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)

Gamma-Aminobutyric acid-B (GABAB) receptor function and regulation in the nucleus of the solitary tract (NTS) was examined in Sprague-Dawley rats made chronically (4 to 5 weeks) hypertensive with the one-kidney, figure-8 renal wrap model of hypertension. NTS microinjection of the GABAB agonist baclofen produced a pressor response that was enhanced in hypertensive rats compared with the response observed in sham-operated normotensive rats (36+/-4 mm Hg increase in mean arterial pressure in 8 hypertensive rats compared with 21+/-2 mm Hg increase in 7 sham-operated normotensive rats, P=0. 03). Responses to microinjection of GABAB antagonists (CGP-55845A and SCH-90511), the GABAA agonist muscimol, the GABAA antagonist bicuculline, and the GABA reuptake inhibitor nipecotic acid were not different comparing normotensive sham-operated and hypertensive rats. Renal sympathetic nerve responses to NTS microinjection of these drugs were not different in hypertensive compared with normotensive rats. Micropunches of the NTS were homogenized and reverse transcriptase-polymerase chain reaction was performed to examine mRNA levels for the GABAB receptor. There was a 3-fold increase in GABAB receptor mRNA levels in the caudal NTS of 7 chronically hypertensive rats compared with levels measured in 8 sham-operated normotensive rats (P=0.01). In conclusion, chronic hypertension is associated with an upregulation of GABAB receptor function; however, the tonic activity of the system does not appear to be different between normotensive and hypertensive rats. The upregulation of GABAB receptor function might be due to an increased number of receptors, as suggested by the elevated levels of GABAB receptor mRNA measured in the NTS of hypertensive rats. All of these alterations suggest that hypertension is associated with dynamic changes in receptor-mediated mechanisms within the NTS, and these alterations could modify baroreflex regulation of cardiovascular function in hypertension.
Hypertension 1999 Jan
PMID:Enhanced gamma-aminobutyric acid-B receptor agonist responses and mRNA within the nucleus of the solitary tract in hypertension. 993 Nov 60

To identify genes that are differentially expressed during the transition from compensated hypertrophy to failure, myocardial mRNA from spontaneously hypertensive rats (SHR) with heart failure (SHR-F) was compared with that from age-matched SHR with compensated hypertrophy (SHR-NF) and normotensive Wistar-Kyoto rats (WKY) by differential display reverse transcriptase-polymerase chain reaction. Characterization of a transcript differentially expressed in SHR-F yielded a cDNA with homology to the extracellular matrix protein osteopontin. Northern analysis showed low levels of osteopontin mRNA in left ventricular myocardium from WKY and SHR-NF but a markedly increased (approximately 10-fold) level in SHR-F. In myocardium from WKY and SHR-NF, in situ hybridization showed only scant osteopontin mRNA, primarily in arteriolar cells. In SHR-F, in situ hybridization revealed abundant expression of osteopontin mRNA, primarily in nonmyocytes in the interstitial and perivascular space. Similar findings for osteopontin protein were observed in the midwall region of myocardium from the SHR-F group. Consistent with the findings in SHR, osteopontin mRNA was minimally increased (approximately 1.9-fold) in left ventricular myocardium from nonfailing aortic-banded rats with pressure-overload hypertrophy but was markedly increased (approximately 8-fold) in banded rats with failure. Treatment with captopril starting before or after the onset of failure in the SHR reduced the increase in left ventricular osteopontin mRNA levels. Thus, osteopontin expression is markedly increased in the heart coincident with the development of heart failure. The source of osteopontin in SHR-F is primarily nonmyocytes, and its induction is inhibited by an angiotensin-converting enzyme inhibitor, suggesting a role for angiotensin II. Given the known biological activities of osteopontin, including cell adhesion and regulation of inducible nitric oxide synthase gene expression, these data suggest that it could play a role in the pathophysiology of heart failure.
Hypertension 1999 Feb
PMID:Myocardial osteopontin expression coincides with the development of heart failure. 1002 24

Platelet-derived growth factor (PDGF) is a potent mitogen for vascular smooth-muscle cells, but its effects on vasomotion remain controversial. Both vasoconstriction and vasodilatation of isolated rat aortic rings have been reported. The effects of PDGF on responses of perfused mesenteric resistance arteries from normotensive Wistar-Kyoto and spontaneously hypertensive rats were studied by using a video dimension analyzer. PDGF receptor messenger RNA (mRNA) expression in endothelial cells isolated from mesenteric arteries of both normotensive and hypertensive rats was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. In both normotensive and hypertensive rats, PDGF-BB concentration-dependently induced vasodilatation (maximal response, 25 +/- 4% and 13 +/- 4% at 10(-8) M, respectively; p < 0.05, normotensive vs. hypertensive rats). Endothelium removal or preincubation with N(omega)-nitro-L-arginine methyl ester, but not indomethacin, inhibited these relaxations, indicating that these vasodilatations are endothelium dependent and mediated by nitric oxide. RT-PCR analysis showed that both PDGF-alpha and -beta receptor mRNAs were present in endothelial cells of the mesenteric arteries of normotensive as well as hypertensive rats. In addition, relaxations induced by both PDGF-AA and -AB were significantly less than those induced by PDGF-BB in both strains, suggesting that vasodilatation is mediated mainly by the PDGF-beta receptor subtype. No vasoconstriction was observed after application of PDGF-BB to both normotensive and hypertensive mesenteric arteries with or without endothelium. In rat mesenteric resistance arteries, PDGF induces endothelium-dependent vasodilatation mediated by nitric oxide. At sites where PDGF is released or locally produced, therefore, the growth factor may participate in regulating vascular tone, and this endothelium-dependent regulation is attenuated in spontaneous hypertension.
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PMID:Platelet-derived growth factor-induced vasodilatation in mesenteric resistance arteries by nitric oxide: blunted response in spontaneous hypertension. 1002 29

This study tests the hypothesis that aldosterone induces cardiac fibrosis through an increase of cardiac angiotensin II (Ang II) AT1 receptor levels, thereby potentiating the fibrotic effect of Ang II by determining the effects of spironolactone and losartan on cardiac fibrosis, AT1 density, and gene expression in aldosterone-salt-treated rats. Fibrosis was quantified by slot blots of collagen I and III mRNA levels and videomorphometry of Sirius red-stained collagen. AT1 receptor density was determined by (125I-Sar1-Ile8)-Ang II competition binding, and AT1 mRNA levels were analyzed by quantitative reverse transcriptase polymerase chain reaction. One month of aldosterone-salt treatment induced a decrease in plasma Ang II and an increase in blood pressure, left ventricular hypertrophy, and ventricular fibrosis. Spironolactone (20 mg/kg per day) and losartan spironolactone (10 mg/kg per day) had no effect on the first 3 parameters. Losartan was as effective as spironolactone in preventing ventricular collagen mRNA increase and fibrosis. Ventricular density of AT1 receptors increased 2-fold and was accompanied by a 3-fold increase in the corresponding mRNA in aldosterone-salt compared with sham-operated rats. Both spironolactone and losartan prevented the elevation of ventricular AT1 density and that of right ventricular AT1 mRNA levels. These results demonstrate that the mechanism by which aldosterone-salt induces cardiac fibrosis involves Ang II acting through AT1 receptors. They also suggest that the cardiac AT1 receptor is a target for aldosterone.
Hypertension 1999 Apr
PMID:Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. 1020 34

NCI-H295, a human adrenocarcinoma cell line, has been proposed as a model system to define the role of the renin-angiotensin system in the regulation of aldosterone production in humans. Because the precise cellular localization of the components of the renin-angiotensin system in human adrenal cortical cells remains unclear, we investigated their localization in this defined cell system. NCI-H295 cells expressed both angiotensinogen and renin as shown by reverse transcriptase polymerase chain reaction and immunohistochemistry. Human angiotensin-converting enzyme (ACE) was not detectable by immunocytochemistry, ACE binding, or reverse transcriptase polymerase chain reaction. However, 3.5 mmol/L K+ stimulated the formation of both angiotensin I and angiotensin II 1. 9- and 2.5-fold, respectively, and increased aldosterone release 3. 0-fold. The K+-induced stimulation of aldosterone release was decreased by captopril and enalaprilat (24% and 26%, respectively) and by the angiotensin type 1 (AT1)-receptor antagonist losartan (28%). Angiotensin II-induced stimulation of aldosterone release was abolished by losartan treatment. Specific [125I]Sar1-angiotensin II binding was detected by receptor autoradiography. The binding of [125I]Sar1-angiotensin II was completely displaced by the AT1 antagonist losartan but not by the AT2 receptor ligand PD 123319, confirming the expression of angiotensin II AT1 receptors in NCI-H295 cells. Our results demonstrate that NCI-H295 cells express most of the components of the renin-angiotensin system. Our failure to detect ACE, however, suggests that the production of angiotensin II in NCI-H295 cells may be ACE independent. NCI-H295 cells are able to produce angiotensin II, and K+ increases aldosterone secretion in part through an angiotensin-mediated pathway. The production of angiotensin II in NCI-H295 cells demonstrates that this human cell line can be useful to characterize the role of locally produced angiotensin II in the regulation of aldosterone release.
Hypertension 1999 Apr
PMID:Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells. 1020 42

In the kidney and colon 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inactivates cortisol to cortisone, thereby protecting the non-selective mineralocorticoid receptor from cortisol. Deficiency of 11beta-HSD2 results in cortisol-mediated sodium retention and hypertension, suggesting that the physiological regulation of 11beta-HSD2 in mineralocorticoid target tissues may be important in modulating sodium homoeostasis and blood pressure control. Using the human epithelial colon cell line SW-620, reverse transcriptase-polymerase chain reaction and enzyme kinetic analysis indicated expression of only 11beta-HSD2 (Km for cortisol 66 nmol/l). Bradykinin (10(-8) to 10(-12) mol/l), frusemide (10(-4) to 10(-9) mol/l), benzamiloride hydrochloride (10(-5) to 10(-10) mol/l) and atrial natriuretic peptide (10(-6) to 10(-10) mol/l) had no effect on 11beta-HSD2 expression. Using a range of concentrations of angiotensin II (2x10(-8) to 2x10(-5) mol/l) a significant reduction in activity was seen but only at supra-physiological concentrations, [e.g. 2x10(-6) mol/l at 4 h pretreatment: 36.7+/-2.0 pmol cortisone. h-1.mg-1 (mean+/-S.E.M.) compared with 45.1+/-1.7 pmol.h-1.mg-1 in control; P<0.05]. The angiotensin-converting enzyme inhibitors captopril, enalapril, lisinopril, perindopril, quinapril and trandolapril at 10(-7) mol/l, but not fosinopril, significantly increased 11beta-HSD2 activity after pretreatment for 16 or 24 h (P<0.05-P<0.01 compared with control). No effects were seen at 4 h pretreatment. Hydrochlorothiazide (10(-7) mol/l) significantly decreased 11beta-HSD2 activity (P<0.05 compared with control) at 4 h pretreatment. Commonly used diuretics, atrial natriuretic peptide and physiological concentrations of angiotensin II and bradykinin do not alter 11beta-HSD2 activity. In contrast, a series of angiotensin-converting enzyme inhibitors significantly increase 11beta-HSD2 activity in vitro. This may explain how intrarenal infusions of angiotensin-converting enzyme inhibitors increase renal sodium excretion independent of circulating concentrations of angiotensin II. The interaction between angiotensin-converting enzyme inhibitors and 11beta-HSD2 may be an additional mechanism by which the former can lower blood pressure.
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PMID:Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by diuretics and the renin-angiotensin-aldosterone axis. 1033 75

Angiotensin II (Ang II) and transforming growth factor (TGF) beta1 play a role in vascular remodeling in hypertension. In this process they may interact on various levels, including that of receptor regulation. This consideration prompted the present study on transcriptional regulation of TGF-beta receptors by Ang II and TGF-beta in vascular smooth muscle cells. Transcriptional expression of the components of the TGF-beta system was demonstrated for TGF-beta and for TGF-beta receptors I, II, and III. As measured by quantitative reverse transcriptase polymerase chain reaction, TGF-beta mRNA increased about 2.4-fold in the presence of 40 pM exogenous TGF-beta. Ang II at 10(-6) M increased TGF-beta mRNA 2.5-fold compared to control cells (P<0.05). Ang II also significantly increased TGF-beta protein concentration in the supernatant of confluent vascular smooth muscle cells. Ang II caused the induction of TGF-beta, but short-term experiments showed TGF-beta receptor II mRNA to be differentially regulated by Ang II and TGF-beta; while TGF-beta caused a 40% decrease in TGF-beta receptor II mRNA after 4 h (P<0.05), Ang II caused an increase by about 70%. In contrast, both TGF-beta and Ang II increased TGF-beta receptor I mRNA to about 260% or 180% of controls (P<0.05). TGF-beta effects were abrogated by coincubation with a TGF-beta neutralizing antibody, and Ang II effects were abrogated by losartan, an AT-1 receptor antagonist. Coincubation of Ang II with the TGF-beta neutralizing antibody did not inhibit the effect of Ang II, indicating that the short-term effects of Ang II on the expression of the TGF-beta receptors are not mediated via TGF-beta. Furthermore, Ang II stimulated DNA synthesis even in the presence of the TGF-beta neutralizing antibody. In conclusion, this study indicates (a) that in vascular smooth muscle TGF-beta receptors are regulated on the RNA level by TGF-beta and Ang II, and (b) that Ang II dependent regulation of TGF-beta receptors is at least partially independent of endogenous TGF-beta. Stimulation of the transcriptional expression of TGF-beta receptors by Ang II may increase sensitivity of vascular smooth muscle cells to TGF-beta.
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PMID:Differential regulation of transforming growth factor receptors by angiotensin II and transforming growth factor-beta1 in vascular smooth muscle. 1042 93

During 1997 a large dengue epidemic occurred in Rio Grande do Norte, a State in north-east Brazil. The co-circulation of dengue virus type 1 and dengue virus type 2 was demonstrated by virus isolation in Aedes albopictus clone C6/36 cell-line and by reverse transcriptase-polymerase chain reaction (RT-PCR). IgM capture enzyme-linked immunosorbent assay confirmed 52.3% of the 8105 studied cases and dengue antigen was demonstrated by immunohistochemical reaction on hepatocytes from 2 out of 5 fatal cases studied. Individual risk factors for development of dengue haemorrhagic fever/dengue shock syndrome, such as hypertension, diabetes mellitus and bronchial asthma, are discussed.
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PMID:Dengue epidemic in the State of Rio Grande do Norte, Brazil, in 1997. 1049 50

The clinical use of the immunosuppressive drug cyclosporin A (CsA) is limited by its side effects, namely hypertension and nephrotoxicity. It has been proposed that reactive oxygen species (ROS) could be involved as mediators of the toxic effects of CsA. Here, we have studied the possible interrelationship between CsA metabolism and production of ROS. Using cultures of rat aortic smooth muscle cells (RASMC), CsA (1 microM) produced a rapid (within 10 min) increase in reactive oxygen species, detected by oxidation of the fluorescent probes 2,7-dichlorofluorescin and dihydrorhodamine-123. DNA synthesis was increased in the presence of CsA as assessed by [3H]thymidine incorporation. The superoxide dismutase inhibitor diethyldithiocarbamate (1 mM) and the iron chelator desferal (5 microM), as well as ketoconazole (1 microM) and troleandomycin (10 microM), inhibitors of the cytochrome P-450 3A, were able to block both effects. High-performance liquid chromatography analysis revealed that RASMC were capable to metabolize CsA to its primary metabolites (AM1, AM9 and AM4N), and that their formation was inhibited by ketoconazole and troleandomycin. Furthermore, mRNAs encoding cytochrome P-450 3A1 and 3A2 were detected in RASMC by reverse transcriptase-polymerase chain reaction. Our data suggest that CsA is metabolized by cytochrome P-450 3A in RASMC producing reactive oxygen species, most likely superoxide and the hydroxyl radical, known to damage lipids and DNA.
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PMID:Metabolism-dependent stimulation of reactive oxygen species and DNA synthesis by cyclosporin A in rat smooth muscle cells. 1064 20

We analyzed the influence of aging and genetic hypertension on the function and expression of soluble guanylyl cyclase (sGC) in the aortas of prehypertensive and old spontaneously hypertensive rats (SHR) as well as in age-matched normotensive Wistar-Kyoto rats (WKY). The expression of heterodimeric sGC (alpha(1) and beta(1)) was assessed at the mRNA and protein level, and its function was assessed by the relaxant responses of phenylephrine-contracted endothelium-denuded aortic rings to the nitric oxide (NO) donor sodium nitroprusside. The vasodilator potency of sodium nitroprusside was significantly reduced (P<0.05) with age (3- to 6-fold increase in the EC(50) in old WKY and SHR compared with their young counterparts) as well as with hypertension (3-fold increase in old SHR compared with age-matched WKY), whereas the vasodilator potency of sodium nitroprusside did not differ between young SHR and WKY. A similar influence of aging and hypertension on NO-stimulated GC activity was revealed at the GC expression level: Whereas the beta(1) protein content was similar in young rats of both strains, old WKY exhibited 60% lower and old SHR exhibited 80% lower beta(1) subunit protein compared with young rats (P<0.05). Moreover, the abundance of alpha(1) and beta(1) mRNA (assessed by reverse transcriptase-polymerase chain reaction) was similar in young rats but was 2.5-fold (alpha(1)) and 4.3-fold (beta(1)) lower in old SHR compared with old WKY. In conclusion, our findings show that both aging and hypertension decrease sGC expression and its NO-dependent activation in aortic tissue. Downregulation of sGC may therefore contribute to arterial dysfunction in senescence and chronic hypertension.
Hypertension 2000 Jan
PMID:Aging and chronic hypertension decrease expression of rat aortic soluble guanylyl cyclase. 1064 73


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