Co-activation of Mas and pGCA receptors suppresses Endothelin-1-induced endothelial dysfunction via nitric oxide/cGMP system.

BACKGROUND: The aortic endothelium is crucial in preserving vascular tone through endothelium-derived vasodilators and vasoconstrictors. Dysfunction in the endothelium is an early indicator of cardiovascular diseases. Our study explores the therapeutic potential of a dual-acting peptide (DAP) to co-activate Mas and pGCA receptors and restore the balance between vasodilators and vasoconstrictors on endothelial dysfunction in DOCA-salt-induced hypertensive rats. METHODS: DOCA-salt was administered to male wistar rats to induce hypertension, and various parameters, including blood pressure (BP), water intake and body weight were monitored. DAP, Ang1-7, BNP, and losartan were administered to hypertensive rats for three weeks. Histological analysis and isometric tension studies were carried out to assess endothelial function. In addition to this, we used primary aortic endothelial cells for detailed mechanistic investigations. RESULTS: DOCA-salt administration significantly elevated systolic, diastolic, mean arterial BP, and water intake whereas, downregulated the gene expression of Mas and pGCA receptors. However, DAP co-administration attenuated BP increase, upregulated the gene expression of Mas and pGCA receptors, normalized serum and urinary parameters, and effectively reduced fibrosis, inflammation, and vascular calcification. Notably, DAP outperformed the standard drug, Losartan. Our findings indicate that DAP restores aortic function by balancing the NO and ET1-induced pathways. CONCLUSION: Co-activating Mas and pGCA receptors with DAP mitigates vascular damage and enhances endothelial function, emphasizing its potential to maintain a delicate balance between vasodilatory NO and vasoconstrictor ET1 in endothelial dysfunction.

Interleukin-33, endothelin-1, and inflammatory parameters in chronic spontaneous urticaria.

Background: Endothelin-1 (ET-1) and interleukin-33 (IL-33) can modulate the activation of mast cells and basophils in the pathophysiology of allergic diseases, interplaying with other mediators of "low-grade inflammation." Objective: To compare ET-1, IL-33, the neutrophil-lymphocyte ratio (NLR), eosinophil-lymphocyte ratio (ELR), platelet-lymphocyte ratio (PLR), eosinophil-basophil ratio (EBR), systemic immune inflammation index (SII), and system inflammation response index (SIRI) in patients with chronic spontaneous urticaria (CSU) and are antihistamine sensitive (AHS), antihistamine resistant (AHR), omalizumab sensitive (OmS), and omalizumab resistant (OmR). Methods: A prospective observational study enrolled 68 consecutive patients with CSU diagnosed and managed according to the dermatology section of the European Academy of Allergology and Clinical Immunology (EAACI), the European Union funded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization guidelines. Patients with a urticaria control test score of >12 are considered treatment sensitive, and ≤ 12 are considered resistant. The control group consisted of 20 sex-matched subjects without urticarial diseases. Total immunoglobulin E (IgE), antinuclear antibodies (ANA), thyroid stimulating hormone, antithyroid peroxidase, mean platelet volume (MPV), NLR, ELR, PLR, EBR, SII, SIRI, ET-1, and IL-33 were measured at the study entry and compared between the study groups. Results: Thirty AHS group, 38 AHR group, and 20 control group patients were included. The AHS, AHR, and control groups did not differ in demographic parameters, but the CSU groups were characterized by higher indicators of inflammation. In comparison with the AHS group, the AHR group was characterized by higher levels of IL-33 (p = 0.007), ET-1 (p = 0.032), C-reactive protein (p = 0.016), MPV (p = 0.002), and higher rates of positive ANA (p = 0.019). Of the 38 patients from the AHR group, 30 (79%) were included in the OmS group and 8 (21%) were included in the OmR group. The OmR group was characterized by higher levels of C-reactive protein (p = 0.022), EBR (p < 0.001), higher rates of ANA (p = 0.004), and lower levels of ET-1 (p = 0.025) than the OmS group. Conclusion: Our study did not confirm NRL, PRL, SII, and SIRI, PLR as the biomarkers of treatment response to antihistamines and/or omalizumab in CSU. Higher blood levels of IL-33 and ET-1 characterize AHR CSU.

Thymol regulates the Endothelin-1 at gene expression and protein synthesis levels in septic rats.

Sepsis is a serious systemic inflammatory response to infections. In this study, effects of thymol treatments on sepsis response were investigated. A total of 24 rats were randomly divided into 3 different treatment groups, namely as Control, Sepsis and Thymol. A sepsis model was created with a cecal ligation and perforation (CLP) in the sepsis group. For the treatment group, 100 mg/kg dose of thymol was administered via oral gavage and sepsis was established with a CLP after 1 h. All rats were sacrificed at 12 h post-opia. Blood and tissue samples were taken. ALT, AST, urea, creatinine and LDH were evaluated to assess the sepsis response in separated sera. Gene expression analysis was conducted for ET-1, TNF-α, IL-1 in lung, kidney and liver tissue samples. ET-1 and thymol interactions were determined by molecular docking studies. The ET-1, SOD, GSH-Px and MDA levels were determined by ELISA method. Genetic, biochemical and histopathological results were evaluated statistically. The pro-inflammatory cytokines and ET-1 gene expression revealed a significant decrease in the treatment groups, while there was an increase in septic groups. SOD, GSH-Px and MDA levels of rat tissues were significantly different in the thymol groups as compared to the sepsis groups (p < 0.05). Likewise, ET-1 levels were significantly reduced in the thymol groups. In terms of serum parameters, present findings were consistent with the literature. It was concluded based on present findings that thymol therapy may reduce sepsis-related morbidity, which would be beneficial in the early phase of the sepsis.

Angiotensin receptor-neprilysin inhibitor (thiorphan/irbesartan) improved cardiac function in a rat model of myocardial ischemic reperfusion injury.

Mitochondria-mediated apoptosis plays a critical role in myocardial ischemia reperfusion (IR) injury and causes a negative impact on cardiac efficiency and function. The combined angiotensin receptor-neprilysin inhibitor (ARNI) is a promising cardioprotective pharmacological agent that could rescue the heart from IR injury. This study investigated the cardioprotective effect of thiorphan (TH) in combination with three different doses of irbesartan (IRB) on myocardial IR injury and detected the most effective dose combination. Male Wistar rats were used and divided into five groups (10 rats/group): (I) Sham, (II) ischemia-reperfusion I/R, (III) TH/IRB + IR (0.1/5 mg/kg), (IV) TH/IRB + IR (0.1/10 mg/kg), and (V) TH/IRB + IR (0.1/15 mg/kg) groups. Thiorphan and irbesartan were injected intraperitoneally 15 min before IR induction. Mean arterial blood pressure, left ventricular end diastolic pressure (LVEDP), left ventricular maximum rate of pressure (LVdp/dtmax ), and cardiac levels of creatine kinase-MB, malondialdehyde, superoxide dismutase, and endothelin-1 were measured. Cardiac mitochondria complexes activities, histopathological examination of myocardial tissues, immunohistochemistry studies for myocardial apoptosis (Bax and Bcl-2), and electron microscopy examination of left ventricle were performed. TH/IRB combination preserved cardiac functions and mitochondria complex activities and mitigated cardiac damage, oxidative stress, and apoptosis following IR. Also, there was an evident improvement in histopathological changes and electron microscopy examination of left ventricle compared with I/R group. TH/IRB in a dose of 0.1/10 mg/kg showed significant improvement compared with the other treated groups. Thiorphan/irbesartan improved cardiac functions following IR injury. This could be explained by the reported improvement of mitochondria complex activities and reduction of oxidative stress, endothelin-1, and apoptosis.

Metformin and simvastatin synergistically suppress endothelin 1-induced hypoxia and angiogenesis in multiple cancer types.

Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti-angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic-related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient-derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET-1), an important regulator of angiogenesis and the hypoxia-related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET-1-induced hypoxia-inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.

Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice.

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6Chigh monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6Chigh monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6Clow monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.

NCX 470 Restores Ocular Hemodynamics and Retinal Cell Physiology After ET-1-Induced Ischemia/Reperfusion Injury of Optic Nerve and Retina in Rabbits.

Purpose: Determine whether NCX 470, a nitric oxide (NO)-donating bimatoprost with clinically demonstrated intraocular pressure (IOP)-lowering effects, improves ocular hemodynamics and retinal physiology. Methods: Endothelin-1 (ET-1)-induced ischemia/reperfusion model in New Zealand white rabbits was used. ET-1 was injected next to the optic nerve twice/week (Monday and Thursday) for 6 weeks. Starting on week 3, animals received NCX 470 (0.1% bid, 6 days/week Monday-Saturday) or vehicle until the end of ET-1 treatment. IOP, ophthalmic artery resistive index (OA-RI) and retina physiology (electroretinogram, ERG) were determined before dosing and at different times post-dosing. All measurements were taken on Mondays before the AM daily dosing (36 h treatment-free). Finally, oxidative stress markers were determined in dissected retina and iris/ciliary body of treated eyes. Results: Injection of ET-1 progressively increased IOP (20.7 ± 0.6, 24.9 ± 1.2, and 27.0 ± 0.6 mmHg at baseline, week 2 and 6, respectively) and OA-RI (0.30 ± 0.02, 0.39 ± 0.02, and 0.42 ± 0.03 at baseline, week 2 and 6, respectively) and reduced rods and/or cones response as indicated by changes in ERG amplitudes under different stimulating conditions. NCX 470 re-established baseline IOP (21.8 ± 1.0 mmHg), OA-RI (0.33 ± 0.02), and ERG amplitude by week 6 (mostly rod response, 0.01Dark_AVeh_6week = 32.2 ± 3.0 µV and 0.01Dark_ANCX470_6week 44.3 ± 4.5 µV; mostly cone response, 3.0Dark_AVeh_6week = 87.6 ± 10.1 µV and 3.0Dark_ANCX470_6week = 122.8 ± 11.4 µV; combined rod/cone response, 3.0Light_AVeh_6week = 49.8 ± 6.5 µV and 3.0Light_ANCX470_6week = 64.2 ± 6.8 µV). NCX 470 also reversed ET-1-induced changes in glutathione and manganese superoxide dismutase (oxidative stress markers) in retina and iris/ciliary body. Conclusions: Repeated ocular topical dosing with NCX 470 reverses ET-1-induced changes in IOP, OA-RI, and ERG suggesting improved ocular hemodynamics and retinal physiology likely independently from its demonstrated IOP-lowering effect.

Evaluation of acute phase proteins, adiponectin and endothelin-1 to determine vascular damage in dogs with heartworm disease (Dirofilaria immitis), before and after adulticide treatment.

Previous studies have shown the existence of an acute phase response in dogs with heartworm (Dirofilaria immitis), probably caused by the vascular inflammation that occurs during the pathogenesis of this disease. In addition, it has been seen that this acute phase response persists after finishing treatment, especially in dogs with pulmonary hypertension (PH). Furthermore, echocardiographic studies have shown that PH and endarteritis appear to persist for at least 10 months after completion of adulticide treatment, suggesting that the vascular changes in these dogs may not be reversible. Therefore, the objective of this study was to evaluate the serum concentrations of different positive acute phase proteins (APP) [C reactive-protein (CRP), haptoglobin and ferritin] and negative APP (albumin and paraoxonase-1 (PON-1)), and the usefulness of the endothelin-1 (ET-1) and adiponectin, in dogs infected by D. immitis to evaluate their usefulness as diagnostic biomarkers of vascular damage and PH and their progression throughout therapy up to 7 months after the end of adulticide treatment. Twenty-five heartworm-infected dogs received adulticide treatment, and serum measurements were performed on the day of diagnosis (day 0), day of discharge (day 90), and 6 months after discharge (day 270). In addition, presence or absence of PH was also echocardiographically determined using the Right Pulmonary Artery Distensibility Index. PH was present in 44% of the dogs on day 0 and day 90, and in 48% of dogs on day 270. Alterations were observed in the concentrations of all APP throughout the study, persisting the alterations in PON-1 and ferritin on day 270. Depending on the presence or absence of PH, CRP showed significant differences throughout the study, as did ET-1. On the other hand, adiponectin did not show variations throughout the study, so it did not seem a useful marker in this disease. These results could reflect the possible persistence of vascular inflammation up to 7 months after finishing treatment, whether or not there was PH, and consolidate the study of APP as useful markers in heartworm disease. Moreover, persistent PH could be the consequent clinical manifestation in dogs with more severe vascular alterations so the study of APP, especially CRP, and ET-1 could be especially advantageous in these patients in the early evaluation of the disease, as well as for the determination of disease severity, monitoring therapeutic responses, and predicting outcomes.

Association of plasma endothelin-1 with blood pressure progression among Blacks: The Jackson Heart Study.

BACKGROUND: Despite pathophysiological links between endothelin (ET)-1 and hypertension in Black adults, there is no population-based data appraising the association of plasma ET-1 with longitudinal blood pressure (BP) changes in Blacks. METHODS: We analyzed data from 1197 Jackson Heart Study participants without hypertension (mean age 47.8 years [SD: 12.0]; 64.2% women), with plasma ET-1 available at the baseline examination (2000-2004). Poisson regression with robust variance was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) of BP progression (an increase by ≥1 BP category based on the 2017 American College of Cardiology/American Heart Association classification) and incident hypertension (BP ≥ 130/80 mm Hg or use of antihypertensive medication) at follow-up (2005-2008 or 2009-2013). RESULTS: Over a median follow-up of 7 years (range: 4-11), 71.2% (n = 854) progressed to a higher BP stage and 64.6% (n = 773) developed hypertension. After adjusting for possible confounders, each unit increment in baseline log (ET-1) was associated with higher risks of BP progression (RR 1.15 [95% CI 1.03-1.29], P = .016) and incident hypertension (RR 1.15 [95% CI 1.01-1.31], P = .032). Compared to those in the lowest ET-1 quartile, participants in the highest quartile had significantly higher risks of BP progression (RR 1.20 [95% CI 1.05-1.37], P = .007) and incident hypertension (RR 1.16 [95% CI 1.00-1.36], P = .052). CONCLUSIONS: In a large, community-based sample of African Americans, higher plasma ET-1 concentrations were associated with higher risks of BP progression and incident hypertension.

Effects of systemic and renal intramedullary endothelin-1 receptor blockade on tissue NO and intrarenal hemodynamics in normotensive and hypertensive rats.

Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.

Mystery of Retinal Vein Occlusion: Vasoactivity of the Vein and Possible Involvement of Endothelin-1.

Retinal vein occlusion (RVO) is a common vascular disease of retina; however, the pathomechanism leading to RVO is not yet clear. In general, increasing age, hypertension, arteriosclerosis, diabetes mellitus, dyslipidemia, cardiovascular disorder, and cerebral stroke are systemic risk factors of RVO. However, RVO often occur in the unilateral eye and sometimes develop in young subjects who have no arteriosclerosis. In addition, RVO show different variations on the degrees of severity; some RVO are resolved without any treatment and others develop vision-threatening complications such as macular edema, combined retinal artery occlusion, vitreous hemorrhage, and glaucoma. Clinical conditions leading to RVO are still open to question. In this review, we discuss how to treat RVO in practice by presenting some RVO cases. We also deliver possible pathomechanisms of RVO through our clinical experience and animal experiments.

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65.

Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 106 PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM.

Coronary ischemia-reperfusion: role of nitric oxide and endothelin-1. A Review / Ischemia-reperfusión coronaria: papel del óxido nitro y endothelina-1. Una Revisión

This Review focus on the myocardial ischemia-reperfusion, paying particular attention to the role of nitric oxide (NO) and endothelin-1 (ET-1) in the regulation of the coronary circulation under normal conditions and after ischemia-reperfusion. Coronary atheromatosis is usually induced by endothelium dysfunction/damage, and is the main cause of acute coronary syndromes (e. g., acute myocardial infarction, AMI). The assessment of endothelial function of patients with coronary artery disease may provide useful information. The most effective treatment of AMI is timely reperfusion for restoring the blood flow to the ischemic myocardial territory, but this procedure may also damage myocardium (reperfusion injury), of which the pathophysiology and treatment remain uncertain. The interaction between NO and ET-1 may be relevant for regulating the coronary circulation, with predominance of NO over ET-1 under normal conditions. The coronary circulation plays a crucial role in ischemia-reperfusion since it is the cause and victim of consequences of this condition. Ischemia-reperfusion damages not only the myocardium but also coronary vasculature, including the endothelium, increases plasma levels of ET-1, induces functional predominace of ET-1 over NO, augments the coronary response to ET-1, and alters the role of endothelin receptors in this response. All these alterations may lead to dysregulation of coronary vasculature and the non-reflow phenomenon, which may underly reperfusion injury. Thus, ET-1 could be of significance in pathophsysiology of ischemia-reperfusion and reperfusion injury, and the use of antagonists for endothelin ETA/ETB receptors could protect the heart against reperfusion injury

Esta Revisión se centra en la isquemia-reperfusión del miocardio, prestando particular atención al papel del óxido nítrico (NO) y endothelina-1 (ET-1) en la regulación de la circulación coronaria en condiciones normales y tras la isquemia-reperfusión. La ateromatosis coronaria suele estar causada por disfunción/daño endotelial, y lidera las causas de los síndromes coronarios agudos (p. e., infarto agudo de miocardio, IAM). El tratamiento más eficaz del IAM es la reperfusión del territorio de miocardio isquémico, pero este procedimiento también causa lesión del miocardio (lesión por reperfusión), cuya fisiopatología y tratamiento siguen siendo inciertos. La interacción entre el NO y ET-1 es relevante en la regulación de la circulación coronaria, y en condiciones normales predomina el NO sobre la ET-1. La circulación coronaria desempeña un papel crucial en la isquemia- reperfusión puesto que ella es la causa y víctima de las consecuencias de esta situación. La isquemia- reperfusión daña no solo el miocardio, sino también el lecho vascular coronario, aumenta los niveles plasmáticos de ET-1, induce el predominio de la ET-1 sobre el NO, aumenta la respuesta coronaria alaET-1 y altera el papel de sus receptores en esta respuesta. Todo ello podría contribuir a la disfunción de la circulación coronaria y el fenómeno de no-reflujo y, como consecuencia, a la lesión por reperfusión. Así, la ET-1 podría ocupar un papel destacado en la fisiopatología de la lesión por reperfusión, y el uso de antagonistas de los receptores ETA/ETB podría proteger al corazón frente a la lesiones por reperfusión

Endothelin therapeutics in cancer: Where are we?

In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein ß-arrestin 1 (ß-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ETAR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional ß-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.

Efectos beneficiosos de la simpatectomía renal sobre el remodelado vascular pulmonar en la hipertensión arterial primaria experimental / Beneficial effects of renal denervation on pulmonary vascular remodeling in experimental pulmonary artery hypertension

Introducción y objetivos. La activación tanto del sistema nervioso simpático como del sistema renina-angiotensina-aldosterona está estrechamente relacionada con la hipertensión arterial pulmonar. Nuestra hipótesis era que la simpatectomía renal reduce la actividad del sistema renina-angiotensina-aldosterona e inhibe la progresión de la hipertensión arterial pulmonar. Métodos. Se asignó aleatoriamente a un total de 22 perros beagle a tres grupos de estudio. Se efectuaron determinaciones de la dinámica pulmonar de esos animales antes y 8 semanas después de la inyección de 0,1 ml/kg de dimetilformamida (perros de control) o de 2 mg/kg de deshidromonocrotalina (perros con hipertensión arterial pulmonar y perros con hipertensión arterial pulmonar + simpatectomía renal). Ocho semanas después de la inyección, se determinaron las concentraciones de neurohormonas y se evaluó la morfología del tejido pulmonar. Resultados. Se observó un aumento significativo de la concentración de angiotensina II y endotelina-1 en plasma después de 8 semanas en los perros con hipertensión arterial pulmonar, y los valores obtenidos en los tejidos pulmonares de estos animales eran superiores a los de los perros del grupo de control y el grupo de simpatectomía renal (medias: angiotensina II, 65 ± 9,8 frente a 38 ± 6,7 y 46 ± 8,1; endotelina-1, 96 ± 10,3 frente a 54 ± 6,2 y 67 ± 9,4; p < 0,01). La deshidromonocrotalina aumentó la presión arterial pulmonar media (16 ± 3,4 frente a 33 ± 7,3 mmHg; p < 0,01), y la simpatectomía renal evitó que se produjera este aumento. La proliferación celular del músculo liso pulmonar fue mayor en los perros con hipertensión arterial pulmonar que en los animales de los grupos de control y de hipertensión arterial pulmonar + simpatectomía renal. Conclusiones. La simpatectomía renal atenúa el remodelado vascular pulmonar y reduce la presión arterial pulmonar en la hipertensión arterial pulmonar experimental. El efecto de la simpatectomía renal puede contribuir a reducir las concentraciones de neurohormonas (AU)

Introduction and objectives. Activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system is closely associated with pulmonary arterial hypertension. We hypothesized that renal denervation decreases renin-angiotensin-aldosterone activity and inhibits the progression of pulmonary arterial hypertension. Methods. Twenty-two beagles were randomized into 3 groups. The dogs’ pulmonary dynamics were measured before and 8 weeks after injection of 0.1 mL/kg dimethylformamide (control dogs) or 2 mg/kg dehydromonocrotaline (pulmonary arterial hypertension and pulmonary arterial hypertension + renal denervation dogs). Eight weeks after injection, neurohormone levels and pulmonary tissue morphology were measured. Results. Levels of plasma angiotensin II and endothelin-1 were significantly increased after 8 weeks in the pulmonary arterial hypertension dogs and were higher in the lung tissues of these dogs than in those of the control and renal denervation dogs (mean [standard deviation] angiotensin II: 65 [9.8] vs 38 [6.7], 46 [8.1]; endothelin-1: 96 [10.3] vs 54 [6.2], 67 [9.4]; P < .01). Dehydromonocrotaline increased the mean pulmonary arterial pressure (16 [3.4] mmHg vs 33 [7.3] mmHg; P < .01), and renal denervation prevented this increase. Pulmonary smooth muscle cell proliferation was higher in the pulmonary arterial hypertension dogs than in the control and pulmonary arterial hypertension + renal denervation dogs (AU)

Medidas protectoras frente a la isquemia cerebral tras hemorragia subaracnoidea (II) / No disponible

No disponible

Resonancia magnética cardiaca y endotelina-1: un nuevo paso en la detección de la obstrucción microvascular / No disponible

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Utilidad de la determinación de endotelina-1 en el infarto agudo de miocardio / Usefulness of endothelin-1 assessment in acute myocardial infarction

Introducción y objetivos. Los valores elevados de endotelina-1 (ET-1) se han relacionado con un mal pronóstico tras un infarto agudo de miocardio con elevación del ST (IAMCEST). La vasoconstricción de la microcirculación coronaria parece ser el mecanismo causal. El objetivo de este estudio es analizar los efectos de la ET-1 sobre la microcirculación coronaria, el tamaño del infarto, la fracción de eyección del ventrículo izquierdo (FEVI) y el miocardio rescatado tras un IAMCEST. Métodos. Se determinaron los valores de ET-1 de 127 pacientes (6-24h) tras un IAMCEST. En 97 pacientes se realizó una resonancia magnética para evaluar la obstrucción microvascular (OM), el tamaño del infarto y la FEVI. El índice de miocardio rescatado (IMR) se definió como el porcentaje de área en riesgo angiográfica sin necrosis en la resonancia. Resultados. La edad media de la población fue de 60,9±11,8 años (77% varones). Los pacientes con valores de ET-1 por encima de la mediana presentaron un mayor porcentaje de OM (77,7% si ET-1>6,8 pg/ml frente a 16,6% si ET-1 ≤ 6,8 pg/ml; p<0,001) y menor IMR (13,8%±26% si ET-1>6,8 pg/ml frente a 37,4%±26% si ET-1 ≤ 6,8 pg/ml; p=0,02). Los valores de ET-1 no se asociaron de manera significativa con el tamaño del infarto (p=0,11) ni con la FEVI (p=0,16). En el análisis multivariable, los valores de ET-1 fueron predictores de OM (odds ratio [OR]=2,78; intervalo de confianza [IC] del 95%, 1,16-6,66; p=0,021) e IMR ≤ percentil 25 (OR=1,69; IC del 95%, 1,01-2,81; p=0,04). Conclusiones. Los valores elevados de ET-1 tras un IAMCEST se asocian a un mayor porcentaje de OM y un menor IMR (AU)

Introduction and objectives: High endothelin-1 (ET-1) levels have been linked to poor clinical outcomes after ST-segment elevation myocardial infarction (STEMI). Vasoconstriction of the coronary microcirculation seems to be the underlying mechanism. The aim of the study was to assess the effect of ET-1 on microvascular integrity, infarct size, left ventricular ejection fraction (LVEF) and myocardial salvage in evolving myocardial infarction (MI). Methods: We measured ET-1 levels acutely (6-24 h) in 127 patients presenting with their first STEMI. Contrast-enhanced cardiac magnetic resonance (ce-CMR) was performed in 94 patients within 1 week to assess microvascular obstruction (MO), infarct size and LVEF. A myocardial salvage index (MSI) was defined as the percentage of at-risk angiographic area without necrosis on the ce-CMR. Results: Mean age was 60.9 >= 11.8 years and 98 (77%) were males. Median ET-1 level within the first 24 h was 6.8 pg/mL (25th –75th percentile range: 5.4–8.5 pg/mL). Patients with ET-1 concentrations over the median presented higher percentage of MO (77.7% for ET-1 > 6.8 pg/mL vs. 16.6% for ET-1 6.8 pg/mL, P < .001) and lower MSI values (13.8 <= 26% for ET-1 > 6.8 pg/mL vs. 37.4 (26%) for ET-1 <= 6.8 pg/mL, P = .02). ET-1 levels did not show a significant association with infarct size (P = .11) and LVEF (P = .16). Multivariate analysis found ET-1 to be a significant predictor of MO (OR = 2.78; CI 95% 1.16-6.66; P = .021) and MSI <= Percentile 25 (OR = 1.69, CI 95% 1.01-2.81; P = .04). Conclusions: High ET-1 levels after myocardial infarction are associated with the presence of microvascular obstruction and lower myocardial salvage index (AU)