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)

In porcine aortic endothelial cells, the 21-amino acid peptide endothelin-1 (ET-1) is formed from a 39-amino acid intermediate big endothelin (big ET) by a putative endothelin-converting enzyme (ECE) that cleaves the 39-mer at the Trp21-Val22 bond. Because big ET has less than 1% of the contractile activity of ET-1, inhibition of ECE should effectively block the biological effects of big ET. Big ET injected intravenously into anesthetized rats produces a sustained pressor response that presumably is due to conversion of big ET to ET-1 by ECE. We determined the type of protease activity responsible for this conversion by evaluating the effectiveness of protease inhibitors in blocking the pressor response to big ET in ganglion-blocked anesthetized rats. The serine protease inhibitor leupeptin, the cysteinyl protease inhibitor E-64, and the metalloprotease inhibitors captopril and kelatorphan were ineffective at blocking the pressor response to big ET. However, the metalloprotease inhibitors phosphoramidon and thiorphan both dose-dependently inhibited the pressor response to big ET, although phosphoramidon was substantially more potent than thiorphan. None of the inhibitors blocked the pressor response to ET-1 and none had any effect on blood pressure when administered alone as an i.v. bolus to the ganglion-blocked anesthetized rat. However, phosphoramidon infused intravenously at 20 mg/kg/h for 4 h lowered the mean arterial pressure (MAP) in conscious spontaneously hypertensive rats (SHRs) whereas kelatorphan at the same dose did not. Our results suggest that ECE is a novel metalloprotease and that ECE inhibitors could have therapeutic potential for the treatment of hypertension.
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PMID:Phosphoramidon blocks the pressor activity of big endothelin[1-39] and lowers blood pressure in spontaneously hypertensive rats. 172 58

Antisense oligodeoxynucleotides (AS-ODN) to AT1 receptor mRNA inhibit high blood pressure in Spontaneously Hypertensive Rats (SHR) when injected into the brain. The effect is presumably through inhibition of the actions of brain angiotensin II (Ang II). Central injection of Ang II elicits several physiological responses including release of vasopressin and motivation to drink. The angiotensin II type-I (AT1) receptor is located in brain regions which have been implicated in mediating these effects. Therefore we hypothesized that AS-ODN to AT1 mRNA would inhibit the drinking and AVP response to central administration of Ang II in adult male SHR. AS-ODN were constructed to bases +63 to +77 (15-mer) of the AT1 receptor RNA. 24 h after AS-ODN treatment (50 micrograms/4 microliters) (intracerebroventricularly, i.c.v.), the drinking response to Ang II (50 ng, i.c.v.) was significantly reduced in the SHR (P < 0.05). The drinking response to Ang II (i.c.v.) was also reduced in the Sprague-Dawley rats (P < 0.05). There was no reduction of water intake in the control animals treated with scrambled ODN (SC-ODN). Repeated injection of AS-ODN did not produce a greater reduction in drinking response. Arginine vasopressin (AVP) release to central Ang II was significantly decreased after AS-ODN treatment when compared to vehicle (P < 0.05) and to SC-ODN injections (P < 0.05). Radioligand binding assays of the hypothalamic block after AS-ODN treatment showed a significant decrease of AT1 receptor binding (P < 0.05). The results show that the antisense inhibition of brain AT1 receptor gene expression decreases the Ang II induced drinking and AVP release responses.
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PMID:Antisense oligonucleotide to AT1 receptor mRNA inhibits central angiotensin induced thirst and vasopressin. 771 85

To determine the role of angiotensinogen and angiotensin II type-1 (AT1) receptor genes in hypertension, spontaneously hypertensive rats (SHR) were injected with synthetic antisense oligodeoxynucleotides (ODNs), intracerebroventricularly (i.c.v). Antisense ODNs were constructed to bases -5 to +13 of angiotensinogen mRNA (18-mer) and to bases +63 to +77 (15-mer) of angiotensin II type-1 receptor mRNA. Hypertension was significantly reduced by the application of 50 micrograms of both antisense ODNs to normotensive levels. The phosphorothioated antisense ODN to the AT1 receptor produced long-lasting (7 days) decreases in blood pressure. After AT1 antisense treatment, AT1 receptors were reduced in the paraventricular nucleus (PVN) and in the anterior third ventricle area (AV3V). Following angiotensinogen antisense treatment, angiotensin II levels were significantly reduced in the brainstem (P < 0.05), indicating arrest of angiotensin II synthesis. The results demonstrate that inhibiting the brain renin-angiotensin system by antisense inhibition of the angiotensinogen and the AT1 receptor genes, lowers high blood pressure in the SHR. The antisense administration to specific genes of the tissue renin-angiotensin system offers the possibility of a new approach to developing antihypertension treatments.
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PMID:Antisense inhibition of AT1 receptor mRNA and angiotensinogen mRNA in the brain of spontaneously hypertensive rats reduces hypertension of neurogenic origin. 813 17

We used antisense oligodeoxynucleotide (ODN) strategy, based on interference of information flow from gene to protein, to determine the role of kininogen and bradykinin B2 receptor genes in the pathogenesis of genetic hypertension in rats. Mean blood pressure of 9-week-old spontaneously hypertensive rats (SHR) increased 4 hours after acute intracerebroventricular injection of synthetic 18-mer antisense ODNs targeting the translation initiation codon of kininogen mRNA (from 164 +/- 5 to 181 +/- 4 mm Hg, P < .01) or bradykinin B2 receptor mRNA (from 161 +/- 5 to 185 +/- 8 mm Hg, P < .01) and then returned to basal levels within 24 hours. Prolonged vasopressor effects were observed after repeated injections of antisense ODN targeting kininogen mRNA. Antisense ODNs to kininogen and B2 receptor mRNAs increased blood pressure of normotensive Wistar-Kyoto rats only slightly compared with SHR (from 116 +/- 3 to 124 +/- 1 and from 116 +/- 2 to 126 +/- 4 mm Hg, respectively; P < .05). Cardiovascular responses were confirmed by the use of antisense ODNs targeted to bind to different non-overlapping regions of kininogen or B2 receptor mRNA. Microinjection of antisense ODN to B2 receptor mRNA into the nucleus tractus solitarii increased mean blood pressure in SHR and prevented the vasodepressor effect induced by intranuclear microinjection of bradykinin. No significant change in mean blood pressure was induced in either strain by intravenous injection of antisense ODNs or by central injection of sense or scrambled ODNs. A strong fluorescent signal was detected at the level of the hippocampus, thalamus, hypothalamus periventricularis, midbrain, and cerebrum 1 hour after central injection of fluorescein isothiocyanate-conjugated antisense ODNs. Kininogen levels were significantly lower in the brain of rats given intracerebroventricular antisense kininogen ODN compared with controls. Our results indicate that the brain kallikrein-kinin system plays a role in the central regulation of blood pressure and suggest that this system may exert a protective action against further elevations of blood pressure levels in SHR.
Hypertension 1996 Dec
PMID:Antisense inhibition of the brain kallikrein-kinin system. 895 86

Antisense oligonucleotide (AS-ODN) inhibition of angiotensin receptors (AT1-R) offers a potentially novel therapeutic approach for hypertension, left ventricular hypertrophy and other aspects of cardiovascular disease. To clarify questions concerning cellular uptake and retention of these oligos, we quantified the trafficking and stability of phosphorothioated modified AS-ODN to AT1 receptor mRNA in adrenal cells, using visual and chromatographic analysis. The AS-ODN to AT1 receptor mRNA was effective in significantly inhibiting AT1 receptor binding in a dose dependent manner. FITC-labeled ODNs were used to determine the cellular uptake in bovine adrena cortex cells; using confocal microscopy, rapid cellular uptake of 15-mer ODNs was observed. Uptake is initially rapid (30 min to 4 h) followed by a slower uptake process 24 h and after. The cellular accumulation of ODN involves a dynamic balance between influx and efflux processes. Efflux of FITC-ODN had a f1/2 = 4.6 days. Uptake was time and dose dependent. No obvious degradation of intracellular ODNs occurred as shown by intact peaks for 15-mer ODN on thin layer chromatography. The results suggest that the AS-ODN to AT1 receptor mRNA was resistant to cellular nucleases. The FITC-ODN accumulated mainly in the nucleus and remained there intact for up to 3 days. No significant change in target mRNA was observed by quantitative RT-PCR. Therefore the antisense inhibition mechanism of this ODN does not appear to stimulate RNase H or block transcription. Since the ODN accesses the nucleus, the results imply that the ODN inhibits specific mRNA transport into the cytoplasm. The data show that AS-ODN, for inhibition of AT1 receptors, is rapidly taken up and stable in cells and produces specific inhibition of AT1 receptors.
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PMID:Uptake and efflux of intact antisense phosphorothioate deoxyoligonucleotide directed against angiotensin receptors in bovine adrenal cells. 924 81

Extrahypothalamic TRH participates in cardiovascular regulation and spontaneous hypertension of the rat. To investigate whether an increase in central TRH activity produces hypertension we studied the effect of the preTRH overproduction induced by I.C.V. transfection with a naked eukaryotic expression plasmid vector which encodes preTRH (pCMV-TRH). Northern blot analysis and RT-PCR showed that pCMV-TRH was transcribed in vitro and in vivo. At 24, 48, and 72 hours, pCMV-TRH (100 microg) in a significant and dose-dependent manner increased 37%, 84%, and 49%, respectively, the diencephalic TRH content and SABP (42+/-3, 50+/-2, and 22+/-2 mm Hg, respectively) with respect to the vector without the preTRH cDNA insert (V[TRH(-)]) as measured by RIA and the plethysmographic method, respectively, in awake animals. In addition, using immunohistochemistry we found that the increase of TRH was produced in circumventricular areas where the tripeptide is normally located. To further analyze the specificity of these effects we studied the actions of 23-mer sense (S), antisense (AS), and 3'self-stabilized sense (Ss) and antisense (ASs) phosphorothioate oligonucleotides against the initiation codon region. Only ASs inhibited the increase of TRH content and SABP induced by pCMV-TRH treatment. In addition, pCMV-TRH-induced hypertension seems not to be mediated by central Ang II or serum TSH. To summarize, central TRH overproduction in periventricular areas induced by I.C.V. transfection produces hypertension in rats which is reversed by specific antisense treatment. This model may help in testing effective antisense oligodeoxynucleotides against other candidate genes.
Hypertension 1997 Sep
PMID:Central overexpression of the TRH precursor gene induces hypertension in rats: antisense reversal. 932 19

Liddle's disease is an autosomal dominant form of human hypertension resulting from a basal activation of amiloride-sensitive Na+ channels (ENaC). This channel activation is produced by mutations in the beta- and/or gamma-carboxy-terminal cytoplasmic tails, in many cases causing a truncation of the last 45-76 amino acids. In this study, we tested two hypotheses; first, beta- and gamma-ENaC C-terminal truncation mutants (beta DeltaC and gamma DeltaC), in combination with the wild-type alpha-ENaC subunit, reproduce the Liddle's phenotype at the single channel level, i.e., an increase in open probability (Po), and second, these C-terminal regions of beta- and gamma-ENaC act as intrinsic blockers of this channel. Our results indicate that alpha beta DeltaC gamma DeltaC-rENaC, incorporated into planar lipid bilayers, has a significantly higher single channel Po compared to the wild-type channel (0.85 vs 0.60, respectively), and that 30-mer synthetic peptides corresponding to the C-terminal region of either beta- or gamma-ENaC block the basal-activated channel in a concentration-dependent fashion. Moreover, there was a synergy between the peptides for channel inhibition when added together. We conclude that the increase in macroscopic Na+ reabsorption that occurs in Liddle's disease is at least in part due to an increase in single channel Po and that the cytoplasmic tails of the beta- and gamma-ENaC subunits are important in the modulation of ENaC activity.
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PMID:Peptide inhibition of ENaC. 989 Sep 17

Large scale human genetic studies require technologies for generating millions of genotypes with relative ease but also at a reasonable cost and with high accuracy. We describe a highly parallel method for genotyping single nucleotide polymorphisms (SNPs), using generic high-density oligonucleotide arrays that contain thousands of preselected 20-mer oligonucleotide tags. First, marker-specific primers are used in PCR amplifications of genomic regions containing SNPs. Second, the amplification products are used as templates in single base extension (SBE) reactions using chimeric primers with 3' complementarity to the specific SNP loci and 5' complementarity to specific probes, or tags, synthesized on the array. The SBE primers, terminating one base before the polymorphic site, are extended in the presence of labeled dideoxy NTPs, using a different label for each of the two SNP alleles, and hybridized to the tag array. Third, genotypes are deduced from the fluorescence intensity ratio of the two colors. This approach takes advantage of multiplexed sample preparation, hybridization, and analysis at each stage. We illustrate and test this method by genotyping 44 individuals for 142 human SNPs identified previously in 62 candidate hypertension genes. Because the hybridization results are quantitative, this method can also be used for allele-frequency estimation in pooled DNA samples.
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PMID:Parallel genotyping of human SNPs using generic high-density oligonucleotide tag arrays. 1085 16

We examined the effects of the platelet-derived growth factor (PDGF) A-chain antisense oligodeoxynucleotides (ODN) on cardiovascular organ growth in stroke-prone spontaneously hypertensive rats (SHR-SP) in vivo. Expression of PDGF A-chain mRNA was higher in the aorta and kidney in 9-week-old SHR-SP than in Wistar-Kyoto (WKY) rats. A phosphorothioate-linked 15-mer antisense ODN complementary to the initiation codon region of rat PDGF A-chain mRNA and a control sense ODN were infused subcutaneously into SHR-SP/Izumo at a dose of 90 ng/g body weight/day for 28 days using an implanted ALZET pump. The PDGF A-chain antisense ODN did not affect blood pressure or body weight. The antisense ODN significantly inhibited [3H]thymidine incorporation into the DNA in the aorta and kidney but not in the heart. Infusion of the antisense ODN considerably reduced production of PDGF A-chain protein but did not affect expression of PDGF A-chain mRNA. Infusion of the antisense ODN considerably improved the arterial and renal tissue damage in SHR-SP morphologically. From these findings, it can be confirmed that suppression of PDGF A-chain by the antisense DNA is useful as a gene therapy for treating cardiovascular organ damage in hypertension.
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PMID:Effects of PDGF A-chain antisense oligodeoxynucleotides on growth of cardiovascular organs in stroke-prone spontaneously hypertensive rats. 1136 65

We evaluated the modulatory action of angiotensin II at the nucleus tractus solitarii on spontaneous baroreceptor reflex response, the angiotensin subtype receptors involved, and the role of Fos protein in this process, using Sprague-Dawley rats anesthetized with pentobarbital sodium. Microinjection bilaterally of angiotensin (Ang ) II (5, 10, 20, or 40 pmol) into the nucleus tractus solitarii significantly suppressed the spontaneous baroreceptor reflex, as represented by the magnitude of transfer function between systemic arterial pressure and heart rate signals. There also was a concomitant increase in Fos-like immunoreactivity in the nucleus tractus solitarii. Both the suppression of spontaneous baroreceptor reflex and Fos expression in nucleus tractus solitarii neurons elicited by Ang II were discernibly attenuated by pretreatment with or comicroinjection into the bilateral nucleus tractus solitarii of a 15-mer antisense c-fos oligonucleotide that targets against the initiation codon of c-fos mRNA. In addition, those 2 actions of Ang II were reversed by the coadministration of the nonpeptide Ang II type 1 (AT(1)) receptor antagonist losartan (1.6 nmol) but not by the nonpeptide AT(2) receptor antagonist PD 123,319 (1.6 nmol). Control treatments with artificial cerebrospinal fluid, sense cDNA, or antisense oligonucleotide with a scrambled sequence were ineffective. We conclude that under minimal cardiovascular perturbation, Fos expression mediated via activation of AT(1) subtype receptors may underlie the inhibitory modulation of beat-to-beat baroreflex control of blood pressure by Ang II at the nucleus tractus solitarii.
Hypertension 2001 Jul
PMID:Inhibition of baroreflex by angiotensin II via Fos expression in nucleus tractus solitarii of the rat. 1146 73


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