Targeting Endothelin in Alzheimer's Disease: A Promising Therapeutic Approach.

Endothelin is a chemical mediator that helps in maintaining balance within the blood-brain barrier by regulating the levels of toxicants and molecules which pass through the brain, suggesting that a rise in its production determines Alzheimer's disease. The inequity in the amyloid ß occurs due to a problem in its clearance from the brain initiating the production of reactive oxygen species and superoxide that activates a cascade wherein the release of inflammatory mediators and various enzymes like endothelin-converting enzymes take place. Furthermore, the cascade increases the levels of endothelin in the brain from endothelial cells. Endothelin levels are upregulated, which can be regulated by modulating the action of endothelin-converting enzymes and endothelin receptors. Hence, endothelin paves a pathway in the treatment of Alzheimer's disease. In this article, we have covered various mechanisms and preclinical studies that support and direct endothelin involvement in the progression of Alzheimer's disease by using various search tools such as PubMed, Science Direct, and Medline. Conclusive outcome data were extracted that all together defy contrivance pathways, potential drugs, endothelin receptors, and endothelin enzymes in our article giving profound importance to target endothelin for prevention and treatment of Alzheimer's disease.

Endothelin: 30 Years From Discovery to Therapy.

Discovered in 1987 as a potent endothelial cell-derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics-the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ETA autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ETB agonists, novel biologics such as receptor-targeting antibodies, or immunization against ETA receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.

Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia.

We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo-controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia-induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single-dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.

Role of endothelin in preeclampsia and hypertension following antiangiogenesis treatment.

PURPOSE OF REVIEW: Preeclampsia is a systemic, pregnancy-related disorder featuring hypertension and proteinuria arising from placental overproduction of soluble FMS-like tyrosine kinase-1, resulting in an antiangiogenic state because of the inhibition of the vascular endothelial growth factor (VEGF) family. Similarly, antiangiogenetic treatment aimed at targeting VEGF in patients with cancer is associated with a preeclampsia-like syndrome. In this study we discuss the pathophysiological role of an activated endothelin system in both conditions. RECENT FINDINGS: In different experimental forms of preeclampsia, in clinical preeclampsia, and in cancer patients on antiangiogenic treatment, activation of the endothelin axis invariably occurs and this activation is directly related to the circulating level of sFlt-1 or the intensity of antiangiogenic treatment. Administration of endothelin receptor A-selective or dual endothelin receptor antagonists can prevent or largely attenuate the hypertension and proteinuria in experimental forms of preeclampsia, as well as in rats exposed to receptor tyrosine-kinase inhibitors targeting VEGF-signaling, supporting the concept that activation of the endothelin axis plays a key role in the manifestations of these disorders. SUMMARY: Activation of the endothelin axis has now emerged as a crucial player in the manifestations of preeclampsia and following antiangiogenic treatment. As a consequence, blockade of the endothelin system may be considered as a treatment option both in preeclampsia and in antiangiogenesis-induced hypertension and renal toxicity in patients with cancer.

Multitarget cardiovascular drugs.

Cardiovascular disease is the number one cause of death globally. Design of cardiovascular drugs based on new paradigms is therefore a prominent goal of medicinal chemistry. Designed multiple ligands, targeting two or more proteins involved in pathogenesis of disease have become a viable concept in drug discovery. Although adjustment of the activities ratio at the different targets is a demanding and challenging task, modulation of two or more targets involved in a cardiovascular disease may be more successful for therapeutic application than treatment directed against each target alone, because of improved pharmacodynamic and pharmacokinetic properties of designed multitarget drugs. The article reviews the applications of multitarget approach to cardiovascular drug design, covering angiotensin-converting enzyme/neutral endopeptidase inhibitors, neutrale endopeptidase/endothelin-converting enzyme inhibitors, angiotensin-converting enzyme/neutral endopeptidase/endothelin-converting enzyme inhibitors, dual angiotensin/endothelin receptor and angiotensin1/angotensin2 receptor antagonists and angiotensin receptor antagonist/neutral endopeptidase inhibitors.

New molecular targets in bone metastases.

Bone metastases have a major impact on morbidity and on mortality in cancer patients. Despite its clinical relevance, metastasis remains the most poorly elucidated aspect of carcinogenesis. The biological mechanisms leading to bone metastasis establishment have been referred as "vicious circle," a complex network between cancer cells and the bone microenvironment. This review is aimed to underline the new molecular targets in bone metastases management other than bisphosphonates. Different pathways or molecules such as RANK/RANKL/OPG, cathepsin K, endothelin-1, Wnt/DKK1, Src have recently emerged as potential targets and nowadays preclinical and clinical trials are underway. The results from those in the advanced clinical phases are encouraging and underlined the need to design large randomised clinical trials to validate these results in the next future. Targeting the bone by preventing skeletal related events (SREs) and bone metastases has major clinical impact in improving survival in bone metastatic patients and in preventing disease relapse in adjuvant setting.

Targeting heart failure therapeutics: a historical perspective.

This article reviews information on the role of genetic variability in the development, progression, and treatment of heart failure. It focuses primarily on genetic variation in neurohormonal systems, where adrenergic receptors and the renin-angiotensin-aldosterone system are the two most explored areas. The article also reviews the endothelin system and natriuretic peptides. Clinical trial design issues are examined, and suggestions for pharmacogenomic clinical trials are presented. Finally, lessons from the oncology field and the changing regulatory landscape are discussed.

The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice.

OBJECTIVES: Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms. BACKGROUND: The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha. METHODS: Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists. RESULTS: Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice. CONCLUSIONS: Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Nicotine inhibits large conductance Ca(2+)-activated K(+) channels and the NO/-cGMP signaling pathway in cultured human endothelial cells.

OBJECTIVE: The effects of nicotine on endothelium-dependent vasorelaxation mediated by nitric oxide (NO) are controversial. Since endothelial NO synthesis has been shown to depend on the activity of large conductance Ca(2 + )-activated K(+) channels (BK(Ca)), the present study investigated whether nicotine alters BK(Ca) single channel activity induced by the K(+) channel opener NS1619, and to examine a possible interaction with the endothelial NO generation. DESIGN: The patch-clamp technique was used to examine the BK(Ca) activity. NO production was measured indirectly using a [(3)H]-cGMP-radioimmunoassay. All experiments were performed using cultured endothelial cells derived from human umbilical cord veins. RESULTS: The BK(Ca) opener NS1619 (10 micromol/l) significantly increased the BK(Ca) open-state probability (NPo) from 0.011+/-0.007 (control) to 0.052+/-0.019. Co-perfusion with nicotine (1 micromol/l) significantly decreased NS1619 induced NPo (n = 14, p < 0.05). Intracellular cGMP levels were significantly increased, if cells were stimulated with NS1619 (+ 225%; n = 10, p < 0.05), which was blocked by Nicotine (1 micromol/l). CONCLUSIONS: The results of the present study demonstrate that BK(Ca) activation by NS1619 plays an important role in the regulation of the NO-/cGMP-signaling-pathway. Endothelial dysfunction caused by nicotine may be connected with a decrease in BK(Ca)-activity.

Endothelin-induced increased aldosterone activity mediates augmented distal nephron acidification as a result of dietary protein.

The hypothesis that increased dietary protein augments distal nephron acidification through endothelin-mediated increased aldosterone activity was tested. Munich-Wistar rats were studied after 3 wk of diets with 50% high protein (HiPro) and 20% control (CON) casein-provided protein, the latter comparable to standard diet. HiPro versus CON rats had higher distal nephron H+ secretion by in vivo microperfusion as shown previously. Perfusion with inhibitors of Na+/H+ exchange (EIPA, 10(-5) M), H+-ATPase (bafilomycin, 10(-7) M), and H+-K+-ATPase (Sch 28080 [10(-5) M] and ouabain [10(-3) M]) support that higher Na+/H+ exchange and higher H+-ATPase but not higher H+-K+-ATPase activity mediated increased H+ secretion in HiPro rats. Oral bosentan, an endothelin A/B receptor antagonist, decreased distal nephron H+ secretion in HiPro rats as a result of reduced Na+/H+ exchange and H+-ATPase activity as shown previously by the authors' laboratory. HiPro versus CON rats had higher plasma aldosterone (60.9 +/- 5.9 versus 42.2 +/- 4.4 pg/ml; P < 0.024) and higher urine aldosterone excretion (21.9 +/- 3.9 versus 10.5 +/- 2.8 ng/d; P < 0.04) in the absence but not presence of bosentan, consistent with endothelin-mediated increased aldosterone secretion. HiPro rats that did versus did not ingest the aldosterone antagonist spironolactone had lower distal nephron H+ secretion (29.2 +/- 3.3 versus 42.1 +/- 3.8 pmol/mm per min; P < 0.05) as a result of lower H+-ATPase activity without differences in Na+/H+ exchange or H+-K+-ATPase activity. The data support that dietary protein provided as casein increases distal nephron acidification through endothelin-stimulated Na+/H+ exchange and endothelin-stimulated aldosterone secretion that increases H+-ATPase activity.

Hemodynamic and hormonal actions of adrenomedullin.

Adrenomedullin, a 52-amino acid residue peptide, has numerous biological actions which are of potential importance to cardiovascular homeostasis, growth and development of cardiovascular tissues and bone, prevention of infection, and regulation of body fluid and electrolyte balance. Studies in man using intravenous infusion of the peptide have demonstrated that, at plasma levels detected after myocardial infarction or in heart failure, adrenomedullin reduces arterial pressure, increases heart rate and cardiac output, and activates the sympathetic and renin-angiotensin systems but suppresses aldosterone. The thresholds for these responses differ, being lower under some experimental circumstances for arterial pressure than for the other biological effects. Adrenomedullin administration inhibits the pressor and aldosterone-stimulating action of angiotensin II in man. By contrast, the pressor effect of norepinephrine is little altered by concomitant adrenomedullin administration. Although in the absence of a safe, specific antagonist of the actions of endogenous adrenomedullin it is difficult to be certain about the physiological and pathophysiological importance of this peptide in man, current evidence suggests that it serves to protect against cardiovascular overload and injury. Hope has been expressed that adrenomedullin or an agonist specific for adrenomedullin receptors might find a place in the treatment of cardiovascular disorders.

Changes of brain endothelin levels and peripheral endothelin receptors by chronic cigarette smoke in spontaneously hypertensive rats.

The present study was conducted to evaluate the contribution of endothelin (ET) to the pharmacodynamic response to chronic cigarette smoke in spontaneously hypertensive rats (SHR). The contribution of ET was studied consequent to the hemodynamic response following 8 weeks of cigarette smoke by determining the changes in tissue ET-1 content and ET receptors. The blood pressure (BP) at the early phase of smoking and the heart rate (HR) 24 h later were apparently reduced in SHR, while the HR at the early phase was transiently elevated in normotensive Wistar Kyoto (WKY) rats. Tissue ET-1 levels in the hypothalamus, striatum, and cortex of SHR were higher than those in WKY rats, and these higher levels in SHR were reduced by exposure to chronic cigarette smoke. The ET-1 contents in the medulla oblongata and midbrain of both strains were clearly increased by smoke exposure, although the levels of SHR and WKY rats were not different. In addition, the immunoreactivity of the ET type A receptor in the adrenal glands and type B receptor in the kidneys of SHR showed a different response to smoke exposure as compared to WKY rats. Our present findings suggest that the changes of ETs may relate to the pharmacodynamic effects of chronic cigarette smoke.

Involvement of proteasome in endothelin-1 production in cultured vascular endothelial cells.

We examined whether the proteasome could regulate endothelin (ET)-1 production in vascular endothelial cells (ECs). A proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu (O-t-Bu)-Ala-leucinal (PSI) significantly decreased ET-1 release from ECs by about 25% of the basal release. PSI also suppressed tumor necrosis factor (TNF)-alpha-induced ET-1 release from ECs in a dose-dependent manner. Similar inhibitory effects were observed using another proteasome inhibitor lactacystin, whereas a calpain inhibitor calpeptin had no apparent effect on ET-1 release. Furthermore, PSI significantly attenuated prepro ET-1 mRNA expression under basal and TNF-alpha-stimulated conditions. Electrophoretic mobility shift assay showed that proteasome inhibitors diminished TNF-alpha-stimulated nuclear factor-kappa B (NF-kappaB) activation in ECs. Pretreatment with antioxidants, pyrrolidine dithiocarbamate and alpha-lipoic acid, both of which are known to be suppressors of NF-kappaB activation, effectively attenuated basal and TNF-alpha-induced ET-1 release. Thus, a proteasome-dependent proteolytic pathway is at least partly involved in ET-1 production under basal conditions, and this proteolytic pathway seems to have a crucial role in ET-1 production enhanced by TNF-alpha. The reduction of NF-kappaB activation may be involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression and ET-1 release.

Sex-specific acute effect of estrogen on endothelium-derived contracting factor in the renal artery of hypertensive Dahl rats.

OBJECTIVE: To determine whether estrogen rapidly affects endothelium-derived contracting factor (EDCF) in the renal artery of hypertensive Dahl rats, and whether factors other than nitric oxide (NO) contribute to the effect of estrogen. DESIGN: Acute effects of estrogen on the acetylcholine-induced vasomotor responses and on prostaglandin H2/thromboxane A2 mimetic, U46619,-induced contraction were examined in isolated arterial rings. METHODS AND RESULTS: Dahl salt-sensitive male and female rats were fed an 8% NaCl diet for 4 weeks. The blood pressure increased more rapidly and to a greater extent in males than in females. Renal arterial rings were prepared for isometric tension recording. 17beta-Estradiol, but not the biologically less active stereoisomer, 17alpha-estradiol, improved the relaxation response to acetylcholine in renal arteries from females. Estrogen also rapidly decreased the contraction evoked by acetylcholine (10(-6) to approximately 10(-4) mol/l) in renal arteries from females and it was effective at a physiological concentration (10(-9) mol/l) in the presence of Nomega-nitro-l-arginine methyl ester (an NO synthase inhibitor). The estrogen receptor antagonist, ICI 182,780, abolished the effect of estrogen, whereas the cytochrome P450 inhibitor, miconazole, had no effect. The contraction induced by U46619 was also suppressed by estrogen, without any contribution from NO. Estrogen had no effect on either relaxation or contraction responses in renal arteries from males. CONCLUSION: 17beta-Estradiol antagonizes increases in vascular tone in hypertensive females by enhancing NO-dependent relaxation, and by suppressing EDCF-mediated mechanisms in an NO-independent manner.

Elevation of serum endothelins and cardiotoxicity induced by particulate matter (PM2.5) in rats with acute myocardial infarction.

Epidemiological studies have defined a significant positive association of acute exposure to ambient concentrations of particulate matter (PM) with increased daily mortality and hospital admission for cardiovascular diseases. Experimental studies have shown that animals with pre-existing cardiovascular diseases are more susceptible to the cardiac effect of PM exposure. The present study was undertaken to investigate possible involvement of upregulation of the endothelin system in PM exposure-induced cardiotoxicity in rats with acute myocardial infarction (MI). Adult male Sprague Dawley rats were subjected to occlusion of the left coronary artery and displayed myocardial infarction 12 h after the surgery. The heart rate significantly decreased and premature ventricular complexes of the electrocardiogram occurred in the myocardial infarct animals. Exposure to PM(2.5) via intratracheal instillation with 2.0 mg in 0.3 mL normal saline significantly worsened the ventricular arrhythmia along with a further decrease in heart rate. The same PM exposure only caused slight cardiac changes in the sham-operated animals. Serum total endothelin concentrations were significantly elevated in both myocardial infarct rats and shamoperated controls in response to PM exposure. However, increased numbers of the endothelin receptor type A on the cardiomyocytes were observed only in the infarct myocardium. This study thus suggests that upregulation of the endothelin system in rats with MI is likely involved in the PM exposure-induced cardiotoxicity.

Possíveis conexões entre hipertensäo e hipercolesterolemia, em relaçäo a aterosclerose: vias de inativaçäo do óxido nítrico e oxidação das lipoproteínas / Possible connections between hypertension and hypercholesterolemia in relation to atherosclerosis inactivation pathways of nitric oxide and lipoprotein

A disfunção endotelial tem um importante papel na patogênese de doenças cardiovasculares. Tem sido sugerido que o colesterol plasmático, particularmente o que está associado à LDL, é um dos principais fatores de risco para a aterosclerose. Contudo, a oxidação da LDL é um evento crucial na patogênese da aterosclerose. Além disso, a redução da biodisponibilidade do óxido nítrico (`ANTPOT. PONTO NOï) tem sido relacionada à disfunção endotelial presente na aterosclerose. A redução da bioatividade do `ANTPOT. PONTO NOï na hipercolesterolemia, na hipertensão e em outras desordens metabólicas associadas com a aterogênese parece ser multifatorial. Contudo, as alterações da produç/biodisponibilidade do `ANTPOT. PONTO NOï na hipercolesterolemia e na hipertensão é ainda controverso...