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)

Adrenomedullin (AM) is a hypotensive peptide that functions as an important regulator in the cardiovascular and renal systems. The current study explored the potential therapeutic effects of delivering the human AM cDNA via a novel double-stranded adeno-associated virus vector (dsAAV) on hypertension and related complications in spontaneously hypertensive rats (SHR). A single dose of dsAAV-AM vector administered by tail vein injection into adult SHR resulted in significant reduction of systolic blood pressure at 2 weeks after gene delivery. This effect was observed through the entire duration of the experiment period (up to 16 weeks). Administration of dsAAV-AM also resulted in a decrease in total urine microalbumin content. Left ventricle and cardiomyocyte hypertrophy, fibrosis in the heart, glomerular sclerosis, and tubular injuries in the kidney were significantly reduced. Moreover, deterioration of hemodynamic variables was prevented in treated rats, as compared with the control groups. We conclude that AAV-mediated AM delivery can render a longterm and stable reduction of hypertension and protect against renal injury and cardiac remodeling in the spontaneously hypertensive rat model. Further preclinical studies are warranted for the development of a gene therapy strategy for human hypertension.
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PMID:Adrenomedullin gene delivery alleviates hypertension and its secondary injuries of cardiovascular system. 1581 32

Central sympathetic activation is one of the possible mechanisms underlying hypertension, in which reactive oxygen species may play a role. Thus, we examined whether adrenomedullin, an antioxidant peptide, is involved in the central regulation of arterial pressure through sympatho-modulatory action. Adrenomedullin knockout mice were fed with high-salt diet for 4 weeks to stimulate adrenomedullin production. In the wild-type littermates, brain adrenomedullin content was significantly increased with salt loading, but not in the knockout mice. Intracerebroventricular hyperosmotic saline increased arterial pressure and sympathetic nerve activity in a dose-dependent fashion. With the normal salt diet, the hyperosmotic saline-induced response did not significantly differ between the knockout and wild-type mice; with the high-salt diet, however, the response was significantly greater in the knockout mice than in wild-type littermates (arterial pressure: 35.3+/-5.7% versus 20.1+/-2.1%, P<0.05; sympathetic nerve activity: 30.3+/-4.8% versus 15.9+/-1.5%, P<0.05; respectively). Moreover, pretreatment with 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a membrane-permeable superoxide dismutase mimetic, inhibited the augmented response to central hyperosmotic saline in salt-loaded knockout mice. Consistently, the hyperosmotic saline-induced production of reactive oxygen species, measured by the lucigenin chemiluminescence method, was significantly greater in the isolated hypothalamus of salt-loaded knockout mice than in that of salt-loaded wild-type ones. In conclusion, endogenous adrenomedullin in the brain may inhibit sympathetic activation through its antioxidant action.
Hypertension 2005 Jun
PMID:Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain. 1586 31

Adrenomedullin was originally discovered as a vasodilative peptide, but recent studies have revealed its pleiotropic effects. Among these studies, the antioxidative properties of adrenomedullin were observed in adrenomedullin knockout mice. Through its antioxidative effect, adrenomedullin can protect organs from damage induced by high blood pressure, ischemia and aging. This indicates that antioxidants that can inhibit reactive oxygen species production but do not have a scavenging effect could be a new effective therapeutic target for organ protection in hypertension as well as metabolic syndrome, in which higher oxidative stress plays a pivotal role.
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PMID:Adrenomedullin as a potent antioxidative and antiatherosclerotic substance. 1591 20

Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator with a bistriazole structure has been identified.(1) In this work, a new series of structurally related compounds has been synthesized by reaction of phenoxyacetic acid with the corresponding dihydrazide, followed by treatment of the formed bisoxadiazoles with benzylamine. The affinity toward AM of the lead compound, and a structurally related family obtained from the small-molecule NCI library together with the synthesized series, has been determined. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study and conformational and molecular dynamics simulations have shown that the presence of a free NH and a phenyl group is essential for the interaction of these compounds with AM.
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PMID:Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin. 1594 80

Adrenomedullin was originally discovered as a vasodilative peptide, but recent studies have revealed its pleiotropic effects. Among these studies, the antioxidative properties of adrenomedullin were observed in adrenomedullin knockout mice. Through its antioxidative effect, adrenomedullin can protect organs from damage induced by high blood pressure, ischemia and aging. This indicates that antioxidants that can inhibit reactive oxygen species production but do not have a scavenging effect could be a new effective therapeutic target for organ protection in hypertension as well as metabolic syndrome, in which higher oxidative stress plays a pivotal role.
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PMID:Adrenomedullin as a potent antioxidative and antiatherosclerotic substance. 1594 48

Adrenomedullin (AM) is an endogenous vasodilatory peptide hormone, which plays a key role in the regulation and preservation of cardiovascular and pulmonary functions. Clinical and experimental studies have demonstrated that AM represents an alternative therapeutic option in the treatment of pulmonary hypertension. In addition, AM proved to be useful in the treatment of cardiovascular dysfunctions, such as arterial hypertension and congestive heart failure following myocardial infarction. Recent research has also shown that AM plays a pivotal role in the development of sepsis-associated hemodynamic and microcirculatory disorders. Experimental studies also suggest that infusion of exogenous AM might be a rational approach to prevent and treat hypodynamic septic shock. The objectives of this review article are to characterize the regulative properties of AM and to discuss clinical and experimental studies which allow to judge the role of AM in the setting of cardiovascular dysfunction and sepsis.
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PMID:[Role of adrenomedullin in the pathogenesis and treatment of cardiovascular dysfunctions and sepsis]. 1599 87

Adrenomedullin (AM) has various physiological actions on the cardiovascular system, including vasodilatation, diuresis, natriuresis, inhibition of aldosterone secretion, and increases of the cardiac output, all of which cause hypotension. Since AM plays a role in the pathophysiology of vascular diseases, genes controlling AM might be involved in the development and etiology of essential hypertension (EH). However, there have been few studies examining the relationship between the AM gene and hypertension. The aims of this study were to genotype some of the genetic markers for the human AM gene in Japanese subjects, and via a haplotype-based case-control study, assess the association between and the AM gene and EH or its risk factors, such as hyperlipidemia, renal damage, and proteinuria. We genotyped 205 EH patients and 210 age-matched normotensive (NT) individuals for two single nucleotide polymorphisms of rs4399321, rs7944706 and a microsatellite polymorphism located approximately 5,400 base pairs downstream of the 3' end of the human AM gene. The overall distribution in each variant and haplotype did not significantly differ between the two groups. However, after dividing the groups into those subjects with and without proteinuria, the haplotype analysis revealed a positive association. In conclusion, a possible mutation linked to the haplotype may indicate a genetic predisposition for proteinuria in EH.
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PMID:Haplotype-based case-control study revealing an association between the adrenomedullin gene and proteinuria in subjects with essential hypertension. 1609 66

Adrenomedullin (AM) is a multifunctional regulatory peptide, and endogenous AM is an important factor in regulating cardiovascular and renal homeostasis as a potent cardio-reno-protective factor. To illustrate the protective mechanism of adrenomedullin (AM) on the cardiovascular system by observing (1) the changes in mRNA and protein levels of AM and its receptor-calcitonin receptor-like receptor (CL) and receptor activity-modifying proteins (RAMPs)-in myocardia and aortas of spontaneously hypertensive rats (SHRs) and (2) the response of cardiovascular tissue to AM. The AM content and cyclic adenosine monophosphate (cAMP) production in myocardia and aortas were measured in SHRs and Wistar Kyoto (WKY) rats (11-week-old) by radioimmunoassay (RIA). The mRNA levels of brain natriuretic peptide (BNP), AM, CL, RAMP1, -2, -3 were determined by semi-quantitative RTPCR. Protein levels of CL, RAMP1, -2, -3 were assayed by Western blotting. SHRs had severe hypertension, and the tail-blood pressure was 76.7% higher, the ratio of heart weight to body weight (heart coefficient) 45.5% higher, and the BNP gene expression 4.5-fold higher than that of WKY rats (all p < 0.01). The AM-ir content in plasma, myocardia and aortas of SHRs increased by 42.5%, 68.3% and 80.4%, respectively (all p < 0.01) compared with WKY rats. Furthermore, the mRNA levels of AM, CL, RAMP1, RAMP2 and RAMP3 were elevated by 46% (p < 0.01), 62% (p < 0.05), 51.2% (p < 0.01), 41% (p < 0.01) and 54% (p < 0.01), respectively, in myocardia and by 72%, 87%, 155%, 53% and 74% (all p < 0.01), respectively, in aortas. The elevated mRNA level of CL, RAMP1 RAMP2 and RAMP3 correlated positively with that of AM mRNA in hypertrophic myocardia (r= 0.943, 0.621, 0.688 and 0.633, respectively, all p < 0.01) and aortas (r = 0.762, 0.892, 0.828 and 0.736, respectively, all p < 0.01). The protein levels of CL, RAMP1, RAMP2 and RAMP3 in myocardia and aortas of SHRs were increased compared with that of WKY rats. The response to AM was potentiated in myocardia and aortas in SHRs, and the production of cAMP was increased by 47% and 65% (both p < 0.01), respectively. AM-stimulated cAMP generation in myocardia and aortas was blocked by both AM(22-52), the specific antagonist of AM, and calcitonin gene-related peptide (CGRP)(8-37), the antagonist of the CGRP1 receptor. In myocardia and aortas of SHRs, the gene expressions and protein levels of AM, CL, RAMP1, RAMP2 and RAMP3 were increased, and the response to AM was potentiated. AM-stimulated cAMP generation in myocardia and aortas was blocked by both AM(22-52) and CGRP(8-37). The results suggest that the changes of AM and its receptors in cardiovascular tissue, and the increased response of cardiovascular tissue to AM might importantly impact the pathogenesis of hypertension.
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PMID:Potentiated response to adrenomedullin in myocardia and aortas in spontaneously hypertensive rat. 1645 76

Adrenomedullin (AM) is a potent endothelial-derived vasodilator secreted under the influence of various stimuli such as hypoxia, shear stress and cytokines. As all of these stimuli might be active under the conditions of obstructive sleep apnoea (OSA), we hypothesized that vascular AM production is increased in these patients. The study included 41 consecutive OSA patients and 28 control subjects without sleep-disordered breathing who were recruited from a pool of patients hospitalized for other reasons. Both groups were matched for anthropometric and comorbid factors. In all patients, i.e. OSA and controls, peripheral venous blood samples were taken at 07:00 hours after diagnostic polysomnography. In subsets of OSA patients, this was repeated after two nights of continuous positive airway pressure (CPAP) therapy (n = 28) and after several months of constant CPAP use (n = 11). The controls and the untreated OSA patients did not have serial blood sampling. In all blood samples, plasma AM levels were measured by an enzyme immunoassay kit. At baseline, the OSA patients had markedly elevated AM concentrations when compared to the controls. There were no differences between normo- and hypertensive OSA patients. After two nights of CPAP therapy, AM levels significantly decreased. Patients on long-term CPAP treatment showed complete normalization of plasma AM concentrations. In conclusion, this pilot study suggests that circulating AM is increased in untreated OSA irrespective of coexistent arterial hypertension and declines after CPAP therapy. AM upregulation might be considered as an adaptive mechanism to counteract the emergence of OSA-related cardiovascular disease.
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PMID:Circulating adrenomedullin in obstructive sleep apnoea. 1649 7

Adrenomedullin (AM) is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, cardiovascular and renal disorders, among others. Interestingly, AM behaves as a protective agent against some pathologies, yet is a stimulating factor for other disorders. Thus, AM can be considered as a new and promising target for the design of non-peptidic modulators that could be useful for the treatment of those pathologies, by regulating AM levels or the activity of AM. A full decade on from its discovery, much more is known about AM molecular biology and pharmacology, but this knowledge still needs to be applied to the development of clinically useful drugs.
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PMID:Adrenomedullin: a new and promising target for drug discovery. 1654 78


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