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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Earlier we have reported a defective dopamine D1-like receptor function, which was accompanied by a decrease in D1 receptor numbers and the inability of dopamine to inhibit Na,K-ATPase and Na,H-exchanger in proximal tubules of hyperinsulinemic obese Zucker rats. The present study was designed to test the hypothesis that the defect in dopamine receptor function is a result of hyperinsulinemia in obese rats. We designed experiments to study D1 receptor function in obese Zucker rats treated with rosiglitazone, as it lowers plasma insulin by improving insulin sensitivity. A group of untreated lean and obese rats served as controls. Rosiglitazone treatment (10 mg/kg orally, 4 weeks) caused significant decreases in plasma insulin, blood glucose, and blood pressure while causing an increase in renal sodium excretion compared with untreated obese rats. In the isolated proximal tubules obtained from untreated lean rats, dopamine caused concentration-dependent inhibition of the Na,K-ATPase activity, but this inhibitory effect was absent in untreated obese rats. In rosiglitazone-treated obese rats, the inhibitory effect of dopamine on Na,K-ATPase was significantly restored. This was accompanied by a complete restoration of D1 receptor numbers in proximal tubular membranes of treated obese rats. In another set of experiments, treatment of primary proximal tubule epithelial cells in culture medium with insulin caused a significant decrease in the D1 receptor abundance, suggesting a direct role of insulin on D1 receptor regulation. We conclude that hyperinsulinemia causes downregulation of D1 receptor function and lowering of plasma insulin levels leads to restoration of renal D1 receptor function.
Hypertension 2002 Dec
PMID:Rosiglitazone treatment restores renal dopamine receptor function in obese Zucker rats. 1246 73

Rosiglitazone, a potent member of the thiazolidinedione class of oral antidiabetic agents, reduces hyperglycaemia by improving insulin sensitivity--an important underlying factor in the development of both type 2 diabetes and its related cardiovascular complications. Rosiglitazone has now been available in clinical practice for more than three years, so there is a large body of evidence supporting its efficacy and safety as an antihyperglycaemic agent in patients with type 2 diabetes. Given the significant burden imposed on patients and healthcare resources by diabetes-related cardiovascular disease (CVD), there is growing interest in the thiazolidinediones in terms of their potential to ameliorate CVD risk factors as a result of their insulin-sensitising action and thus improve cardiovascular outcomes in individuals with type 2 diabetes. As reviewed below, rosiglitazone has a beneficial impact on a number of factors associated with insulin resistance and CVD, including microalbuminuria, hypertension, dyslipidaemia, visceral fat, elevated plasminogen activator inhibitor-1 levels and increased concentrations of C-reactive protein. These thiazolidinedione compounds are not problem-free and the long-term implications of some of rosiglitazone side-effects such as weight gain, changes in LDL-cholesterol concentration and fluid retention remain to be resolved. Large-scale clinical outcome studies should give a clearer picture for rosiglitazone and related thiazolidinediones in relation to the extent of their impact on diabetes disease progression and incident cardiovascular events.
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PMID:Rosiglitazone: potential beneficial impact on cardiovascular disease. 1266 97

Hypertension related to insulin resistance results from increased sodium retention. Dopamine, by activating D1A receptors in renal proximal tubules, increases sodium excretion. Recently, dopamine has been shown to augment its own signaling by recruiting intracellular D1A receptors to cell surface in proximal tubules. In this study, we hypothesized that coupling of D1A receptors to G proteins and dopamine-induced recruitment of D1A receptors to the plasma membrane are impaired in obese Zucker rats, resulting in a diminished natriuretic and diuretic response to D1A receptor agonist, SKF-38393. We also examined effects of rosiglitazone (3 mg/kg per day, 15 days) in restoring the defects in D1A receptor signaling and function in these animals. In obese rats, D1A receptors did not couple to G proteins, as shown by a lack of fenoldopam-sensitive [35S] GTPgammaS binding. In addition, we observed, by using radioligand binding and immunoblotting, that dopamine recruited D1A receptors to cell surface in lean Zucker rats but failed to do so in obese rats. Rosiglitazone treatment resulted in restoration of G-protein coupling of D1A receptors and their recruitment by dopamine in obese rats similar to that seen in lean rats. Furthermore, SKF-38393 failed to increase natriuresis and diuresis in obese rats compared with lean rats. However, in rosiglitazone-treated obese rats, SKF-38393 elicited a diuretic and natriuretic response similar to that in lean rats. Collectively, these results suggest that insulin resistance may be responsible for impaired renal dopamine D1A receptor signaling and function as treatment with an insulin-sensitizer, rosiglitazone, normalizes these parameters in obese Zucker rats.
Hypertension 2004 Feb
PMID:Rosiglitazone restores G-protein coupling, recruitment, and function of renal dopamine D1A receptor in obese Zucker rats. 1471 63

The peroxisome proliferator activated receptor (PPARgamma) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R(+)A(+)). Rosiglitazone decreased systolic (138+/-5 versus 128+/-5 mm Hg) and mean blood pressure (145+/-5 versus 126+/-7 mm Hg) of R(+)A(+) mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R(+)A(+) mice when compared with littermate controls (RA(-)). There were no effects of rosiglitazone on RA(-) mice; however, relaxation to acetylcholine (49+/-10 versus 82+/-9% at 100 micromol/L) and nitric oxide (51+/-11 versus 72+/-6% at 10 micromol/L) was significantly improved in treated R(+)A(+) mice. Rosiglitazone treatment of R(+)A(+) mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R(+)A(+) and RA(-) mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPARgamma-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (200 micromol/L) or the PPARgamma antagonist bisphenol A diglycidyl ether; 4,4'-isopropylidenediphenol diglycidyl ether (100 micromol/L). These data suggest that in addition to potential genomic regulation caused by PPARgamma activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.
Hypertension 2004 Mar
PMID:PPAR(gamma) agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. 1474 30

The class of antidiabetic drugs called thiazolidinediones (TZD), possesses as its main feature, the ability to ameliorate insulin sensitivity. As diabetes and hypertension share common ground in insulin resistance, the aim of this study was to evaluate if Rosiglitazone (RSG) may exert antihypertensive properties. Diabetic patients selected for the study were free from complications and/or other diseases. They were not known hypertensives, not on any antihypertensive treatment and they were on up to 2550 mg of metformin per day. Twenty-four hour blood pressure (24-h BP) measurements were recorded and monitored. Thirty-eight patients with a nocturnal decline in BP less than 10% (nondippers) participated in the study. Patients were randomly assigned to metformin+placebo (19 patients: group A) or to metformin+RSG 4 mg b.i.d. (19 patients: group B). Patients from both groups continued to take the same dosage of metformin during the study period. After 12 months of treatment, 24-h BP measurements were recorded. Fasting blood glucose, insulin, HbA1c, total cholesterol and trigliceryde levels were taken at the beginning and again at the end of the study. After 12 months of treatment with RSG+metformin we observed an amelioration of metabolic parameters (reduction of HOMA index, glucose, insulin, HbA1c, total cholesterol and triglycerides); an increase in body weight and BMI; a significant reduction of systolic and diastolic BP values both during the day and night and variations in the HOMA index were positively related to the reduction of diurnal and nocturnal BP (HOMA index versus diurnal systolic BP (P<0.001; r2=0.727); versus diastolic BP (P<0.001; r2=0.757); versus nocturnal systolic BP (P<0.001; r2=0.842), versus diastolic BP (P<0.001; r2=0.773)). These findings indicate firstly that RSG is able to induce a reduction of BP and secondly the amelioration of insulin sensitivity is associated with the reduction of BP.
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PMID:Rosiglitazone effects on blood pressure and metabolic parameters in nondipper diabetic patients. 1612 19

The present study evaluated the effects of peroxisome proliferator-activated receptor (PPAR)-gamma activators on ANG II-induced signaling pathways and cell growth. Vascular smooth muscle cells (VSMC) derived from rat mesenteric arteries were treated with ANG II, with/without the AT1 receptor blocker valsartan or the AT2 receptor blocker PD-123319, after pretreatment for 24 h with the PPAR-gamma activators 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) or rosiglitazone. Both 15d-PGJ2 and rosiglitazone decreased ANG II-induced DNA synthesis. Rosiglitazone treatment increased nuclear PPAR-gamma expression and activity in VSMC. However, rosiglitazone did not alter expression of PPAR-alpha/beta, ERK 1/2, Akt, or ANG II receptors. 15d-PGJ2 and rosiglitazone decreased ERK 1/2 and Akt peak activity, both of which were induced by ANG II via the AT1 receptor. Rosiglitazone inhibited ANG II-enhanced phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), as well as Src homology (SH) 2-containing inositol phosphatase 2 (SHIP2). PPAR-gamma activation reduced ANG II-induced growth associated with inhibition of ERK 1/2, Akt, 4E-BP1, and SHIP2. Modulation of these pathways by PPAR-gamma activators may contribute to regression of vascular remodeling in hypertension.
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PMID:PPAR-gamma inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1. 1615 1

Rosiglitazone is a peroxisome proliferator active receptor. gamma agonist, which increases insulin sensitivity in adipose tissue, muscle, and liver. Rosiglitazone is a member of the thiazolidinedione group, and because of its significantly positive effect on glycemic control, it is especially preferred in type 2 diabetic patients with a high cardiovascular disease risk. This drug, because of its decreasing effect on insulin resistance, is used alone or combined with type 2 diabetic drugs. A 73-year-old female patient was admitted to the emergency department with dyspnea, pink frothing phlegm, cyanosis, and tiredness. She was lethargic, uncooperative, and had no orientation. In arterial blood gases, hypoxemia and hypercapnia were found. She was taken to the general intensive care unit, and oxygen was applied via mask. The patient had a history of 10 years of diabetes mellitus, hypertension, and atherosclerotic cardiac disease, and she was using rosiglitazone for the past 6 weeks. Her chest x-ray was taken, and acute pulmonary edema was diagnosed. In her last echocardiography, which was performed 1 year before, no signs indicating cardiac failure and pleural effusion could be found. Therefore, it was concluded that pulmonary edema occurred as a complication of rosiglitazone use. After stabilizing the patient's vital signs, blood glucose levels, and lactate levels, medical treatment of diabetes mellitus was rearranged, and she was discharged on the seventh day after her admittance. In a patient with diabetes mellitus who has been admitted to the intensive care unit because of acute pulmonary edema, for differential diagnosis, use of rosiglitazone should be kept in mind during the determination of treatment. Therefore, the authors aim to discuss the effect of rosiglitazone on creating acute pulmonary edema with a case report presentation.
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PMID:Acute pulmonary edema due to rosiglitazone use in a patient with diabetes mellitus. 1669 44

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
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PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

Altered vascular responses to various vasopressors in animal models of insulin resistance (IR) and diabetes have been well documented. However, the precise mechanisms about vascular responses in IR with or without frank hyperglycemia (prediabetic state) are not available. Moreover, recently the role of peroxisome proliferators activated receptor-gamma (PPAR gamma) has been linked to influence the vascular responses in hypertensive and diabetic state. Hence, the present study was conceived to determine the role of hyperglycemia on angiotensin II (Ang II) mediated vascular responses in the high fat diet (HFD) induced insulin resistance either with mild or frank hyperglycemia [induced by injection of low dose streptozotocin (STZ) to HFD fed rats (HFD+STZ)]. In addition, insulin-sensitizing agent such as rosiglitazone and pioglitazone were also studied on biochemical and vascular responses. Ang II-induced contractions were studied isometrically in thoracic aortic rings isolated from 4 weeks of normal pellet diet (NPD) fed control, HFD and HFD+STZ fed insulin resistant rats. Specific binding of Ang II receptors were carried out using radioligand ([(3)H]-Ang II) binding studies. After 4 weeks of HFD feeding, rats exhibited characteristics features of insulin resistance such as mild hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and hypertension; whereas HFD+STZ treated rats showed all above parameters along with frank hyperglycemia. Maximal contractile response (E(max)) to Ang II is increased in HFD fed rats as compared to control rats. Moreover, E(max) values are further elevated in HFD+STZ group where the frank hyperglycemia was induced by low dose of streptozotocin. Rosiglitazone (5 mg kg(-1), p.o.) and pioglitazone (10 mg kg(-1), p.o.) treatment significantly lowered the plasma glucose, triglycerides, insulin and cholesterol levels in insulin resistance rats. In addition, it also restored the elevated systolic, mean arterial, diastolic blood pressure and attenuated the enhanced contractile responses to Ang II in thoracic aortic rings obtained from both HFD and HFD+STZ treated rats. Specific binding of [(3)H]-Ang II is upregulated in HFD-fed and HFD+STZ treated rats. Treatment with pioglitazone and rosiglitazone significantly decreased the AT(1)R specific binding in HFD fed rats. Our results indicate the role of hyperglycemia in the elevation of Ang II induced vascular responses in thoracic aorta isolated from insulin resistant rats and PPAR gamma agonists can attenuate these responses.
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PMID:PPAR gamma agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance. 1736 46

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid x receptor agonist 9-cis-retinoic acid, but was prevented by PPARgamma antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1beta, interleukin-6, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-beta and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARgamma activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. 1739 60


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