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)

Hypertriglyceridemia is a common feature of patients with increased blood pressure as well as several rodent models of hypertension. The goal of this study was to evaluate the effects of gemfibrozil on established abnormalities of triglyceride (TG) secretion and TG clearance in the Dahl salt-sensitive rat. Consequently, Dahl salt-sensitive rats received 12 days treatment with gemfibrozil (30 mg/kg/day) or vehicle by p.o. gavage and the following measurements were made: 1) fasting plasma TG levels; 2) TG secretion rate after suppression of TG removal with Triton WR 1339; 3) TG removal rate (half-time of disappearance of prelabeled very low density lipoprotein); and 4) lipoprotein lipase (LPL) activity and mRNA in soleus muscle, fat and liver tissues. Gemfibrozil produced a 50% reduction in fasting plasma TG concentrations, with no effect on TG secretion rate (17 +/- 2 vs. 15 +/- 1 mg/100 g b.wt./hr). The half-time of prelabeled very low density lipoprotein-TG removal was significantly lower in drug-treated animals (3.9 +/- 0.3 vs. 6.1 +/- 0.9 min), and this was associated with a tissue-specific increase in LPL activity in soleus muscle (153 +/- 5 vs. 135 +/- 5 U/g, P < .02). Expression of LPL mRNA, relative to beta-actin mRNA, was similar in both groups of rats. Thus, in this rodent model of hypertension and dyslipidemia, gemfibrozil lowers plasma TG levels by 50% with no effect on TG secretion; the hypotriglyceridemic effect is due mainly to an increase in TG removal rate associated with a post-transcriptional increase in LPL activity in skeletal muscle.
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PMID:Effects of gemfibrozil on triglyceride metabolism in Dahl salt-sensitive rats. 807 73

We studied the effect of selective inhibition of the neural isoform of nitric oxide synthase in the rat renal medulla in conscious Sprague-Dawley rats. Continuous renal medullar interstitial infusion of an antisense oligonucleotide complementary to the initiation region of the mRNA for neural nitric oxide synthase increased blood pressure 14 +/- 1 mm Hg in rats maintained on a high sodium intake. Medullary interstitial infusion of saline vehicle or a scrambled oligonucleotide probe failed to alter blood pressure in separate groups of high salt control rats. Renal medullary interstitial infusion of the antisense oligonucleotide significantly decreased the level of neural nitric oxide synthase in the renal medulla by 53 +/- 8% and decreased total renal medullary nitric oxide synthase activity by 28 +/- 8%. No alterations were detected in the levels of inducible nitric oxide synthase or beta-actin in the antisense oligonucleotide-infused rats. To confirm the antisense oligonucleotide data, we administered a mechanistically different inhibitor of neural nitric oxide synthase, 7-nitroindazole, to an additional group of rats maintained on a high salt diet. Direct renal medullary interstitial infusion of this selective enzyme inhibitor significantly increased mean arterial pressure (15 +/- 6 mm Hg) and decreased total renal medullary nitric oxide synthase activity by 37 +/- 12% in rats on a high sodium diet. The present experiments demonstrate a role for the neural isoform of nitric oxide synthase in the long-term control of blood pressure in the presence of a high salt diet.
Hypertension 1996 Aug
PMID:Neural nitric oxide synthase in the renal medulla and blood pressure regulation. 870 97

This study was designed to determine whether the kallikrein-kinin system exerts a protective action in hypertension induced by chronic inhibition of nitric oxide synthase. N omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/100 ml water) was given orally to Sprague-Dawley rats, while controls received regular tap water. Hepatic kininogen mRNA levels in the L-NAME-treated group were 2.9- and 2.5-fold higher at 3 and 4 wk, respectively, compared with control rats, whereas kallikrein-binding protein (KBP) mRNA levels were 82% and 45% of the values found in control rats at 3 and 4 wk, respectively. There was no significant change in hepatic alpha 1-antitrypsin mRNA levels under the same conditions. At 3 and 4 wk post L-NAME treatment, renal kallikrein mRNA levels were 2.5- and 3.4-fold higher than in controls, whereas renal beta-actin mRNA levels were similar between groups. Changes in the transcript levels of renal kallikrein, kininogen, and KBP were consistent with their protein levels. Immunoreactive total kininogen and low-Mr kininogen levels in sera and tissue kallikrein levels in kidney were significantly higher in the L-NAME-treated group, whereas KBP levels in the circulation were lower compared with controls. Systolic blood pressure was increased by 58 +/- 4 mmHg after 4 wk of L-NAME treatment. This effect was enhanced in rats given L-NAME in combination with HOE-140, a bradykinin B2-receptor antagonist, at the dose of 100 micrograms/day ip (79 +/- 5 vs. 58 +/- 4 mmHg, P < 0.05). This difference was confirmed by direct measurement of mean blood pressure (MBP). An intra-arterial bolus injection of 200 ng bradykinin significantly decreased MBP of L-NAME-treated rats, and this effect was blunted in the group treated with the bradykinin antagonist (-29 +/- 3 vs. -9 +/- 2 mmHg, P < 0.01). These results suggest that enhanced kallikrein and kininogen synthesis may have a protective role against the cardiovascular effects induced by chronic inhibition of nitric oxide synthesis.
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PMID:Differential regulation of kallikrein, kininogen, and kallikrein-binding protein in arterial hypertensive rats. 876 Feb 46

The Dahl strain of genetically salt resistant (R) and salt sensitive (S) rats affords an opportunity to explore mechanisms for salt resistance and sensitivity. Because of the evidence that opioid peptides and their receptors can be involved in cardiovascular regulation, the objective of this study was to test the hypothesis that proopiomelanocortin (POMC), the precursor of beta-endorphin, is involved in the development of hypertension, through the determination of POMC mRNA in the pituitary. Three-week-old inbred Dahl R and S rats were maintained on a high salt diet (8% NaCl) or low salt diet (0.4% NaCl) for 6 weeks. POMC mRNA and for comparison preproenkephalin A (preproENK) mRNA were examined from tissues of Dahl R and S rats as determined by Northern blot analysis using beta-actin as an internal standard. POMC mRNA was abundant in the pituitary tissues. There was more POMC mRNA in the pituitary tissue of R rats compared with that of S rats on the high salt diet. Differences in POMC mRNA in the pituitary were not observed between R and S on the low salt diet. There were no differences in the levels of preproENK mRNA in the pituitary tissues of R and S rats on high or low salt diet. From these data, we propose that inefficient production of POMC mRNA is a characteristic of the Dahl S rat on a high salt diet.
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PMID:Differences in pituitary expression of proopiomelanocortin in Dahl salt-resistant and salt-sensitive rats on a high salt diet. 890 76

Heterogeneous distribution and function of alpha 1-adrenergic receptor subtypes on arterial and venous vessels, together with evidence for altered alpha-adrenergic receptor expression in hypertension, led us to examine whether mechanical load influences expression of alpha 1B- and alpha 1D-adrenergic receptors in rat aortic smooth muscle cells (SMCs). We used RNase protection and radioligand binding assays to measure mRNA and alpha 1-adrenergic receptor density. In the first model, SMCs were subjected to phasic loading using flexible culture plates. As a positive control for the load stimulus, postconfluent, quiescent passage 5 cells demonstrated the expected load-dependent morphological realignment. However, no changes were detected in expression of either alpha 1D- or alpha 1B-adrenergic receptor mRNAs or receptor density after 24 to 48 hours of loading. beta-Actin and SMC-specific alpha-actin mRNA, as well as cell number and per-cell total RNA and protein, were also unaffected. In a second model, intact thoracic aortas, in either the presence or absence of endothelial cells, were cultured for 48 hours under tonic load. Like cultured cells, 48 hours of load did not affect SMC expression of alpha 1-adrenergic receptor mRNAs. We used suprarenal aortic coarctation to examine effects of increased pressure in vivo. As with the previous in vitro and in situ models, hypertension (30 days) had no effect on expression of alpha 1B- and alpha 1D-adrenergic receptor mRNAs in the suprarenal aorta compared with sham coarctation. To separate pressure per se from humoral influences, we also measured mRNAs in the subrenal, normotensive aorta, alpha 1B mRNA levels decreased to 68 +/- 14% of sham-coarcted controls in subrenal aorta exposed to normal blood pressure but also to systemic humoral changes induced by coarctation. As a positive control for a load effect, SMC-specific alpha-actin mRNA increased for loaded aorta in organ culture and in hypertensive aorta in vivo, whereas expression of beta-actin mRNA was unaffected. These results from cell culture, organ culture, and in vivo models suggest that pressure (load) alone has no effect on alpha 1B- and alpha 1D-adrenergic receptor expression. In coarctation hypertension, smooth muscle protected from the hypertension showed a decline in alpha 1B mRNA that may be due to a humoral factor or factors.
Hypertension 1997 May
PMID:Effect of mechanical loading on vascular alpha 1D- and alpha 1B-adrenergic receptor expression. 914 81

On the basis of paradigms in development wherein discrete transcriptional events are pivotal regulatory steps, we tested the hypothesis that transcriptional sodium (Na+)-response mechanisms are involved in in vivo Na+-induced responses relevant to normal (homeostatic) and pathophysiological (salt-sensitive hypertension) conditions. We used Na,K-ATPase alpha-subunit genes as molecular probes and the Na+ ionophore monensin to induce a dose-specific incremental increase in [Na+]i in rat A10 embryonic aortic smooth muscle cells. RNA blot analysis of rat A10 cells revealed a dose-specific (0.022 to 30 micromol/L monensin) upregulation of alpha1-, alpha2-, and beta1-subunit Na,K-ATPase RNA levels. Control beta-actin and alpha-tropomyosin RNA levels did not change. With the use of chloramphenicol acetyltransferase (CAT) as reporter gene, CAT assays of rat alpha1[-1288]CAT and human alpha2[-798]CAT promoter constructs exhibited induction of CAT activity in monensin (10 micromol/L)-treated A10 cells compared with untreated A10 cells. Promoter deletion constructs for rat alpha1[-1288]CAT defined a positive Na+-response regulatory region within -358 to -169 that is distinct from the basal transcriptional activation region of -155 to -49 previously defined. Similarly, a positive Na+-response regulatory region is delimited to within -301 in the human alpha2 Na,K-ATPase 5' flanking region. Analysis of transgenic TgH alpha2[-798]CAT rats demonstrated sodium activation of human alpha2[-798]CAT transgene expression in aorta parallel to observations made in rat A10 aortic tissue culture cells. Southwestern blot analysis of nuclear extracts from monensin (10 micromol/L)-treated and control untreated A10 cells revealed a nuclear DNA binding protein (approximately 95 kD) that is upregulated by increased [Na+]i. These data provide initial characterization of a transcriptional Na+-response mechanism delimiting a positive Na+-response regulatory region in two target genes (alpha1 and alpha2 Na,K-ATPase) as well as detection of a Na+-response nuclear DNA binding protein. The in vitro data are corroborated by in vivo experimental and transgenic promoter expression studies, thus validating the biological relevance of the observations.
Hypertension 1997 Aug
PMID:Characterization of a sodium-response transcriptional mechanism. 926 Sep 79

This study was designed to determine whether pressure-induced expression of early response genes in the arterial wall is dependent on an increase in cell stretch or an increase in wall stress. Mesenteric arteries (245 to 385 microm in diameter) were isolated from Wistar rats and subjected to static pressures of either 90 mm Hg (control), 140 mm Hg, or 165 mm Hg for a period of 3 hours. Arteries developed a range of myogenic tone such that wall stresses in the 140 and 165 mm Hg arteries (1.60 to 4.44x10(6) dynes/cm2) were equivalent in some cases to those of controls (1.76 to 2.63x10(6) dynes/cm2). Vessels subjected to 140 or 165 mm Hg intraluminal pressure had diameters ranging from 74% to 104% of their relaxed diameter at 90 mm Hg, whereas control vessel diameters ranged from 88% to 100%. At the end of each experiment, vessels were fixed in 10% formalin, embedded in paraffin, and sectioned for in situ hybridization. Wall stress significantly correlated with c-myc mRNA and 18S rRNA expression. Gene expression did not correlate with vessel diameter, expressed as a percentage of the relaxed diameter at 90 mm Hg, ie, cell stretch. The expression of beta-actin mRNA did not differ between vessels and showed no correlation with wall stress, suggesting that the induction of c-myc mRNA and 18S rRNA was part of a specific response. These findings show that in an isolated artery, a pressure stimulus can be perceived as an increase in wall stress, independently of cell stretch. Therefore, wall stress may be the signaling parameter in hypertension where arteries are tonically constricted. The inhibition of gene expression by myogenic constriction may explain why hypertrophy takes place in large arteries during hypertension but not in arterioles where increased tone reduces wall stress.
Hypertension 1997 Aug
PMID:Myogenic tone attenuates pressure-induced gene expression in isolated small arteries. 926 Sep 81

Smooth muscle cell differentiation and proliferation are increasingly seen to be intimately tied to the etiology of atherosclerosis and hypertension. To determine the role of PKC alpha in the regulation of smooth muscle cell differentiation and proliferation, the rat embryonic smooth muscle cell line A7r5 was transfected with an expression vector containing the full-length PKC alpha cDNA. Neomycin-resistant clones which exhibited increased PKC alpha levels compared to wild-type cells were selected. The A7r5 cells overexpressing PKC alpha had altered morphology and decreased growth rates compared to wild-type cells and cells transfected only with the neomycin resistance gene. Electrophoretic mobility shift assays showed that nuclear extracts from overexpressing clones gave a different pattern of protein-DNA binding to an AP-1 consensus oligonucleotide compared to wild-type cells. In contrast to the growth characteristics of these clones, their levels of cell differentiation marker proteins such as vinculin and desmin were not affected by PKC alpha overexpression. Moreover, the smooth muscle-specific differentiation marker alpha-actin was markedly reduced, while beta-actin levels were found to remain unchanged. Northern blot analysis confirmed that alpha-actin downregulation occurred at the RNA level. Western blot analysis revealed that A7r5 cells have five different PKC isoforms and that these isoform protein levels were not changed by PKC alpha overexpression. These findings suggest that PKC alpha regulates growth and differentiation of A7r5 smooth muscle cells and that these changes might result from altered expression/function of AP-1 transcription factors.
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PMID:Effects of protein kinase C alpha overexpression on A7r5 smooth muscle cell proliferation and differentiation. 934 91

A potential role for the renin-angiotensin system (RAS) in the development and/or maintenance of hypertension in the genetic model of rat hypertension, spontaneously hypertensive rats (SHR), has been suggested by studies indicating that treatment of immature animals with angiotensin-converting enzyme (ACE) inhibitors prevents subsequent development of hypertension. Because young SHR also demonstrate RAS-dependent increased sodium retention, we examined proximal tubule type 1 angiotensin II receptor (AT1R) mRNA expression in young (4 wk) or adult (14 wk) SHR compared with age-matched Wistar-Kyoto (WKY) rats. Proximal tubules were isolated by Percoll gradient centrifugation, and AT1R mRNA expression was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). At 14 wk, when SHR had established hypertension [mean arterial blood pressure (MAP) of SHR vs. WKY: 145 +/- 6 vs. 85 +/- 5 mmHg, n = 14-15], there were no differences in proximal tubule AT1R mRNA levels [SHR vs. WKY: 79 +/- 14 vs. 72 +/- 14 counts/min (cpm) per cpm mutant AT1R per cpm beta-actin x 10(-6), n = 6; not significant (NS)]. In contrast, in 4 wk SHR, at a time of minimal elevations in blood pressure (MAP: 70 +/- 8 vs. 63 +/- 3), SHR proximal tubule AT1R mRNA levels were 263 +/- 30% that of WKY (143 +/- 18 vs. 60 +/- 11 cpm per cpm of mutant AT1R per cpm beta-actin x 10(-6), n = 8; P < 0.005). We have recently shown that chronic ACE inhibition decreases proximal tubule AT1R expression and have also shown that chronic L-3,4-dihydroxyphenylalamine (L-DOPA) administration inhibits AT1R expression in adult Sprague-Dawley proximal tubule and cultured proximal tubule, and this inhibition is mediated via Gs-coupled DA1 receptors. When 3-wk-old animals were given L-DOPA or captopril for 1 wk, MAP was not altered (70 +/- 8 vs. 60 +/- 4 or 61 +/- 5 mmHg), but proximal tubule AT1R mRNA was no longer significantly different between SHR and WKY (68 +/- 9 vs. 38 +/- 7 or 20 +/- 3 vs. 47 +/- 15 cpm per cpm of mutant AT1R per cpm beta-actin x 10(-6)), due to a significant decrease in proximal tubule AT1R expression in SHR (P < 0.005, compared with untreated SHR). Immunoreactive proximal tubule AT1R expression also was increased in 4 wk SHR and was reversed with captopril or L-DOPA treatment. Therefore, these results indicate that young, but not adult, SHR have increased expression of proximal tubule AT1R and that chronic L-DOPA or captopril treatment decreased the elevated AT1R expression to control levels. These results provide further support for an important role of the RAS in the development of hypertension in SHR.
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PMID:Young SHR express increased type 1 angiotensin II receptors in renal proximal tubule. 945 18

Both dopamine D1-like (D1A and D1B) and D2-like (D2, D3, and D4) receptor subfamilies are present in the kidney. Blockade of the intrarenal D1-like receptor family is associated with natriuresis and diuresis. Because the D1A and D1B receptor subtypes are not distinguishable by currently available dopaminergic agents, their functional role remains undefined. In the present study, the effect of selective inhibition of the renal D1A receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) was investigated in conscious uninephrectomized rats. After renal interstitial administration of Texas red-labeled D1A receptor AS-ODN, intense fluorescent signal was localized in the renal tubular epithelium and vasculature. In rats on normal salt intake, AS-ODN injected interstitially into the kidney reduced daily urinary sodium excretion (1.4+/-0.04 versus 0.8+/-0.2 mEq/d, n=5, P<0.05) and urine output (16.9+/-3.8 versus 12.5+/-3.6 mL/d, n=5, P<0.05). In rats on high sodium intake, continuous renal interstitial administration of D1A receptor AS-ODN transiently decreased daily urinary sodium excretion (5.4+/-0.5 versus 4.2+/-0.3 mEq/d, n=7, P<0.01) and urine output (27.6+/-4.5 versus 18.1+/-1.8 mL/d, n=7, P<0.01). Neither vehicle nor sense oligodeoxynucleotide had significant effects. Systolic blood pressure remained unchanged. The renal D1A receptor protein was significantly decreased by 35% and 46% at the end of the study in AS-ODN-treated rats on normal and high salt intake, respectively, whereas the D1B receptor and beta-actin were not affected. These results provide the first direct evidence that the renal D1A receptor subtype plays an important role in the control of sodium excretion.
Hypertension 1999 Jan
PMID:Selective inhibition of the renal dopamine subtype D1A receptor induces antinatriuresis in conscious rats. 993 Nov 56


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