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)

Tetrahydrobiopterin (BH4) acts as an important co-factor for endothelial nitric oxide synthase (eNOS). Glucocorticoids have been shown to inhibit expression of the rate-limiting enzyme for tetrahydrobiopterin synthesis, GTP cyclohydrolase, in other cell types. We hypothesized that endothelium-dependent vasodilator responses would be blunted in rats made hypertensive with dexamethasone. Further, we hypothesized that treatment of rat vascular segments with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression. We report that endothelium-dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone-hypertensive rats compared with sham values. Dexamethasone incubation abolishes contraction to Nomega-nitro-L-arginine (L-NNA, 10(-5) M) in endothelium-intact aortic rings, and inhibits expression of GTP cyclohydrolase. We conclude that inhibition of BH4 synthesis by glucocorticoid regulation of GTP cyclohydrolase expression may contribute to reduced endothelium-dependent vasodilation characteristic of glucocorticoid-induced hypertension.
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PMID:Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function. 1136 34

We investigated the impact of intrauterine growth retardation and fetal programming of hypertension by maternal dexamethasone treatment on cardiac uncoupling protein (UCP) expression during development and in adulthood in the rat. Dexamethasone administered via an indwelling osmotic pump (100 micrograms/kg body mass per day from day 15 of gestation) decreased fetal body mass at day 21 of gestation (by 13%; P < 0.05), elicited significant (+24%, P < 0.01) systolic hypertension and elevated corticosterone levels (+15%; P < 0.05) in adult (24-week-old) male offspring. Cardiac UCP-2 and UCP-3 protein expression was significantly upregulated during early postnatal development, reaching 1.7-fold and 2.7-fold the respective fetal day-21 levels by postnatal day 7 and reaching plateaus at postnatal days 15-21 (2.5-fold and 3.5-fold of respective fetal levels). Cardiac UCP protein expression at fetal day 21 and the ontogeny of cardiac UCP expression during early postnatal life were unaffected by prenatal dexamethasone treatment. Prenatal dexamethasone treatment did not abrogate the postnatal surge in corticosterone levels or modify plasma non-esterified fatty acid (NEFA) levels over this period. However, UCP-2 and UCP-3 protein expression was significantly downregulated in the hearts of adult hypertensive male offspring of dexamethasone-treated mothers (to 27% and 65% of control values respectively). We propose that changes in cardiac UCP protein expression are linked with changes in cardiac metabolic fuel selection (from glucose-->fatty acids at birth and from fatty acids-->glucose during hypertension).
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PMID:Excessive glucocorticoid exposure during late intrauterine development modulates the expression of cardiac uncoupling proteins in adult hypertensive male offspring. 1141 22

Patients with steroid-resistant nephrotic syndrome often have an unsatisfactory long-term outcome and are at risk of developing chronic renal failure. We prospectively treated 65 children with idiopathic steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with intravenous pulses of corticosteroids and oral cyclophosphamide. Dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg) was administered intravenously, initially 6 pulses on alternate days, followed by 4 fortnightly and 8 monthly pulses. Oral cyclophosphamide therapy was given for 12 weeks and tapering doses of prednisolone were administered for 52 weeks. The mean age at treatment was 85.7+/- 44.9 months. Five patients developed serious infections during administration of initial alternate-day pulses and were excluded. Of 59 patients who completed initial alternate-day therapy, 17 had complete and 8 partial remission; 34 (57.6%) patients did not respond to treatment. The median urine protein to creatinine ratio decreased from 10.0 to 0.75 (P<0.005) and serum albumin increased from 1.9 g/dl to 2.4 g/dl (P<0.01). The median duration of follow-up after stopping pulse therapy was 25.6 months. Thirty-four patients were followed for more than 3 years (median 4.5 years). Of these, 22 (64.7%) patients had a favorable outcome; persistent complete remission was seen in 15 patients and steroid-responsive relapses in 7. Seven patients had non- nephrotic-range proteinuria, 2 had nephrotic-range proteinuria, and 3 (8.8%) were in chronic renal failure. There was no significant difference in the short- and long-term outcome of patients with initial (n=28) and late resistance (n=31). The outcome in patients receiving intravenous dexamethasone (n=48) or methylprednisolone (n=11) was also similar. The chief side effects included worsening of height standard deviation score (47.4%), transient hypertension (42.5%), and serious infections (18.5%). We conclude that prolonged treatment with intravenous corticosteroids and oral cyclophosphamide is beneficial in patients with steroid-resistant FSGS. Expensive protocols can be successfully modified and used, depending upon the availability of health resources.
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PMID:Treatment of focal glomerulosclerosis with pulse steroids and oral cyclophosphamide. 1168 98

Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 microg/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.
Hypertension 2002 Jul
PMID:Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. 1210 34

Dexamethasone (DM) was administered to pregnant ewes as three weekly courses of four injections of 2 mg at 12-h intervals. DM (n = 7) or saline (n = 7) was given starting at 103 days of gestation (dGA; term approximately 149 days). Fetal femoral arteries (approximately 300-microm internal diameter) were evaluated using wire myography at 119 dGA. DM-exposed fetuses were significantly smaller than saline-exposed fetuses. DM exposure increased maximal contraction to 125 mM KCl, and maximum tension developed along with sensitivity to endothelin-1 and relaxation to bradykinin. Preincubation with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester shifted the dose-response curves to endothelin-1 and acetylcholine to the right in controls but not in the DM-exposed group. Relaxation to acetylcholine and to the nitric oxide donor sodium nitroprusside was similar in both groups. The combination of enhanced endothelin-induced vasoconstriction, abnormal endothelium-dependent relaxation, and normal endothelium-independent relaxation indicates microvessel dysfunction following antenatal DM administration. Because such dysfunction is associated with several forms of adult hypertension, our results indicate the potential for consequences of antenatal glucocorticoid exposure on adult cardiovascular health.
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PMID:Evidence for microvascular dysfunction after prenatal dexamethasone at 0.7, 0.75, and 0.8 gestation in sheep. 1218 88

The aim of this study was to test whether increased coronary vascular resistance in hypertensive subjects can be reduced by centrally inhibiting sympathetic overactivity with dexamethasone. Coronary vascular resistance was quantitated in 11 men with untreated mild essential hypertension (RR 149 +/- 13/98 +/- 10 mm Hg) and 23 healthy, normotensive, otherwise matched men using positron emission tomography and [(15)O]H(2)O. The measurements were performed at baseline and during adenosine stimulation. Each subject was studied twice, with and without previous dexamethasone treatment for two days (0.5 mg x 4 per day). Before dexamethasone treatment, cardiac index and plasma norepinephrine concentration (1.9 +/- 0.6 vs. 1.3 +/- 0.5 nmol/l, p < 0.01) were significantly higher in hypertensive than in normotensive subjects. Additionally, both baseline and hyperemic coronary vascular resistances were higher in hypertensive than normotensive subjects (147 +/- 31 vs. 113 +/- 24 and 36 +/- 9 vs. 25 +/- 10 mm Hg.min.g.ml(-1); p < 0.05). Dexamethasone treatment significantly decreased plasma norepinephrine concentrations in hypertensive subjects, leading to comparable plasma norepinephrine concentrations in hypertensive and normotensive subjects (1.4 +/- 0.5 vs. 1.2 +/- 0.4 nmol/l; NS). However, coronary vascular resistances remained increased in hypertensive subjects. In conclusion, hypertensive subjects are characterized by sympathetic overactivity, which can be normalized by dexamethasone. However, coronary vascular resistances remained increased in hypertensive subjects after dexamethasone treatment, suggesting that other mechanisms than sympathetic overactivity-induced vasoconstriction explain the increased coronary vascular resistance in hypertension.
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PMID:Increased coronary vascular resistance cannot be reduced by inhibiting sympathetic overactivity in hypertension. 1229 8

Theoretically, disturbancies in sodium (Na) and potassium (K) homeostasis and a magnesium (Mg) deficit could be possible factors in the development of obesity, type 2 diabetes, and hypertension. Therefore, we measured electrolyte content and [3H]ouabain binding capacity of skeletal muscle in 20 relatives of type 2 diabetic patients and in 20 controls before and after glucose infusion and before and after treatment with dexamethasone, which decreases insulin sensitivity. Muscle electrolyte content and [3H]ouabain binding capacity did not differ between groups. Infusion of glucose increased muscle Na content 25%, decreased muscle potassium content 9%, and muscle Mg content 5%. Muscle potassium/Mg ratio decreased only in relatives. Treatment with dexamethasone increased muscle Na content 15% and decreased muscle Mg content 7%, whereas muscle potassium/Na ratio decreased 17%. Dexamethasone increased muscle [3H]ouabain binding capacity by 42% in both groups. Basal and 1-hour intramuscular glucose content correlated inversely with basal muscle potassium/Na ratio in relatives only. In conclusion, persons who were predisposed to the development of type 2 diabetes exhibited an increased interdependency between glucose, Na, and potassium handling in skeletal muscle. Muscle Na content and [3H]ouabain binding capacity increased during treatment with dexamethasone, and muscle potassium/Na ratio decreased. Intravenous (IV) glucose injection decreases muscle Mg content, as does a decrease in insulin sensitivity, without any differences between relatives and controls.
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PMID:Magnesium, sodium, and potassium content and [3H]ouabain binding capacity of skeletal muscle in relatives of patients with type 2 diabetes: effect of dexamethasone. 1237 Aug 55

Overexpression of the conserved Ca(2+)-binding proteins calreticulin and calsequestrin impairs cardiac function, leading to premature death. Calreticulin is vital for embryonic development, but also impairs glucocorticoid action. Glucocorticoid overexposure during late fetal life causes intra-uterine growth retardation and programmed hypertension in adulthood. To determine whether intra-uterine growth retardation or programmed hypertension was associated with altered calreticulin or calsequestrin expression, effects of prenatal glucocorticoid overexposure (maternal dexamethasone treatment on days 15-21 of pregnancy) were examined during fetal life and postnatal development until adulthood (24 weeks). Dexamethasone (100 or 200 microg/kg of maternal body weight) was administered via osmotic pump. Calreticulin was detected as a 55 kDa band and calsequestrin as 55 and 63 kDa bands in 21 day fetal hearts. Only the 55 kDa calsequestrin band was detected postnatally. Prenatal glucocorticoid overexposure at the higher dose decreased calreticulin protein expression (26%; P <0.05) but increased calsequestrin protein expression, both 55 and 63 kDa bands, by 87% ( P <0.01) and 78% ( P <0.01); only the 55 kDa calsequestrin band was increased at the lower dose (66%; P <0.05). Offspring of dams treated at the lower dexamethasone dose were studied further. In control offspring, cardiac calreticulin protein expression declined between 2 and 3 weeks of age, and remained suppressed until adulthood. Cardiac calsequestrin protein expression increased 2-fold between fetal day 21 and postnatal day 1 and continued to increase until adulthood, at which time it was 3.4-fold higher ( P <0.001). Prenatal dexamethasone exposure minimally affected postnatal calsequestrin protein expression, but the postnatal decline in calreticulin protein expression was abrogated and calreticulin protein expression in adulthood was 2.2-fold increased ( P <0.001) compared with adult controls. In view of the known associations between cardiac calreticulin overexpression and impaired cardiac function, targeted up-regulation of calreticulin may contribute to the increased risk of adult heart disease introduced as a result of prenatal overexposure to glucocorticoids.
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PMID:Effects of prenatal glucocorticoid exposure on cardiac calreticulin and calsequestrin protein expression during early development and in adulthood. 1251 72

1. Prenatal dexamethasone leads to low birth weight and compromises organogenesis, but its effects on nephrogenesis in male and female rats have not yet been investigated extensively. Reduced renal mass may be responsible for hypertension and renal haemodynamic and morphological adjustments to maintain the glomerular filtration rate (GFR). Subsequently, these compensatory mechanisms determine glomerular sclerosis and irreversible reduction in GFR. When a high-protein diet is associated with reduced renal mass, it accelerates glomerular sclerosis and the decline in renal function. The aim of the present study was to evaluate whether rats subjected to prenatal dexamethasone and a high-protein diet during growth present a premature decline in renal function. 2. The number of nephrons and renal haemodynamics were estimated in Wistar rats fed a high-protein diet (40% protein) after weaning in offspring of dams treated with either dexamethasone (0.1 mg/kg per day) or its vehicle (control; physiological solution, 0.1 mL/kg per day) during gestation. 3. At 70 days of age, rat offspring were anaesthetized and prepared surgically for renal haemodynamic measurements. 4. Mean arterial pressure (MAP), renal blood flow (RBF) and GFR were measured using a blood pressure transducer, a flow probe and inulin clearance, respectively. 5. The number of nephrons was counted using the acid-maceration technique. 6. Dexamethasone during pregnancy induced a lower weight gain in the dams (65%; P < 0.0001) and a lower birth weight in both male and female offspring (14 and 13%, respectively; P < 0.01). 7. Compared with control, the number of nephrons in male rats was reduced by 13% (30 703 +/- 1262 vs 26 308 +/- 1305, respectively; P < 0.05), but was unaltered in female rats (23 197 +/- 553 vs 24 231 +/- 1009, respectively). 8. Male and female rats did not show any alteration in MAP. In addition, they did not show any alteration in renal vascular resistance, RBF, filtration fraction or GFR. 9. In conclusion, prenatally administered dexamethasone (0.1 mg/kg during the entire pregnancy) induced a low birth weight. The magnitude of the reduction in nephrogenesis in male offspring from mothers treated with dexamethasone was not sufficient to alter renal function (measured at 70 days), even when rats had been fed a high-protein diet.
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PMID:Renal function in adult rats subjected to prenatal dexamethasone. 1254 50

Dexamethasone is frequently administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine if prenatal dexamethasone programmed a progressive increase in blood pressure and renal injury in rats. Pregnant rats were given either vehicle or 2 daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 20% reduction in glomerular number compared with control at 6 to 9 months of age (22 527+/-509 versus 28 050+/-561, P<0.05), which was comparable to the percent reduction in glomeruli measured at 3 weeks of age. Six- to 9-month old rats receiving prenatal dexamethasone on days 17 and 18 of gestation had a 17% reduction in glomeruli (23 380+/-587) compared with control rats (P<0.05). Male rats that received prenatal dexamethasone on days 15 and 16, 17 and 18, and 13 and 14 of gestation had elevated blood pressures at 6 months of age; the latter group did not have a reduction in glomerular number. Adult rats given dexamethasone on days 15 and 16 of gestation had more glomeruli with glomerulosclerosis than control rats. This study shows that prenatal dexamethasone in rats results in a reduction in glomerular number, glomerulosclerosis, and hypertension when administered at specific points during gestation. Hypertension was observed in animals that had a reduction in glomeruli as well as in a group that did not have a reduction in glomerular number, suggesting that a reduction in glomerular number is not the sole cause for the development of hypertension.
Hypertension 2003 Feb
PMID:Prenatal dexamethasone programs hypertension and renal injury in the rat. 1257 3


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