Effects Of Endothelin Receptor Blockade Research Articles

Anti-inflammatory effects of endothelin receptor blockade in left atrial tissue of spontaneously hypertensive rats.

ObjectiveIn spontaneously hypertensive rats (SHR) atrial remodeling has been shown to involve increase in endothelin (ET) signaling. Furthermore, inflammatory processes may further contribute to tissue remodeling. The aimed of this study was to investigate whether an endothelin receptor antagonist, macitentan, could reduce left atrial (LA) remodeling in arterial hypertension.MethodsMolecular characterization of atria was performed in SHR at the age of 8 months and their age-matched normotensive control rats (WKY). SHR were treated with macitentan and, for comparison with a blood pressure reducing drug, with doxazosin. After two months of treatment, molecules involved in endocardial inflammation and atrial calcium handling were assessed. The molecular changes provoked by rapid-pacing (RAP) were analyzed in atrial tissue slices.ResultsDoxazosin reduced the systolic blood pressure compared with the untreated SHR (159 ± 26 vs. 176 ± 17; P < 0.05) or macitentan (vs. 189 ± 21; P < 0.05). Macitentan lowered the increased levels of atrial ET-1 and abrogated the pacing-induced upregulation of preproET-1-mRNA in atrial slices from SHR. Macitentan reduced the elevated levels of atrial 8-isoprostanes, the increased expression of pro-inflammatory ICAM-1 and IL-8, the phosphorylation of MAP kinases, ERK and p38, the phosphorylation of NF-κB and the expression of VCAM-mRNA. Major Ca2+-regulating proteins and markers of hypertrophy and fibrosis, however, were not affected. Doxazosin elicited similar changes, except for the alterations in ET-1 levels, NF-κB phosphorylation and VCAM-mRNA.ConclusionMacitentan reversed pro-inflammatory remodeling in hypertensive atria in a blood pressure-independent manner, which might prevent endocardial dysfunction and thereby, thrombogenesis in arterial hypertension.

Anti-Inflammatory Effects of Endothelin Receptor Blockade in Left Atrial Tissue of Spontaneously Hypertensive Rats

Anti-Inflammatory Effects of Endothelin Receptor Blockade in Left Atrial Tissue of Spontaneously Hypertensive Rats

Effects of endothelin receptor blockade and COX inhibition on intestinal I/R injury in a rat model: Experimental research.

Intestinal ischemia is a highly morbid and mortal condition with no specific treatment. The present study aimed to investigate the effects of cyclooxygenase (COX) inhibition synchronized with nitric oxide (NO) release and endothelin (ET) receptor blockade on oxidative stress, inflammation, vasoconstriction, and bacterial translocation which occur during ischemia-reperfusion (I/R) injury in in-vivo rat intestinal I/R model. 36 male Wistar rats were randomly divided into six groups (n=6). Superior mesenteric artery blood flow (SMABF) was recorded; SMA was occluded for 30min; SMABF was re-recorded at the beginning of the reperfusion phase. Rats were sacrificed after the reperfusion period of 60min. Blood and tissue samples were obtained. Acetylsalicylic acid (ASA), NO-ASA, flurbiprofen (FLUR), and Tezosentan (TS) were administered 15min after ischemia. Histopathological examination, bacterial translocation, and biochemical analysis were performed in plasma and tissue samples. SMABF difference, mean Chiu's score and bacterial translocation were increased in the I/R group and decreased in the treatment groups. Plasma LDH, transaminases, intestinal fatty acid-binding protein (I-FABP), TNF-α, ICAM-1, interferon-gamma (IFN-Ɣ) and proinflammatory cytokine panel; tissue lipid peroxidation, MPO, xanthine oxidase (XO), NO, NF-kB levels and the expression of TNF-α were significantly elevated in the I/R group and markedly decreased in the treatment groups. The tissue antioxidant status was decreased in the I/R group and increased in the treatment groups. It is suggested that NO-ASA, TS, and FLUR can be introduced as promising therapeutics to improve intestinal I/R injury. 2018-29-05 (Animal Experimentations Ethics Committee, Hacettepe University).

Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model

This study aimed to investigate the role of endothelin-1 (ET-1), originally known as the potent vasoconstrictor, and its receptors in chondrocyte senescence and osteoarthritis (OA) development. Temporal changes of ET-1 and its receptors with OA development were characterized in a posttraumatic OA (PTOA) mouse model at time zero, 1-month and 4-month after surgical induction via destabilization of medial meniscus (DMM). A transgenic ET-1 overexpression (TET-1) mouse model was deployed to assess the impact of upregulated ET-1 on chondrocyte senescence and cartilage degradation. Effects of endothelin receptor blockade on chondrocyte senescence and OA development were further examined both in vitro and in vivo. Local expression of ET-1 in subchondral bone and synovium upregulated after DMM with an increase of plasma ET-1 level from 3.18±0.21pg/ml at time zero to 6.47±0.34pg/ml at 4-month post-surgery. Meanwhile, endothelin type B receptor (ETBR) (53.31±2.42% to 83.8±2.65%) and p16INK4a (10.91±1.07% to 28.2±1.0%) positve chondrocytes accumulated in articular cartilage since 1-month prior to cartilage loss at 4-month post-surgery. Overexpressed ET-1 promoted p16INK4a-positive senescent chondrocytes accumulation and cartilage degradation in TET-1 mice. Selective blockade of ETBR, but not ETAR, lowered the expression of p16INK4a in ET-1 or H2O2-induced chondrocyte senescence model, and mitigated the severity of murine PTOA. Intriguingly, reactive oxygen species (ROS) scavenger, Vitamin C, could rescue ET-1-induced chondrocyte senescence in vitro associated with restoration of mitochondrial dynamics. ET-1 could induce chondrocytes senescence and cartilage damages via ETBR in PTOA.

Endothelin-1 and antiangiogenesis.

Antiangiogenesis, targeting vascular endothelial growth factor (VEGF), has become a well-established treatment for patients with cancer. This treatment is associated with nitric oxide (NO) suppression and a dose-dependent activation of the endothelin system, resulting in preeclampsia-like features, particularly hypertension and renal injury. Studies in endothelium NO synthase (eNOS)-deficient mice and pharmacological treatment with endothelin receptor blockers and sildenafil indicate that an activated endothelin system, rather than NO suppression, mediates the side effects of angiogenesis inhibitors. Activation of the endothelin system is also observed in preeclamptic women, where it is related to the increased placental production of sFlt-1, the soluble form of the VEGF receptor-1. This receptor binds VEGF, thereby having the same consequences as antiangiogenic treatment with VEGF inhibitors. The side effects of antiangiogenic treatment in patients with cancer may be dose limiting, thereby impairing its therapeutic potential. In addition, because endothelin exerts proangiogenic effects, investigation of the effects of endothelin receptor blockade in patients with cancer treated with angiogenesis inhibitors is warranted.

Endothelin receptor blockade ameliorates vascular fragility in endothelial cell-specific Fli-1-knockout mice by increasing Fli-1 DNA binding ability.

It is generally accepted that blockade of endothelin receptors has potentially beneficial effects on vasculopathy associated with systemic sclerosis (SSc). The aim of this study was to clarify the molecular mechanism underlying these effects using endothelial cell-specific Fli-1-knockout (Fli-1 ECKO) mice, an animal model of SSc vasculopathy. Levels of messenger RNA for target genes and the expression and phosphorylation levels of target proteins were determined in human and murine dermal microvascular endothelial cells by real-time quantitative reverse transcription-polymerase chain reaction and immunoblotting, respectively. The binding of Fli-1 to the target gene promoters was evaluated using chromatin immunoprecipitation. Expression levels of Fli-1 and α-smooth muscle actin in murine skin were evaluated using immunohistochemistry. Vascular structure and permeability were evaluated in mice injected with fluorescein isothiocyanate-dextran and Evans blue dye, respectively. In human dermal microvascular endothelial cells, endothelin 1 induced phosphorylation of Fli-1 at Thr(312) through the sequential activation of c-Abl and protein kinase Cδ, leading to a decrease in Fli-1 protein levels as well as a decrease in binding of Fli-1 to the target gene promoters, whereas bosentan treatment reversed those effects. In Fli-1 ECKO mice, 4 weeks of treatment with bosentan increased endothelial Fli-1 expression, resulting in vascular stabilization and the restoration of impaired leaky vessels. The vascular fragility of Fli-1 ECKO mice was improved by bosentan through the normalization of Fli-1 protein levels and activity in endothelial cells, which may explain, in part, the mechanism underlying the beneficial effects of endothelin receptor blockade on SSc vasculopathy.

The effect of endothelin-receptor blockade on atrial electrophysiology in obesity

The effect of endothelin-receptor blockade on atrial electrophysiology in obesity

Impact of endothelin blockade on acute exercise-induced changes in blood flow and endothelial function in type 2 diabetes mellitus.

Positive vascular effects of exercise training are mediated by acute increases in blood flow. Type2 diabetes patients show attenuated exercise-induced increases in blood flow, possibly mediated by the endothelin pathway, preventing an optimal stimulus for vascular adaptation. We examined the impact of endothelin receptor blockade (bosentan) on exercise-induced blood flow in the brachial artery and on pre- and postexercise endothelial function in type2 diabetes patients (n=9, 60±7years old) and control subjects (n=10, 60±5years old). Subjects reported twice to the laboratory to perform hand-grip exercise in the presence of endothelin receptor blockade or placebo. We examined brachial artery endothelial function (via flow-mediated dilatation) before and after exercise, as well as blood flow during exercise. Endothelin receptor blockade resulted in a larger increase in blood flow during exercise in type2 diabetes patients (P=0.046), but not in control subjects (P=0.309). Exercise increased shear rate across the exercise protocol, unaffected by endothelin receptor blockade. Exercise did not alter brachial artery diameter in either group, but endothelin receptor blockade resulted in a larger brachial artery diameter in type2 diabetes patients (P=0.033). Exercise significantly increased brachial artery flow-mediated dilatation in both groups, unaffected by endothelin receptor blockade. Endothelin receptor blockade increased exercise-induced brachial artery blood flow in type2 diabetes patients, but not in control subjects. Despite this effect of endothelin receptor blockade on blood flow, we found no impact on baseline or post-exercise endothelial function in type2 diabetes patients or control subjects, possibly related to normalization of the shear stimulus during exercise. The successful increase in blood flow during exercise in type2 diabetes patients through endothelin receptor blockade may have beneficial effects in repeated exercise training.

Impairment of exercise hyperaemia in familial hypercholesterolaemia: complex interplay of vasodilators vs. vasoconstrictors.

Impairment of exercise hyperaemia in familial hypercholesterolaemia: complex interplay of vasodilators vs. vasoconstrictors.

Endothelin in Coronary Artery Disease and Myocardial Infarction

Coronary artery disease remains a major cause of morbidity and mortality. Experimental and clinical data have indicated an important role of endothelin-1 at various subclinical and clinical stages of the disease. Endothelin-1 causes endothelial dysfunction and inflammation and may contribute to atherosclerotic plaque formation. During acute myocardial infarction, endothelin-1 enhances myocardial necrosis and arrhythmogenesis, but seems to exert a favorable effect on subsequent infarct healing and early ventricular remodeling. In the chronic postinfarction phase, endothelin-1 increases left ventricular afterload and participates in the myocardial fibrotic process. The progressive understanding of these actions has stimulated a large number of experimental and clinical studies examining the various effects of endothelin receptor blockade in coronary artery disease and chronic heart failure. However, this research has yielded largely contradictory results that have stirred scientific debates and controversies. This review summarizes the current state-of-the-art on this exciting topic, focusing on potential clinical ramifications.

Endothelin Receptor Blocker Medication during Mechanical Circulatory Support Does Not Influence Myocardial Fibrosis in Ventricular Assist Device Patients

Purpose Endothelins are potent vasoconstrictors mediating their activity through endothelin receptor-A (ETA) and -B (ETB). Endothelin receptor blockade (ERB) is used as an adjuvant medication for the treatment of pulmonary hypertension during ventricular assist device (VAD) support. Currently, the antifibrotic effect of ERB on myocardial collagen synthesis during VAD-support has not been investigated. The aim of this study was to investigate if inhibition or reduction of fibrosis by this adjuvant therapy plays a role in myocardial recovery during VAD support. Methods and Materials 103 paired transmural myocardial samples collected at VAD-implantation (VAD-IP) and later at the time of heart transplantation (VAD-HTx) of heart failure patients were analysed for the 4-hydroxy-proline (4OH-P) content and Collagen IA1-, IIIA1- and TGF-beta1-mRNA content using amino acid analysis or real time RT-PCR, respectively. 30 rejected donor hearts were used as a control. About 20% of our patient cohort received Bosentan medication during VAD-support for the treatment of pulmonary hypertension. Results The 4OH-P-content and the ratio of 4OH-P at VAD implantation of Bosentan treated patients was not different from patients without ERB-medication. Similar results were seen at the time of transplantation. Furthermore, mRNAs of Collagen IA1, Col IIIA1 and TGF-beta1-mRNA were not different between samples from patients with VAD-Implantation or undergoing a heart transplantation. Conclusions Adjuvante medication with Endothelin receptor antagonists during VAD-support does not seem to have a significant effect on the progression or reduction of myocardial fibrosis. ERB should not be applied for antifibrotic treament of the failing unloaded heart.

Effect of endothelin receptor blockade on monocrotaline-induced pulmonary hypertension in rats

Purpose : To examine the effect of bosentan, a dual endothelin receptor (ER) antagonist, on the development of monocrotaline (MCT)-induced pulmonary hypertension in rats by especially focusing on the pulmonary vascular morphology changes. Methods : Sprague-Dawley rats were treated as follows: controls received a subcutaneous saline injection, MCT-treated rats received a subcutaneous MCT injection, and bosentan-treated rats received a MCT injection followed by treatment with bosentan (20 mg/kg/day). To assess the effects of ER blockade on the time course, the animals were exsanguinated, and their hearts and lungs were dissected after 7, 14, or 28 days. Results : The mean body weights of the MCT- and bosentan-treated rats were significantly lower than that of the control rats on days 7, 14, and 28. Bosentan administration significantly inhibited the progression of right ventricular hypertrophy on day 28 (right ventricle/[left ventricle＋septum]: 0.710.10 in MCT-treated rats vs. 0.490.09 in bosentan-treated rats; P＜0.05). Quantitative analysis of peripheral pulmonary arteries revealed that the increase in medial wall thickness after MCT injection was significantly attenuated in the bosentan-treated rats on day 28 (49.9610.06% in MCT-treated rats vs. 47.0910.48% in bosentan-treated rats; P＜0.05). In addition, the increase in the number of intra-acinar muscular arteries after MCT injection was reduced by bosentan on days 14 and 28. Conclusion : Bosentan administration in intermediate doses exerts inhibitory effects on lung vascular hypertrophy and right ventricular hypertrophy during the development of MCT-induced pulmonary hypertension in rats.

Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease

The importance of pleiotropic effects of statins on endothelial function and inflammatory markers was investigated in patients with dysglycaemia and coronary artery disease (CAD). Thirty-nine patients were randomized to simvastatin 80 mg daily (S80; n = 20) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10; n = 19) for 6 weeks, aiming at similar cholesterol reduction. Endothelial function, evaluated by brachial artery flow-mediated vasodilatation (FMD) and the effect of endothelin receptor blockade, serum lipids, and inflammatory markers were evaluated at baseline and follow-up. At follow-up, low-density lipoprotein cholesterol decreased from 3.1 (2.8-3.4) (median and quartiles) to 1.5 mmol/L (1.4-1.7) and from 3.0 (2.5-3.4) to 1.3 mmol/L (1.1-1.8), in the S80 and E10/S10 groups, respectively. In the entire study group, FMD increased from 4.3% (3.4-6.1) at baseline to 5.5% (3.4-6.6) at follow-up, while C-reactive protein decreased from 3.1 (1.7-7.6) to 2.3 mg/L (0.9-6.5). The changes in FMD and C-reactive protein from baseline to follow-up were not significantly different between patients on S80 and E10/S10 groups. Endothelin blockade enhanced endothelium-dependent vasodilatation both at baseline and follow-up. Lipid lowering is more important than pleiotropic effects of statins for improvement in endothelial function and inflammatory markers in patients with dysglycaemia and CAD.

The Effects of Endothelin Receptor Blockade by Bosentan on the Healing of a Bowel Anastomosis in an Experimental Crohn’s Disease Model

ObjectiveIt was previously described that endothelins may contribute to the pathogenesis of Crohn’s disease. In this study, it was aimed to investigate the effects of endothelin receptor blockade by bosentan on the healing of a bowel anastomosis in an experimental Crohn’s disease model. Material and MethodsTwenty-eight Sprague–Dawley rats were divided into four groups. Groups I and II were used as sham-operated and control groups, respectively. Bowel inflammation induced by intrajejunal injection of iodoacetamide in groups III and IV. Rats in group IV were treated with oral preparation of bosentan 60 mg/kg/day. Three days after induction of the inflammation, partial resection of test loop and anastomosis was performed. Re-laparotomy was performed, anastomosis bursting pressures and peritonitis scores were measured, and tissue samples were obtained for the measurements of tissue hydroxylproline level and mucosal damage index 4 days later. ResultsThe mean mucosal damage index and peritonitis score of group IV were significantly lower, and the mean tissue hydroxyproline level and anastomotic bursting pressure of group IV were significantly higher than those of group III. ConclusionThe blockade of endothelin receptors by bosentan decreases the severity of iodoacetamide induced intestinal inflammation, increases the wound healing in the inflamed intestinal tissue, and decreases the severity of peritonitis.

Effects of endothelin receptor blockade on hypervasoreactivity in streptozotocin-diabetic rats: vessel-specific involvement of thromboxane A2

Increased vasoconstrictor response to norepinephrine (NE) and endothelin (ET)-1 in arteries from diabetic animals is ameliorated by chronic endothelin receptor blockade with bosentan and was absent in endothelium-denuded arteries, suggesting the involvement of ET-1 and an endothelium-derived contracting factor such as thromboxane A2 (TxA2). To examine this possibility, we determined the effects of acute blockade of ET receptors or inhibition of TxA2 synthesis on the vascular function of superior mesenteric arteries (SMA) and renal arteries (RA) isolated from nondiabetic and 11-week streptozotocin (STZ) diabetic rats chronically treated with either bosentan or vehicle. Both in vitro incubation with bosentan and a selective ETA receptor blocker, BQ123, eradicated the increase in NE contractile responses in diabetic SMA. Additionally, in vitro incubation with the thromboxane synthase inhibitor, dazmegrel, abrogated the exaggerated NE and ET-1 contractile responses in diabetic SMA. Conversely, in RA, no significant acute effect of bosentan, BQ123, nor dazmegrel on vascular responses to NE was observed. Dazmegrel incubation attenuated the maximum contractile responses to ET-1 in diabetic RA; however, these responses in diabetic RA remained significantly greater than those of other groups. Diabetic RA but not SMA exhibited an enhanced contractile response to the TxA2 analogue U46619, which was corrected by chronic bosentan treatment. Immunohistochemical analyses in diabetic SMA revealed an increase in ETA receptor level that was normalized by chronic bosentan treatment. These data indicate that an interaction between ET-1 and TxA2 may be involved in mediating the exaggerated vasoconstrictor responses in diabetic arteries. Furthermore, the underlying mechanisms appear to be vessel specific.

Endothelin in unilateral ureteral obstruction: vascular and cellular effects.

Unilateral ureteral obstruction results in decreased blood flow and tissue loss in the obstructed kidney. This condition is compensated by increased perfusion and trophic changes in the contralateral kidney. Vascular mediators' effects are central to these changes and of these mediators endothelin is the most potent vasoconstrictor known. We explored the role of endothelin and the effects of endothelin receptor blockade in unilateral ureteral obstruction. Rats were subjected to unilateral ureteral obstruction for 24 hours. Endothelin-1 mRNA expression was determined in kidney extracts from control, obstructed and contralateral (nonobstructed) kidneys. Cortical and medullary blood flow was determined in control and obstructed kidneys, and after endothelin receptor blockade with bosentan. Apoptotic rates were determined in control and obstructed kidneys after treatment with bosentan using the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end technique. RESULTS After 24 hours of unilateral ureteral obstruction endothelin-1 mRNA expression was increased in the obstructed kidney and decreased in the contralateral kidney. Obstruction was associated with a decrease in renal blood flow, which was reversed by endothelin receptor blockade. Unilateral ureteral obstruction also increased apoptosis, which was blocked by endothelin inhibition. Endothelin expression increases in the obstructed kidney. Inhibition of its action protects against vascular and cellular changes. Decreased endothelin expression in the contralateral kidney may facilitate trophic changes and compensatory increased blood flow.

Nitric oxide blunts the endothelin-mediated pulmonary vasoconstriction in exercising swine.

We have previously shown that vasodilators and vasoconstrictors that are produced by the vascular endothelium, including nitric oxide (NO), prostanoids and endothelin (ET), contribute to the regulation of systemic and pulmonary vascular tone in swine, in particular during treadmill exercise. Since NO and prostanoids can modulate the release of ET, and vice versa, we investigated the integrated endothelial control of pulmonary vascular resistance in exercising swine. Specifically, we tested the hypothesis that increased NO and prostanoid production during exercise limits the vasoconstrictor influence of ET, so that loss of these vasodilators results in exaggerated ET-mediated vasoconstriction during exercise. Fifteen instrumented swine were exercised on a treadmill at 0-5 km h(-1) before and during ET(A)/ET(B) receptor blockade (tezosentan, 3 mg kg(-1) I.V.) in the presence and absence of inhibition of NO synthase (N(omega)-nitro-L-arginine, 20 mg kg(-1) I.V.) and/or cyclo-oxygenase (indometacin, 10 mg kg(-1) I.V.). In the systemic circulation, ET receptor blockade decreased vascular resistance at rest, which waned with increasing exercise intensity. Prior inhibition of either NO or prostanoid production augmented the vasodilator effect of ET receptor blockade, and these effects were additive. In contrast, in the pulmonary bed, ET receptor blockade had no effect under resting conditions, but decreased pulmonary vascular resistance during exercise. Prior inhibition of NO synthase enhanced the pulmonary vasodilator effect of ET receptor blockade, particularly during exercise, whereas inhibition of prostanoids had no effect, even after prior NO synthase inhibition. In conclusion, endogenous endothelin limits pulmonary vasodilatation in response to treadmill exercise. This vasoconstrictor influence is blunted by NO but not by prostanoids.

Alterations in vascular matrix metalloproteinase due to ageing and chronic hypertension: effects of endothelin receptor blockade

To determine the effects of age and dual endothelin (ET)A/ETB receptor antagonism (bosentan) on aortic matrix metalloproteinase (MMP) abundance and tissue inhibitor of metalloproteinase (TIMP) expression in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Male SHR and control WKY rats were randomly assigned to receive placebo or bosentan (100 mg/kg per day) for 3 months. Animals were killed under terminal anaesthesia at either 20 weeks (adult) or 17-20 months (senescent). Aortic gelatinase activity was determined by zymography, whereas MT-1 MMP and TIMP-1 expression were assessed by immunoblotting. In WKY rats, aortic MMP-2 but not proMMP-2 activity was 3.6-fold higher (P < 0.02) in the senescent compared with the adult group. TIMP-1 (twofold) and MT-1 MMP (3.8-fold) expression increased (P < 0.05) with age in the WKY groups. Short-term hypertension (adult SHR versus adult WKY) increased MMP-2 to 74.7 +/- 14.1 from 18.9 +/- 3.5 arbitrary units (AU) (P = 0.0012), but did not alter proMMP-2 activity. This increased further on progression to chronic hypertension (117.4 +/- 12.2 versus 74.7 +/- 14.1 AU; P < 0.02). Bosentan decreased MMP-2 (78.9 +/- 3.8 versus 117.4 +/- 12.2 AU; P = 0.014) and proMMP-2 activity (P < 0.006) in the senescent SHR group. Ageing and the development/progression of hypertension are associated with increased MMP-2 activity in the aorta, which is consistent with ongoing remodelling of the vasculature. However, the underlying mechanisms regulating MMP-2 abundance in ageing and hypertension appear to be divergent, as MT-1 MMP expression is differentially altered. Dual ETA/ETB receptor antagonism did not alter the age-dependent increase in aortic MMP activity in normotensive rats. However, bosentan decreased pro and active MMP-2 activity in senescent SHR rats, indicating that ET modulates late events in vascular remodelling in hypertension.

Meta-analysis of the effects of endothelin receptor blockade on survival in experimental heart failure

BackgroundAlthough an initial study of endothelin receptor blockade reported positive findings, subsequent experiments and clinical trials in humans found little or no benefit. MethodsWe applied meta-analytic methods to assess the methodologic rigor of preclinical studies of endothelin blockade and to quantitatively evaluate the totality of evidence regarding the effect of endothelin receptor blockers in experimental heart failure. A total of 396 animals were assigned to control and 594 were assigned to experimental therapy in the pooled analysis. Of the 9 studies identified, no study reported a priori sample size justification. Although there was a tendency to increased mortality with early administration (relative risk 1.39, P=.15) and decreased mortality with late administration (relative risk 0.85, P=.6), in the overall analysis, there was no significant evidence of benefit or harm (relative risk 1.03, P=.9). Studies with a small sample size had estimated effects that tended to deviate further from the pooled estimate of all studies. ConclusionsConsideration of mortality effects in the totality of studies revealed no significant effect of endothelin antagonists in animal models of experimental heart failure. Given the potential for between-study variability, reliance on studies with small sample size may lead to unrealistic expectations when extrapolating preclinical experimental results to future research.

The endothelin system and its role in acute myocardial infarction.

Immediately after an acute myocardial infarction (AMI) or in models of ischemia-reperfusion injury, cardiac endothelin (ET) system is markedly activated, and plasma levels of ET are increased. In the heart, expression of the main components of the ET system (ET-1 peptide, both receptor subtypes ETA and ETB, though not endothelin converting enzyme) are increased both at the gene level and protein level, in the viable myocardium, and--even more substantially--in the necrotic area. Despite these conspicuous abnormalities, the role of ET in this setting remains unclear. In the absence of human data, most short-term studies in animals (in terms of hours to up to 8 days post-AMI) and in the reperfused ischemic heart, have found beneficial effects of ET receptor blockade on survival rate, incidence of arrhythmias, cardiac function, and morphology. In contrast, many studies in which a long-term ET inhibition was started immediately post-infarction and the late effects were examined in animals with ensuing chronic heart failure (14-100 days postinfarction), adverse effects were also observed, such as scar thinning, further ventricular dilation, or even a worse survival rate. It appears that the ET system plays a dual role during the early post-AMI period. At present, it is not clear whether the short-term beneficial effects or long-term adverse effects of ET receptor blockade would prevail. Acute use of short-acting ET receptor antagonists in patients with AMI complicated by an acute heart failure is an attractive possibility that also remains to be investigated.