Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ETs) are a family of potent peptidic vasoconstrictors that have been implicated in the pathogenesis of many cardiovascular disorders such as hypertension, myocardial infarction, congestive heart failure, atherosclerosis and restenosis. Suppression of the production of these peptides by inhibitors of endothelin-converting enzyme-1 (ECE-1), which is involved in the final step of post-translational processing of ETs, may therefore have beneficial effects for the treatment of these disorders. A number of non-selective and selective ECE-1 inhibitors have been identified, and this article reviews the pharmacological effects of these agents in animal models of cardiovascular diseases and presents available clinical data.
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PMID:Utility of endothelin-converting enzyme inhibitors for the treatment of cardiovascular diseases. 1458 51

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.
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PMID:Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders. 1472 28

We assessed whether large-scale expression profiling of leukocytes of patients with essential hypertension reflects characteristics of systemic disease and whether such changes are responsive to antihypertensive therapy. Total RNA from leukocytes were obtained from untreated (n=6) and treated (n=6) hypertensive patients without apparent end-organ damage and from normotensive controls (n=9). RNA was reverse-transcribed and labeled and gene expression analyzed using a 19-K oligonucleotide microarray using dye swaps. Samples of untreated and of treated patients were pooled for each sex and compared with age- and sex-matched controls. In untreated patients, 680 genes were differentially regulated (314 up and 366 down). In the treated patients, these changes were virtually absent (4 genes up, 3 genes down). A myriad of changes was observed in pathways involved in inflammation. Inflammation-dampening interleukin receptors were decreased in expression. Intriguingly, inhibitors of cytokine signaling (the PIAS family of proteins) were differentially expressed. The expression of several genes that are involved in regulation of blood pressure were also differentially expressed: angiotensin II type 1 receptor, ANP-A receptor, endothelin-2, and 3 of the serotonin receptors were increased, whereas endothelin-converting enzyme-1 was decreased. Strikingly, virtually no changes in gene expression could be detected in hypertensive patients who had become normotensive with treatment. This observation substantiates the long-standing idea that hypertension is associated with a complex systemic response involving inflammation-related genes. Furthermore, leukocytes display differential gene expression that is of importance in blood pressure control. Importantly, treatment of blood pressure to normal values can virtually correct such disturbances.
Hypertension 2004 May
PMID:Broadly altered gene expression in blood leukocytes in essential hypertension is absent during treatment. 1500 37

Endothelin (ET)-mediated vasoconstriction has been implicated in the pathophysiology of various disorders, e.g. hypertension, chronic heart failure, acute renal failure, pulmonary hypertension, and subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. The potential involvement of ETs in cerebral vasospasm following SAH has triggered considerable interest in designing therapeutic strategies to inhibit biological effects of ET. Major approaches include: (a) reducing the levels of circulating ET- 1 by the the specific anti- ET- 1 antibodies, (b) antagonizing the ET receptors, and (c) suppressing the biosynthesis of ET-1. To date, numerous antagonists of ET(A) and/or ET(B) receptors have been discovered, and some are under clinical evaluation. Inhibitors of endothelin-converting enzymes (ECEs), which catalyze the biosynthesis of ET-1, have also been synthesized. Two types of ECE-1 inhibitors have been evaluated in various animal disease models: dual ECE-1/neutral endopeptidase 24.11 (NEP) inhibitors and selective ECE-1 inhibitors. In this article, the effects of ET receptor antagonists and ECE-1 inhibitors on the prevention and reversal of SAH-induced cerebral vasospasm in preclinical animal models are reviewed.
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PMID:Endothelin and subarachnoid hemorrhage-induced cerebral vasospasm: pathogenesis and treatment. 1527 81

Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor (ACEi) is an effective therapy in hypertension. Vasopeptidase inhibition was initially proposed with compounds inhibiting both angiotensin-converting enzyme and neutral endopeptidase (omapatrilat), but clinical trials revealed that reducing angiotensin II while blocking the degradation of vasodilatory peptides was not without concerns. We have previously investigated the combination of an ACEi with an endothelin-converting enzyme inhibitor (ECEi); now we add a neutral endopeptidase inhibitor (NEPi) toward triple vasopeptidase inhibition. Male spontaneously hypertensive rats were surgically implanted with a vascular catheter and treated with an ACEi (benazepril), a NEPi (CGS 24592) and an ECEi (CGS 35066) (continuous intra-arterial infusion at 1 or 5 mg/kg/day x 5 days each). After 15 days, drugs administration was stopped for 3 days. ACEi (1 mg/kg per day) reduced the mean arterial blood pressure by 8.4%. The addition of a NEPi and an ECEi at the same dose did not shown any added benefit. The mean arterial blood pressure came back to baseline upon cessation of treatment. ACEi (5 mg/kg per day) reduced the mean arterial blood pressure by 28%. The mean arterial blood pressure remained attenuated by 21% and 19% with the addition of the NEPi and the ECEi. Again, the mean arterial blood pressure rose back to 148 +/- 4 mmHg following cessation of treatment. Daily biochemical and hematological analysis of plasma did not reveal any signs of toxicity, except for a rapid elevation in K (40%) after 1 day of ACEi. Thus, angiotensin II inhibition plays a primary role in controlling the blood pressure of spontaneously hypertensive whereas additional NEPi and ECEi did not provide further benefits under the present dose combinations. The normalizing effect of the higher dose of ACEi by itself made it impossible to discriminate the role of neutral endopeptidase and endothelin-converting enzyme-modulated peptides and to further define the paradigm of triple vasopeptidase inhibition toward better control of vascular hemodynamics. Additional studies are underway.
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PMID:Triple vasopeptidase inhibition of angiotensin-converting enzyme/neutral endopeptidase/endothelin-converting enzyme activities on the hemodynamic profile of chronically instrumented unrestrained conscious spontaneously hypertensive rats. 1583 31

CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.
Hypertension 2005 Jun
PMID:Dual ECE/NEP inhibition on cardiac and neurohumoral function during the transition from hypertrophy to heart failure in rats. 1589 63

The precursor of endothelin-1, big endothelin-1, can be hydrolyzed by chymase to generate endothelin-1 (1-31) in vitro. In the present study, we explored the processes involved in the production of endothelin-1 (1-31) as well as its pharmacodynamic characteristics in the rabbit in vivo. Endothelin-1 (1-31) (1 nmol/kg, injected into the left cardiac ventricle) induced a monophasic increase of mean arterial blood pressure similarly to big endothelin-1 (1-38), whereas endothelin-1 induces a biphasic response. Phosphoramidon, a dual neutral endopeptidase and endothelin-converting enzyme inhibitor, blocked both pressor responses to endothelin-1 (1-31) and big endothelin-1 but not those afforded by endothelin-1. Thiorphan, a neutral endopeptidase inhibitor, markedly inhibited the response to endothelin-1 (1-31) but only weakly reduced that of big endothelin-1. In contrast, CGS 35066, an endothelin-converting enzyme inhibitor, was significantly more efficient against the pressor response to big endothelin-1 than to endothelin-1 (1-31). Furthermore, injection of big endothelin-1 concomitantly with phosphoramidon induced an increase in endothelin-1 (1-31) plasma levels. Finally, intracardiac-administered endothelin-1 (1-31) induced an increase of endothelin-1 plasma levels, which are markedly reduced by phosphoramidon and thiorphan but not by CGS 35066. Our results thus demonstrate that endothelin-1 (1-31) is an alternate intermediate in the production of endothelin-1 after big endothelin-1 administration in the rabbit in vivo.
Hypertension 2005 Jul
PMID:Endothelin-1 (1-31) is an intermediate in the production of endothelin-1 after big endothelin-1 administration in vivo. 1595 17

The effects of iptakalim, a new ATP-sensitive potassium channel opener, were studied in spontaneously hypertensive rats (SHR). Treatment of 12-week-old male SHR (six animals in each group) with iptakalim by gastric lavage at doses of 1, 3, or 9 mg/kg/day for 12 weeks resulted in a lowering of blood pressure. Iptakalim provided significant renoprotection to SHR rats as measured by decreased proteinuria and improved renal function. Histological evidence demonstrated that iptakalim could reverse renal vascular remodeling (of afferent arterioles, arcuate arteries, or interlobular arteries), and improve pathological changes of glomerular, renal interstitial, and glomerular filtration membranes. These effects were accompanied by the decreased circulation and intrarenal concentrations of endothelin 1 and transforming growth factor beta1 (TGF-beta1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-beta1, and the subunits of ATP-sensitive potassium channels (K(ATP)), Kir1.1 and Kir6.1, in the kidney during hypertension. Abnormal expression of matrix components [collagen IV, fibronectin, matrix metalloproteinase 9 (MMP-9) and MMP tissue inhibitor 1 (TIMP-1)] was also significantly reversed by iptakalim. Our results demonstrate that chronic treatment with iptakalim not only reduces blood pressure but also preserves renal structure and function in SHR. In addition to reducing blood pressure, the renoprotective of iptakalim may be involved in inhibiting the circulation and intrarenal concentrations of endothelin 1 and TGF-beta1, regulating the expression of K(ATP) genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.
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PMID:A new ATP-sensitive potassium channel opener protects the kidney from hypertensive damage in spontaneously hypertensive rats. 1605 97

Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin (ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations (ie, gene polymorphisms) in ET-related gene might affect exercise-induced improvement in arterial stiffness with age in human subjects. The present study provides a cross-sectional investigation of 191 healthy middle-aged and older (65+/-1 years) human subjects to clarify the relationship between the regular exercise-induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme (ECE)-1, ECE-2, ET-A receptor (ET-A), and ET-B receptor (ET-B). The study subjects were divided into active and inactive groups based on the median value (186 kcal/d) of energy expenditure. Brachial-ankle arterial pulse wave velocity (baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013(+289)A/G in intron 17 of ECE-1, 669(+17)T/C in intron 5 of ECE-2, 958A/G in exon 6 of ET-A, and 831A/G in exon 4 of ET-B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE-1 influenced basal blood pressure. Polymorphisms in ECE-1 and ECE-2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET-A and ET-B affected baPWV in the 2 groups. The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure.
Hypertension 2006 May
PMID:Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects. 1656 85

CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme-1 with respective IC50 values of 22, 2, and 55 nM. We characterized the safety profile and toxicity of escalating doses of CGS 35601 over a 20-day period in chronically instrumented, unrestrained, conscious, male, spontaneously hypertensive rats (SHR). Once instrumented with an arterial catheter, the SHR were placed in metabolic cages allowing daily assessment of hemodynamics and blood sampling for biochemical and hematological measurements. After a 7-day stabilization period, the SHR were divided into 2 groups: Gr. 1, (n = 13 to 18) receiving CGS 35601 at 0.01, 0.1, 1 and 5 mg kg(-1) day(-1) (continuous i.a. infusion) for 5 consecutive days/dose, followed by a 5-day washout; and Gr. 2, (n = 10) receiving vehicle (saline). The highest dose of CGS 35601 dose-dependently reduced MABP from 156 +/- 4 up to 94 +/- 5 mm Hg, whereas heart rate, metabolic, electrolytic, and hematological profiles, growth, diuresis, and renal activity were unaffected, and no hepatic or liver toxicities were observed. These results suggest that this novel triple VPI presents no safety concerns at this stage and may become of interest for the treatment of hypertension and other cardiovascular disorders. Long-term chronic experiments are needed to assess possible angioedema and increases in vascular permeability.
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PMID:The first preclinical pharmacotoxicological safety assessment of CGS 35601, a triple vasopeptidase inhibitor, in chronically instrumented, conscious, and unrestrained spontaneously hypertensive rats. 1670 27


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