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Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention S

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Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2017/02/21/jpet.116.234930.DC1 1521-0103/361/2/322–333$25.00 https://doi.org/10.1124/jpet.116.234930 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 361:322–333, May 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Endothelin ETA Receptor Blockade, by Activating ETB Receptors, Increases Vascular Permeability and Induces Exaggerated Fluid Retention s Magali Vercauteren, Frederic Trensz, Anne Pasquali, Christophe Cattaneo, Daniel S. Strasser, Patrick Hess, Marc Iglarz, and Martine Clozel Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland Received May 9, 2016; accepted February 17, 2017 Downloaded from ABSTRACT Endothelin (ET) receptor antagonists have been associated with ETA-selective antagonism increased vascular permeability via ETB fluid retention. It has been suggested that, of the two endothelin receptor overstimulation. Acutely, ETA-selective but not dual receptor subtypes, ETB receptors should not be blocked, because antagonism activated sympathetic activity and increased plasma of their involvement in natriuresis and diuresis. Surprisingly, arginine vasopressin and aldosterone concentrations. The hem- clinical data suggest that ETA-selective antagonists pose a greater atocrit/hemoglobin decrease induced by ETA-selective antago- jpet.aspetjournals.org risk of fluid overload than dual antagonists. The purpose of this nism was reduced in Brattleboro rats and in Wistar rats treated study was to evaluate the contribution of each endothelin receptor with an arginine vasopressin receptor antagonist. Finally, the to fluid retention and vascular permeability in rats. Sitaxentan and decrease in hematocrit/hemoglobin was larger in the venous than ambrisentan as ETA-selective antagonists and bosentan and in the arterial side, suggesting fluid redistribution. In conclusion, by macitentan as dual antagonists were used as representatives of activating ETB receptors, endothelin receptor antagonists (partic- each class, respectively. ETA-selective antagonism caused a ularly ETA-selective antagonists) favor edema formation by dose-dependent hematocrit/hemoglobin decrease that was pre- causing: 1) fluid retention resulting from arginine vasopressin at ASPET Journals on September 24, 2021 vented by ETB-selective receptor antagonism. ETA-selective and aldosterone activation secondary to vasodilation, and 2) antagonism led to a significant blood pressure reduction, plasma increased vascular permeability. Plasma volume redistribution volume expansion, and a greater increase in vascular permeability may explain the clinical observation of a hematocrit/hemoglobin than dual antagonism. Isolated vessel experiments showed that decrease even in the absence of signs of fluid retention. Introduction molecules (Battistini et al., 2006). In fact, drugs selective for the ETA receptor seem to cause a higher incidence and severity Endothelin (ET)-1 may play a role in the pathophysiology of of fluid overload and edema rate than dual ERAs. In clinical a number of diseases (Lerman et al., 1991; Lüscher et al., studies, the ETA-selective antagonists darusentan in resistant 1993). Efforts to oppose its deleterious effects have led to the hypertension (Black et al., 2007), zibotentan and atrasentan discovery of selective and dual antagonists of one or both of its in prostate cancer (Carducci et al., 2007; James et al., 2009), receptors, ETA and ETB. Soon after the first clinical studies avosentan in diabetic nephropathy (Mann et al., 2010), and were initiated, it became clear that endothelin receptor ambrisentan (Galiè et al., 2008) and sitaxentan (Barst et al., antagonists (ERAs) can cause decreases in hematocrit (Hct)/ 2004) in pulmonary arterial hypertension (PAH) induced hemoglobin (Hb) and signs of fluid retention. The decrease in edema or fluid overload in 12%, 38%, 28%, 15%, 18%, and Hb was clearly secondary to an increase in plasma volume, 8% of patients (placebo-corrected), respectively, and some- since there were no signs of red blood cell changes, bone times increased risk of heart failure and death (Lüscher et al., marrow depression, hemolysis, or bleeding. Signs of fluid 2002; Carducci et al., 2007; Mann et al., 2010). In the retention are seen with virtually all ERAs and may be severe AMBITION trial in patients with PAH, the combination of depending on the clinical context, the dose, and the degree of ET -selective ambrisentan with phosphodiesterase-5 inhibi- selectivity between ET and ET receptors of the different A A B tor tadalafil led to a higher incidence of edema (45% in combination) than with tadalafil alone (28%) (Galiè et al., 2015). In contrast, among dual ERAs, bosentan induced fluid This research was supported by Actelion Pharmaceuticals Ltd. https://doi.org/10.1124/jpet.116.234930. retention in only 1.7% of patients with PAH (placebo- s This article has supplemental material available at jpet.aspetjournals.org. corrected) (Rubin et al., 2002). The rate was higher in patients ABBREVIATIONS: AVP, arginine vasopressin; BQ-123, 2-[(3R,6R,9S,12R,15S)-6-(1H-indol-3-ylmethyl)-9-(2-methylpropyl)-2,5,8,11,14-pentaoxo- 12-propan-2-yl-1,4,7,10,13-pentazabicyclo[13.3.0]octadecan-3-yl]acetic acid; BQ-788, N-[(cis-2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-L- leucyl-1-(methoxycarbonyl)-D-tryptophyl-D-norleucine sodium salt; ERA, endothelin receptor antagonist; ET, endothelin; FF, glomerular filtration fraction; GFR, glomerular filtration rate; Hb, hemoglobin; Hct, hematocrit; NO, nitric oxide; PAH, pulmonary arterial hypertension; RPF, renal plasma flow; SU5416, 1,3-dihydro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-2H-indol-2-one; VEGF, vascular endothelial growth factor. 322 Exaggerated Fluid Retention with ETA-Selective Antagonists 323 with chronic heart failure (Kaluski et al., 2008). Macitentan, 5 ml/kg body weight. ERAs were synthesized by Actelion Pharmaceu- alone or in combination with phosphodiesterase-5 inhibitors, ticals Ltd. (Allschwil, Switzerland). caused no increase in edema rate compared with placebo in the Effect of Acute Administration of ERAs on Fluid Retention. phase III SERAPHIN trial in patients with PAH (Pulido et al., Because the decrease in Hct and Hb observed with ERAs appears to be 2013). secondary to an increase in plasma volume in humans, the change in these two variables was used as a marker of fluid retention. Dose- A higher risk of edema with ET -selective receptor antag- A response curves of sitaxentan (n 5 8 per dose) and bosentan (n 5 7 per onists seems in contradiction with publications showing that dose), with doses ranging from 10 to 300 mg/kg for both drugs, were ETB-selective receptor antagonists or ETB knockout cause performed; the dose inducing the maximal decrease in Hct and Hb was fluid retention and edema (Gariepy et al., 2000; Ge et al., selected for all acute experiments. Animals were assigned to groups in 2006). It is intriguing that selective blockade of either ETB or a stratified random manner according to their body weight and ETA receptor inhibits water and sodium excretion (Girchev baseline Hct. A single oral dose of each drug or vehicle (gelatin) was et al., 1998; Nakano and Pollock, 2009; Boesen and Pollock, administered by gavage; at 24 hours, sublingual blood was sampled under isoflurane-induced anesthesia (Attane; Minrad Inc., Buffalo, 2010). Interestingly, the fluid retention caused by ETA-or NY). Hct, Hb, and erythrocyte indices were measured using a ETB-selective inhibition could be abolished by the addition of an antagonist of the other (ET or ET ) receptor, respectively hematology analyzer (Coulter AcT; Beckman Coulter, Nyon, Switzer- B A land; and Advia 2120i; Siemens Healthcare Diagnostics GmbH, (Elmarakby et al., 2004; Ohkita et al., 2005; Kitada et al., Zurich, Switzerland). The highest effective doses of sitaxentan (100 or 2009; Boesen and Pollock, 2010), showing that it was not the 300 mg/kg) and bosentan (300 mg/kg) were selected for further studies. Downloaded from blockade of one receptor, but rather the overactivation of the The selected dose of bosentan was demonstrated to block both ETA and other, that caused the phenotype of water or salt retention. It ETB receptors in vivo (Clozel et al., 1994). thus seems that in both cases, selective blockade of one Role of ETB Receptors in the Mechanism of Fluid Re- receptor subtype causes an imbalance and allows ET-1 (an tention. Prior to the experiment and under isoflurane-induced ETA/ETB agonist) to overactivate the nonantagonized recep- narcosis, the left jugular vein of rats was cannulated with a NaCl- tor. This asymmetry of blockade can be assimilated to the heparin filled catheter. The catheter was then connected to a tether phenomenon of cross-talk, by which a selective antagonism or and harness attached to a swivel system equipment (Instech Labora- jpet.aspetjournals.org selective receptor knockout can be inefficient to block the tories Inc., Plymouth, MA). After a 2-day recovery period, conscious rats were infused either with vehicle (NaCl, 0.9%) or ET -selective action of the agonist because of the persistent route of B receptor antagonist BQ-788 (N-[(cis-2,6-dimethyl-1-piperidinyl)- signaling by the unblocked receptor. In tissues expressing carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-D- both receptors, many examples of cross-talk have been reported norleucine sodium salt; Tocris Bioscience, Abingdon, UK) for 6 hours, with endothelin receptors (Clozel and Gray, 1995; Pollock, starting at the time of vehicle or sitaxentan administration (300 2005; Sauvageau et al., 2007) probably due to ETA/ETB mg/kg, n 5 8 per group); 24 hours later, hematologic variables were receptor heterodimerization (Harada et al., 2002; Gregan measured. The dose of 1 mg/kg BQ-788 per hour was selected, as it at ASPET Journals on September 24, 2021 et al., 2004). We hypothesized that this asymmetry of blockade completely inhibited the ETB-dependent blood pressure decrease in between both receptors could contribute to the higher rates of response to ET-1 in conscious rats (Okada and Nishikibe, 2002).
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