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

Acute severe hypertension induced by intravenous norepinephrine or angiotensin in anesthetized cats equipped with a cranial window caused prolonged arteriolar vasodilation associated with reduced responsiveness to arterial hypercapnia or hypocapnia and passive response to changes in arterial blood pressure. Scanning and transmission electron microscopy of such pial arterioles showed discrete destructive endothelial lesions the density of which correlated with the degree of vasodilation. Abnormalities of the vascular smooth muscle were seen in all dilated arterioles but affected only a small number of smooth muscle cells. The oxygen consumption of pial arterioles from cats subjected to hypertension was significantly reduced in comparison to that of vessels from normal animals. The arteriolar abnormalities induced by hypertension were inhibited by pretreatment with inhibitors of cyclooxygenase (indomethacin or AHR-5850) or by topical application on the brain surface of scavengers of free oxygen radicals (mannitol or superoxide dismutase). The results suggest that the mechanism of the arteriolar abnormalities from acute hypertension involves a sudden increase in prostaglandin synthesis that leads to generation of free oxygen radicals.
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PMID:Mechanism of cerebral arteriolar abnormalities after acute hypertension. 722 3

We tested the hypothesis that food restriction would attenuate the development of hypertension in spontaneously hypertensive rats (SHR). Furthermore, we hypothesized that food restriction would reduce the tonic sympathetic nervous system support of blood pressure in the SHR. Male SHR (Charles River, age 5 wk) were randomly assigned to ad libitum (ADLIB, n = 8) or food-restricted (FR, n = 9) groups. ADLIB rats were given free access to nonpurified diet and demineralized water. Food-restricted rats ate 60% of the amount of nonpurified diet consumed by rats in the ADLIB group. After 8 wk of treatment, ADLIB rats were heavier than FR rats (ADLIB = 318 +/- 4 g; FR = 193 +/- 5 g, P < 0.05). Blood pressure and heart rate (HR) were measured after chronic implantation of iliac arterial and jugular venous catheters. Food-restricted rats had lower mean arterial blood pressure (MAP) than ADLIB rats, measured in conscious, unrestrained state 4-6 h after catheterization (ADLIB = 162 +/- 3 mmHg; FR = 142 +/- 3 mmHg, P < 0.05) and measured on the day after surgery (ADLIB = 150 +/- 6 mmHg; FR = 130 +/- 3 mmHg, P < 0.05). There were no significant differences in resting HR on either day. Food-restricted rats exhibited augmented cardiac baroreflex-mediated bradycardia (bolus phenylephrine, 0.5-4.0 pg/kg intravenously) as assessed by linear slope of the AHR/AMAP relationship (ADLIB = -0.73 beats/(min x mmHg); FR = -1.62 beats/(min x mmHg), P < 0.05). Sympathetic support of blood pressure quantified by the depressor response to ganglionic blockade (hexamethonium 30 mg/kg; atropine 0.1 mg/kg intravenously), was greater in the ADLIB group (ADLIB: -59 +/- 8 mmHg; FR: -36 +/- 2 mmHg, P < 0.05). The results support the hypotheses that chronic food restriction reduces the development of hypertension and sympathetic support of MAP in spontaneously hypertensive rats.
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PMID:Food restriction reduces sympathetic support of blood pressure in spontaneously hypertensive rats. 910 19

Differential mRNA display showed that a cDNA band disappeared after treatment of mice with 3-methylcholanthrene (MC). The cDNA encoded low-molecular-weight (LMW) prekininogen, known to be the precursor of a potent vasodilator, bradykinin. MC is generally known to bind to aryl hydrocarbon receptor (AhR) as an initial event to cause effects in vivo. In accordance with the results, Northern blot analysis for LMW prekininogen mRNA using total RNAs from wild-type and AhR-null mice indicated that the suppression of the mRNA expression by MC was seen in wild-type mice but not in AhR-null mice. The expression of LMW prekininogen mRNA was almost completely lost within 1 h after treatment of mice with MC, while a clear increase of CYP1A2 mRNA, as a positive control, was noted 4 h after the treatment. The plasma concentration of bradykinin released from LMW prekininogen was decreased by MC in wild-type mice, but not in AhR-null mice. Based on these results, we conclude that AhR inhibits bradykinin synthesis in mice via suppression of the expression of LMW prekininogen. Possible mechanism(s) responsible for hypertension caused by treatment of mice with MC is also discussed.
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PMID:Aryl hydrocarbon receptor-mediated suppression of expression of the low-molecular-weight prekininogen gene in mice. 1154 91

We tested the hypothesis that endothelial dysfunction induced by angiotensin II (Ang-hypertension) would impair regulatory control of vascular smooth muscle L-type Ca2+ channels by endothelial nitric oxide synthase (eNOS). We studied cerebral lenticulostriate arterioles (LSAs) from control rats, from rats infused with Ang (240 microg x kg(-1) x h(-1) SQ x4 days), which were normotensive, and from Ang-hypertensive rats (AHR; 240 microg x kg(-1) x h(-1) x28 days). Patch-clamp measurements on isolated LSA smooth muscle cells (SMCs) showed a significant increase in Ca2+ channel availability with 4- and 28-day infusions versus controls (0.47+/-0.03 and 0.66+/-0.05 vs 0.36+/-0.03 pS/pF, respectively; P<0.01), with Western blots showing no change in channel protein expression, consistent with altered channel regulation. In LSAs from 28-day AHR, 4,5-diaminofluorescein diacetate imaging showed diminished NO production in response to acetylcholine stimulation in vivo, and inhibition of eNOS with NG-nitro-L-arginine methyl ester failed to increase Ca2+ channel availability in isolated SMCs, indicating an abnormality with the eNOS/NO-signaling pathway regulating the channel. Immunofluorescence imaging showed that in 1 of 53, 33 of 109, and 53 of 62 LSAs from controls and from rats with 4- and 28-day infusions, respectively, eNOS was absent from its normal location at the abluminal border and was mislocalized to perinuclear Golgi. Ca2+ channel availability in LSA SMCs from controls and from rats with 4- and 28-day infusions was proportional to the fraction of LSAs showing eNOS mislocalization, but not blood pressure. These data provide the first evidence linking Ang-induced eNOS mislocalization, eNOS dysfunction, and Ca2+ channel upregulation, and they provide novel mechanistic insights into pathological changes in LSAs associated with stroke.
Hypertension 2003 May
PMID:Mislocalization of eNOS and upregulation of cerebral vascular Ca2+ channel activity in angiotensin-hypertension. 1266 86

Nitrate tolerance (NT) in hypertension is attributed to reduced activity of soluble guanylyl cyclase (sGC). We examined NT in basilar artery vascular smooth muscle cells (VSMCs) from control rats, rats infused with angiotensin II (Ang; 240 microg/kg per hour for 4 days), which were normotensive, and Ang-hypertensive rats (AHR; 240 microg/kg per hour for 28 days). Ca2+-activated K+ (Maxi-K) channels in VSMCs from AHR showed reduced activation by NO donor, consistent with NT. The concentration-response relationship for 8-Br-cGMP was shifted 2.5-fold to the right, indicating that abnormal sGC alone could not account for NT. Inside-out patches from AHR showed normal activation with exogenous cGMP-dependent protein kinase I (cGKI), suggesting no abnormality downstream of cGKI. We hypothesized that the reduction in apparent affinity of 8-Br-cGMP for cGKI in AHR might be due to a change in relative amounts of cGKIalpha versus cGKIbeta, since cGKIbeta is less sensitive to cGMP activators than cGKIalpha. This was substantiated by showing the following in AHR: (1) reduced effect of the cGKIalpha-selective activator 8-APT-cGMP; (2) reduced total cGKI protein (both isoforms), but an increase in cGKIbeta protein in quantitative immunofluorescence and Western blots; (3) similar changes in cGKI isoforms immunoisolated with Maxi-K channels; and (4) a large increase in cGKIbeta mRNA and a decrease in cGKIalpha mRNA in real-time PCR and Northern blots. Upregulation of cytosolic cGKIbeta was evident 4 days after Ang infusion, before development of hypertension. Our data identify a functional role for cGKIbeta in VSMCs previously ascribed exclusively to cGKIalpha. Ang-induced alternative splicing of cGKI represents a novel mechanism for reducing sensitivity to NO/cGMP.
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PMID:Alternative splicing of cGMP-dependent protein kinase I in angiotensin-hypertension: novel mechanism for nitrate tolerance in vascular smooth muscle. 1464 36

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of AhR results in hypertension, and cardiac hypertrophy and fibrosis, associated with elevated plasma angiotensin II (Ang II) and endothelin-1 (ET-1), thus AhR appears to contribute to cardiovascular homeostasis. In these studies, we tested the hypothesis that ET-1 mediates cardiovascular pathology in AhR null mice via ETA receptor activation. First, we determine the time courses of cardiac hypertrophy, and of plasma and tissue ET-1 expression in AhR wildtype and null mice. AhR null mice exhibited increases in heart-to-body weight ratio and age-related expression of cardiac hypertrophy markers, beta-myosin heavy chain (beta-MHC), and atrial natriuretic factor (ANF), which were significant at 2 months. Similarly, plasma and tissue ET-1 expression was significantly elevated at 2 months and increased further with age. Second, AhR null mice were treated with ETA receptor antagonist, BQ-123 (100 nmol/kg/day), for 7, 28, or 58 days and blood pressure, cardiac fibrosis, and cardiac hypertrophy assessed, respectively. BQ-123 for 7 days significantly reduced mean arterial pressure in conscious, catheterized mice. BQ-123 for 28 days significantly reduced the histological appearance of cardiac fibrosis. Treatment for 58 days significantly reduced cardiac mass, assessed by heart weight, echocardiography, and beta-MHC and ANF expression; and reduced cardiac fibrosis as determined by osteopontin and collagen I mRNA expression. These findings establish ET-1 and the ETA receptor as primary determinants of hypertension and cardiac pathology in AhR null mice.
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PMID:Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice. 1609 89

The risk for and predictors of atrial fibrillation (AF) after kidney transplantation are not well described. Registry data that were collected by the United States Renal Data System were used to investigate retrospectively new-onset AF among adult first renal allograft recipients and transplant candidates who received a transplant or were wait-listed in 1995 to 2001 with Medicare as the primary payer. AF events were ascertained from billing records, and participants were followed until loss of Medicare coverage or December 31, 2001. Cox hazards analysis was used to identify independent correlates of posttransplantation AF (adjusted hazard ratio [AHR]; 95% confidence interval [CI]) and to examine AF as an outcomes predictor. Among 31,136 eligible transplant recipients, the cumulative incidence of new-onset AF was 3.6% (95% CI 3.4 to 3.8%) and 7.3% (95% CI 7.0 to 7.6%) at 12 and 36 mo and declined below the demographics-adjusted cumulative incidence on the waiting list by approximately 17 mo. Risk factors for posttransplantation AF included older recipient age, male gender, white race, renal failure from hypertension, and coronary artery disease. Extended pretransplantation dialysis duration, posttransplantation diabetes, and graft failure were identified as potentially modifiable correlates of AF. In separate analyses, AF independently predicted death (AHR 3.2; 95% CI 2.9 to 3.6) and death-censored graft loss (AHR 1.9; 95% CI 1.6 to 2.3). As the population of renal transplant recipients grows older, the incidence and prevalence of AF among these patients will likely increase. Appropriate risk stratification may identify transplant recipients who are in need of close monitoring for and management of this adverse cardiovascular event.
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PMID:Incidence, predictors, and associated outcomes of atrial fibrillation after kidney transplantation. 1769 19

The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that mediates induction of metabolic enzymes and toxicity of certain environmental pollutants. Although AHR knockout (KO) mice develop cardiac hypertrophy, conflicting reports associate this pathology with hypotension or endothelin (ET)-1-dependent hypertension. Because hypertension occurred at modest altitude, we tested the hypothesis that loss of AHR increases the sensitivity to hypoxia-induced ET-1, contributing to systemic hypertension. We found that AHR KO mice were hypertensive at modest altitude (1632 m) but hypotensive at low altitude (225 m). When AHR KO mice residing at 1632 m were exposed to the partial pressure of inspired oxygen (PIO(2)) at sea level for 11 days, blood pressure declined to levels measured at 225 m. Although plasma ET-1 in AHR KO mice was significantly elevated at 1632 m and decreased at 225 m and sea level PIO(2), pulmonary prepro-ET-1 mRNA was significantly reduced at 1632 m and decreased further at 225 m and sea level PIO(2). Blood gas analysis revealed that AHR KO mice were hypoxemic, hypercapnic, and acidotic at 1632 m, values that were attenuated and normalized after 24 hours and 11 days under sea level PIO(2), respectively. Lastly, AHR inactivation in endothelial cells by small interfering RNA significantly reduced basal prepro-ET-1 mRNA but did not alter hypoxia-induced expression. Our studies establish the AHR KO mouse as a model in which modest decreases in PIO(2) lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression.
Hypertension 2008 Mar
PMID:Loss of the aryl hydrocarbon receptor induces hypoxemia, endothelin-1, and systemic hypertension at modest altitude. 1821 70

1 The hypothesis that alpha(1D)-adrenoceptors may mediate the pro-hypertensive actions of angiotensin II (Ang II) was tested in isolated aorta (alpha(1D)-adrenoceptor bearing tissue) of the aryl hydrocarbon receptor null mouse (AhR(-/-)), which shows increased levels of Ang II, cardiac hypertrophy and hypertension. 2 The effect of captopril (an angiotensin converting enzyme inhibitor) on both blood pressure and aortic alpha(1D)-adrenoceptor expression and function in mice were determined. 3 Basal blood pressure was higher in AhR(-/-) mice, while captopril therapy decreased it to wild-type (WT) values. 4 Aortas of adult WT and AhR(-/-) mice were stimulated by phenylephrine or noradrenaline to induce contraction; the maximal effect was higher in AhR(-/-) mice, without a significant change in pEC(50). 5 PA(2) values for the selective alpha(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazynil]ethyl]-8-azaspiro [4.5]decane-7,9-dione) were 9.19 and 8.94 for WT and AhR(-/-), respectively; while Schild slopes were not different from 1. 6 PCR experiments showed c. 77% increase in AhR(-/-)alpha(1D)-adrenoceptors cDNA compared with WT mice; while western blot analysis demonstrated c. 88% increase in alpha(1D)-adrenoceptor protein in AhR(-/-) mice. 7 Captopril therapy decreased alpha(1D)-adrenoceptor-induced contraction and protein in AhR(-/-) mice to WT levels. 8 These data support the hypothesis that under conditions where Ang II is elevated, vascular alpha(1D)-adrenoceptors are increased, and further suggest that both Ang II and vascular alpha(1D)-adrenoceptors could be related in the onset of hypertension.
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PMID:Vascular alpha-1D-adrenoceptors are overexpressed in aorta of the aryl hydrocarbon receptor null mouse: role of increased angiotensin II. 1859 87

Studies in our laboratory have demonstrated that subchronic 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) exposure of adult mice results in hypertension, cardiac hypertrophy, and reduced nitric oxide (NO)-mediated vasodilation. Moreover, increased superoxide anion production was observed in cardiovascular organs of TCDD-exposed mice and this increase contributed to the reduced NO-mediated vasodilation. Since cytochrome P4501A1 (CYP1A1) can contribute to some TCDD-induced toxicity, we tested the hypothesis that TCDD increases reactive oxygen species (ROS) in endothelial cells by the induction of CYP1A1. A concentration-response to 24h TCDD exposure (10pM-10nM) was performed in confluent primary human aortic endothelial cells (HAECs). Oxidant-sensitive fluorescent probes dihydroethidium (DHE) and 2',7'-dichlorofluorescin diacetate (DCFH-DA), were used to measure superoxide anion, and hydrogen peroxide and hydroxyl radical, respectively. NO was also measured using the fluorescent probe diaminofluorescein-2 diacetate (DAF-2DA). These assessments were conducted in HAECs transfected with siRNA targeting the aryl hydrocarbon receptor (AhR), CYP1A1, or CYP1B1. TCDD concentration-dependently increased CYP1A1 and CYP1B1 mRNA, protein, and enzyme activity. Moreover, 1nM TCDD maximally increased DHE (Cont=1.0+/-0.3; TCDD=5.1+/-1.0; p=0.002) and DCFH-DA (Cont=1.0+/-0.2; TCDD=4.1+/-0.5; p=0.002) fluorescence and maximally decreased DAF-2DA fluorescence (Cont=1.0+/-0.4; TCDD=0.68+/-0.1). siRNA targeting AhR and CYP1A1 significantly decreased TCDD-induced DHE (siAhR: Cont=1.0+/-0.1; TCDD=1.3+/-0.2; p=0.093) (siCYP1A1: Cont=1.0+/-0.1; TCDD=1.1+/-0.1; p=0.454) and DCFH-DA (siAhR: Cont=1.0+/-0.2; TCDD=1.3+/-0.3; p=0.370) (siCYP1A1: Cont=1.0+/-0.1; TCDD=1.3+/-0.2; p=0.114) fluorescence and increased DAF-2DA fluorescence (siAhR: Cont=1.00+/-0.03; TCDD=0.97+/-0.03; p=0.481) (siCYP1A1: Cont=1.00+/-0.03; TCDD=0.92+/-0.03; p=0.034), while siRNA targeting CYP1B1 did not. These data suggest that TCDD-induced increase in ROS is AhR-dependent and may be mediated, in part, by CYP1A1 induction.
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PMID:2,3,7,8-tetrachlorodibenzo-p-dioxin increases reactive oxygen species production in human endothelial cells via induction of cytochrome P4501A1. 2017 76


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