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

Chronic inhibition of endothelial NO synthesis by the administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation (monocyte infiltration into coronary vessels and monocyte chemoattractant protein-1 expression) as well as subsequent arteriosclerosis. The small GTPase Rho controls cell adhesion, motility, and proliferation and is activated by several growth factors such as angiotensin II. We investigated the effect of a specific inhibitor of Rho-kinase, Y-27632, in rats treated with L-NAME to determine the role of the Rho/Rho-kinase pathway in the development of arteriosclerosis. We found here increased activity of Rho/Rho-kinase after L-NAME administration and its prevention by angiotensin II type 1 receptor blockade. Hydralazine or lecithinized superoxide dismutase (l-SOD) did not affect Rho/Rho-kinase activity. Co-treatment with Y-27632 did not affect the L-NAME-induced increase in cardiovascular tissue ACE activity or L-NAME-induced decrease in plasma NO concentrations, but did prevent the L-NAME-induced early inflammation and late coronary arteriosclerosis. In addition, Y-27632 prevented the increased gene expression of monocyte chemoattractant protein-1 and transforming growth factor-beta1 as well as cardiac fibrosis and glomerulosclerosis. These findings suggest that increased activity of Rho/Rho-kinase pathway mediated via the angiotensin II type 1 receptor may thus be important in the pathogenesis of early vascular inflammation and late remodeling induced by chronic inhibition of NO synthesis. The beneficial effects of Rho-kinase inhibition are not mediated by restoration of NO production. The Rho-kinase pathway could be a new therapeutic target for treatment of vascular diseases.
Hypertension 2002 Feb
PMID:Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. 1184 92

Renal fibrosis is one of the major complications associated with the development of hypertension. The objective of the present study was to determine whether and by which mechanisms treatment with AT1 receptor antagonists makes possible the regression of renal vascular and glomerular fibrosis. Experiments were performed in the hypertensive model of nitric oxide (NO) deficiency in rats. After 4 wk of hypertension, mortality rates averaged 20%; the surviving animals displayed a decline of renal function (urine protein/creatinine, 1.89 +/- 0.63 versus 0.24 +/- 0.03 mg/mmol; creatininemia, 110 +/- 14 versus 38 +/- 2 mmol/L in hypertensive animals and control, respectively; P < 0.01) and an exaggerated gene and protein expression of TGF-beta, collagen I, and collagen IV (P < 0.001) within the renal vasculature associated with the development of glomerulosclerosis (sclerotic index, 2.26 +/- 0.29 versus 0.12 +/- 0.04; P < 0.001). In addition, activities of matrix metalloproteinases 2 and 9 were increased twofold in renal vessels and glomeruli (P < 0.01). Afterwards, losartan, an antagonist of angiotensin receptor type I, or hydralazine were administered in subgroups of hypertensive animals. After 1 wk of angiotensin II antagonism, collagen I, collagen IV, and TGF-beta gene and protein expressions were decreased and glomerulosclerosis was less marked (sclerotic index 1.04 +/- 0.45), whereas activities of metalloproteinases remained twofold higher than controls (P < 0.01). Hydralazine failed to improve renal function despite a similar degree of systolic pressure decrease. After 4 wk of losartan, the renal functional and histologic parameters were completely normalized, whereas they remained damaged in the hypertensive animals in which the mortality rate reached 85%. These data suggest that the progression of renal vascular fibrosis is a reversible process, at least in the NO deficiency model. The mechanism of the regression appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade.
 ...
PMID:Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases. 1270 11

Twenty-one patients have been treated for hypertension with oral doses of hexamethonium salts, Apresoline(R) or combinations of both. Three of 18 patients had good or excellent response to hexamethonium alone. Five of 13 treated with hexamethonium salts plus Apresoline had good or excellent results, as did 8 of 14 treated with Apresoline alone. The addition of very small doses of hexamethonium chloride to optimal doses of Apresoline improved the effect of the Apresoline in three patients. Postural hypotension and constipation due to hexamethonium were the most serious undesirable effects.
 ...
PMID:Hexamethonium and hydralazine hydrochloride for treatment of hypertension. 1312 25

Hypertensive crises are situations when arterial hypertension shows its immediate damaging potential, and in such circumstance, antihypertensive therapy provides its life-saving effectiveness. Among these situations are hypertensive emergencies, hypertensive urgencies, hypertensive encephalopathy, and also accelerated-malignant hypertension characterised by the presence of grade 3 or grade 4 Keith-Wagener retinopathy and numerous complications (acute renal failure, heart failure, haemorrhagic brain stroke or acute coronary events). Despite of antihypertensive therapy, the mortality rate of accelerated-malignant hypertension is about 25% after the 5th year. We present the case of a thirty-three years old male, with a five-year history of non-treated hypertension, who develops accelerated- hypertension with heart failure, microangiopathic haemolytic anaemia and renal failure that requires renal replacement therapy. After a strict control of blood pressure; initially using parenteral agents such as Solinitrin and Urapidil, followed by angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers, calcium channel blockers and Hydralazine, the patient partially recovers his renal function, resulting in the withdrawal of haemodialysis.
 ...
PMID:[Accelerated arterial hypertension in a young male]. 1521 76

The transcription factor nuclear factor (NF)-kappaB plays a leading role in cardiac hypertrophy associated with heart failure, but whether it is involved in cardiac mass reduction is not known. We evaluated whether inhibiting the NF-kappaB cascade with pyrrolidine dithiocarbamate (PDTC) in spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto rats (WKYs) affected hypertrophy. We measured NF-kappaB signaling components [NF-kappaB translocation, IkappaBalpha, p65, mRNA and protein levels, and IkappaB kinase-beta (IKKbeta) activity] at 12 and 36 wk in WKYs and SHRs and at 10 wk in PDTC-treated rats (n = 9). NF-kappaB activation was also evaluated in rats treated for 10 wk with captopril or hydralazine alone or with either drug plus PDTC. All components were increased in SHRs compared with WKYs. After PDTC treatment, NF-kappaB activity was inhibited, and heart weight-to-body weight ratio in SHRs was significantly attenuated (3.52 +/- 0.04 to 3.32 +/- 0.05 mg/kg). Captopril treatment significantly reduced cardiac mass (3.5 vs. 3.05 mg/kg; n = 9) and inhibited NF-kappaB activity (169.71 +/- 5.70 to 106.7 +/- 12.44). Hydralazine had no effect on cardiac mass (3.5 vs. 3.42 mg/kg) or NF-kappaB activity (169.71 +/- 5.70 to 155.52 +/- 6.11). Hydralazine plus PDTC reduced blood pressure (191.16 +/- 1.7 to 158.5 +/- 2.36 mmHg) and inhibited NF-kappaB activity (169.71 +/- 5.70 to 97.29 +/- 3.65). Our data suggest that 1) cardiac hypertrophy in SHRs is partly due to NF-kappaB activation, 2) inhibition of NF-kappaB activity by PDTC parallels regression of hypertrophy, and 3) regression of hypertrophy is partly due to inhibition of NF-kappaB activity, independent of hypertension. The relationship between NF-kappaB activity and cardiac remodeling is causal, not coincidental.
 ...
PMID:Inhibition of NF-kappaB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats. 1596 73

We investigated the role of angiotensin II type 1 (AT1) and AT2 receptors, matrix metalloproteinases (MMPs), and extracellular matrix (ECM) components involved in vascular remodeling of resistance arteries induced by angiotensin II (Ang II). Sprague-Dawley rats received Ang II (120 ng/kg per minute SC) +/- the AT1 antagonist losartan (10 mg/kg per day PO), the AT1/AT2 antagonist Sar1-Ile8-Ang II (Sar-Ile; 10 microg/kg per minute SC), or hydralazine (25 mg/kg per day PO) for 7 days. Structure and mechanical properties of small mesenteric arteries were evaluated on a pressurized myograph. Ang II increased growth index (+21%), which was partially decreased by losartan (-11%) and abrogated by Sar-Ile. Hydralazine markedly increased growth index (+32%) despite systolic blood pressure (BP) lowering, suggesting a BP-independent effect of Ang II on vascular growth. Elastic modulus was increased by Sar-Ile compared with Ang II and control. Vascular type I collagen was reduced (P<0.05), whereas fibronectin increased significantly with Sar-Ile. Vascular tissue inhibitor of metalloproteinase-2 binding to MMP-2 was abrogated by Sar-Ile, but MMP-2 activity was significantly increased compared with losartan, Ang II, and controls. Thus, AT1 blockade exerted antigrowth effects and reduced stiffness of small resistance arteries by decreasing nonelastic fibrillar components (collagen and fibronectin). Concomitant AT1/AT2 blockade prevented growth, reduced collagen type I and elastin deposition but increased vascular stiffness, fibronectin, and MMP-2 activity. These results demonstrate opposing roles of AT1 receptors that increase fibronectin and vascular stiffness and AT2 receptors that decrease MMP-2 and increase elastin. Changes in vascular wall mechanics, ECM deposition, and MMP activity are thus modulated differentially by Ang II receptors.
Hypertension 2005 Sep
PMID:Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries. 1604 61

Hydralazine was one of the first orally active antihypertensive drugs developed. Currently, it is used principally to treat pregnancy-associated hypertension. Hydralazine causes two types of side effects. The first type is an extension of the pharmacologic effect of the drug and includes headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness, and salt retention. The second type of side effects is caused by immunologic reactions, of which the drug-induced lupus-like syndrome is the most common, and provides clues to underscoring hydralazine's DNA demethylating property in connection with studies demonstrating the participation of DNA methylation disorders in immune diseases. Abnormalities in DNA methylation have long been associated with cancer. Despite the fact that malignant tumors show global DNA hypomethylation, regional hypermethylation as a means to silence tumor suppressor gene expression has attracted the greatest attention. Reversibility of methylation-induced gene silencing by pharmacologic means, which in turns leads to antitumor effects in experimental and clinical scenarios, has directed efforts toward developing clinically useful demethylating agents. Among these, the most widely used comprise the nucleosides 5-azacytidine and 2'deoxy-5-azacytidine; however, these agents, like current cytotoxic chemotherapy, causes myelosuppression among other side effects that could limit exploitation of their demethylating properties. Among non-nucleoside DNA demethylating drugs currently under development, the oral drug hydralazine possess the ability to reactivate tumor suppressor gene expression, which is silenced by promoter hypermethylation in vitro and in vivo. Decades of extensive hydralazine use for hypertensive disorders that demonstrated hydralazine's clinical safety and tolerability supported its testing in a phase I trial in patients with cancer, confirming its DNA demethylating activity. Hydralazine is currently being evaluated, along with histone deacetylase inhibitors either alone or as adjuncts to chemotherapy and radiation, for hematologic and solid tumors in phase II studies.
 ...
PMID:Hydralazine target: from blood vessels to the epigenome. 1650

Supine hypertension is a common finding in patients with autonomic failure; it is associated with end-organ damage and produces nighttime pressure diuresis with worsening of orthostatic hypotension. During the daytime, it is best treated by avoiding the supine posture. At night, simple measures such as raising the head of the bed by 6 to 9 inches can be effective, but most patients require pharmacologic treatment. Transdermal nitroglycerin (0.1 to 0.2 mg/h) or nifedipine (30 mg, orally) has proved to be effective. Hydralazine and minoxidil are usually less effective but may be useful in a given patient. One key therapeutic concept is the hypersensitivity of these patients to depressor agents, requiring a careful titration of the doses on an individual basis. For those patients with proven residual sympathetic tone, as in multiple system atrophy, central sympatholytics such as clonidine may provide an alternative.
 ...
PMID:Management of hypertension in the setting of autonomic dysfunction. 1653 84

Acrolein, a major lipid peroxidation product, has been associated with both CNS trauma and neurodegenerative diseases. Because of its long half-life, acrolein is a potent endogenous toxin capable of killing healthy cells during the secondary injury process. Traditionally, attempts to intervene in the process of progressive cell death after the primary injury have included scavenging reactive oxygen species (so-called free radicals). The animal data supporting such an approach have generally been positive, but all human clinical trials attempting a similar outcome in human CNS injury have failed. New drugs that might reduce toxicity by scavenging the products of lipid peroxidation present a promising, and little investigated, therapeutic approach. Hydralazine, a well-known treatment for hypertension, has been reported to react with acrolein, forming hydrazone in cell-free systems. In the companion paper, we have established an acrolein-mediated cell injury model using PC12 cells in vitro. Here we test the hypothesis that the formation of hydrazone adducts with acrolein is able to reduce acrolein toxicity and spare a significant percentage of the population of PC12 cells from death. Concentrations of approximately 1 mM of this aldehyde scavenger can rescue over 80% of the population of PC12 cells. This study provides a basis for a new pharmacological treatment to reduce the effects of secondary injury in the damaged and/or diseased nervous system. In particular, we describe the need for new drugs that possess aldehyde scavenging properties but do not interfere with the regulation of blood pressure.
 ...
PMID:Hydralazine rescues PC12 cells from acrolein-mediated death. 1661 36

The role of angiotensin II type 2 receptors (AT2Rs) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats, AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. Because FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old-rat resistance arteries. Mesenteric resistance arteries (250 mum in diameter) were isolated from old (24 months) and control (4 months) rats receiving hydralazine (16 mg/kg per day; 2 weeks) or water. FMD, NO-mediated dilation, and endothelial NO synthase expression were lower in old versus control rats. AT2R blockade improved FMD in old rats, suggesting that AT2R stimulation produced vasoconstriction. AT2R expression was higher in old rats and mainly located in the smooth muscle layer. In old rats, AT2R stimulation induced endothelium-independent contraction, which was suppressed by the antioxidant Tempol. Reactive oxygen species level was higher in old-rat arteries than in controls. Hydralazine improved FMD and NO-dependent dilation in old rats without change in AT2R expression and location. In old rats treated with hydralazine, reactive oxygen species level was reduced in endothelial and smooth muscle cells, and AT2R-dependent contraction was abolished. Thus, AT2R stimulation induced vasoconstriction through activation of reactive oxygen species production, contributing to decrease FMD in old-rat resistance arteries. Hydralazine suppressed AT2R-dependent reactive oxygen species production and AT2R-dependent contraction, improving FMD. Importantly, endothelial alterations in aging were reversible. These findings are important to consider in the choice of vasoactive drugs in aging.
Hypertension 2007 Jul
PMID:Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats. 1748


<< Previous 1 2 3 4 5 6 7 8 9 10