) was infused for 120 min via a 27 SWG cannula sited in the brachial artery of the nondominant arm. Each dose level was administered twice on consecutive visits. The dose order was randomized. Results are expressed as percentage change from baseline at 120 min (mean ± s.e. mean). Results ET-1 caused significant vasoconstriction (P < 0.0001 anova) at both doses (38 ± 3%, 2.5 pmol min,1 and 62 ± 3%, 10 pmol min,1; mean visit 1 and 2). There was no difference in the response to either dose on repeated challenge. Responses appeared to be less variable when expressed as percentage change in the ratio of blood flow (infused:noninfused) in both arms than as percentage change in blood flow in the infused arm alone, as indicated by repeatability coefficients (15% vs 21%, 2.5 pmol min,1 and 11% vs 13%, 10 pmol min,1; ratio vs infused arm alone). Conclusions We have shown dose-dependent vasoconstriction in the forearm vascular bed to intra-arterial infusion of ET-1 and that this response is less variable when expressed as percentage change in the ratio of forearm blood flow than percentage change in the infused arm. These data should also provide useful information to determine the power of early clinical pharmacology studies investigating the activity of endothelin receptor antagonists. [source] REVIEW: Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension: An OverviewCARDIOVASCULAR THERAPEUTICS, Issue 5 2010Shahzad G. Raja The last decade has seen major advances in the pharmacotherapy of pulmonary arterial hypertension (PAH). One of these advances has been the discovery of endothelin receptor antagonists (ERAs). ERAs are a class of potent vasodilators and antimitotic substances, which could specifically dilate and remodel pulmonary arterial system, and have been proposed as an alternative to traditional therapies for PAH. Current available evidence suggests that ERAs improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening for patients with PAH. This review attempts to provide an overview of the pharmacology, therapeutic benefits, and safety profile of ERAs in patients with PAH. [source] | ||||||||||||||||||||||