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)

Liddle syndrome is a mendelian form of hypertension characterized by constitutively elevated renal Na reabsorption that can result from activating mutations in the beta or gamma subunit of the epithelial Na channel. All reported mutations have deleted the last 45-76 normal amino acids from the cytoplasmic C terminus of one of these channel subunits. While these findings implicate these terminal segments in the normal negative regulation of channel activity, they do not identify the amino acid residues that are critical targets for these mutations. Potential targets include the short highly conserved Pro-rich segments present in the C terminus of beta and gamma subunits; these segments are similar to SH3-binding domains that mediate protein-protein interaction. We now report a kindred with Liddle syndrome in which affected patients have a mutation in codon 616 of the beta subunit resulting in substitution of a Leu for one of these highly conserved Pro residues. The functional significance of this mutation is demonstrated both by the finding that this is a de novo mutation appearing concordantly with the appearance of Liddle syndrome in the kindred and also by the marked activation of amiloride-sensitive Na channel activity seen in Xenopus oocytes expressing channels containing this mutant subunit (8.8-fold increase compared with control oocytes expressing normal channel subunits; P = 0.003). These findings demonstrate a de novo missense mutation causing Liddle syndrome and identify a critical channel residue important for the normal regulation of Na reabsorption in humans.
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PMID:A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. 852 90

Recent reports indicate that alpha 1-Na,K-ATPase from Dahl salt-sensitive (DS) rats contains a glutamine for leucine substitution associated with increased Na-K coupling at unchanged maximal velocity. Genetic analyses suggest that alpha 1-Na,K-ATPase is a potential hypertension gene. Therefore, we investigated whether renal Na+ metabolism could constitute a pathophysiological link between the molecular/functional change in Na,K-ATPase and hypertension. We simulated the consequences of increased Na-K coupling on overall Na-bicarbonate reabsorption in a proximal tubular transport model that incorporates apical Na-H exchanger and basolateral Na-bicarbonate cotransporter, K+ channel, and Na,K-ATPase. As expected, increases in the levels of the former three transport pathways yielded higher Na+ reabsorption. In contrast, increases in the maximal velocity of the Na,K-ATPase with a normal 3:2 (Na-K) coupling ratio did not increase Na+ reabsorption when apical Na-H exchange activity was limiting overall absorption. However, an increase in the Na-K coupling from 3:2 to 3:1, reported for the mutant alpha 1-Na,K-ATPase in DS rats, was associated with greater Na+ reabsorption. This increase is a consequence of lower cytosolic pH and secondary stimulation of the Na-H exchanger at its allosteric H+ site. Decreased pH results from activation of Na-bicarbonate cotransport by Na,K-ATPase-dependent membrane hyperpolarization due to greater charge movement in 3:1 Na-K coupling. Thus, an increase in the Na-K coupling ratio results in an altered set point for cellular Na+ metabolism, with higher sodium reabsorption at unchanged Na,K-ATPase levels. The simulations thereby lend support for a unifying explanation for the salt sensitivity of DS rats, which has been proposed to stem from a mutation in the alpha 1-Na,K-ATPase.
Hypertension 1996 Feb
PMID:Pathophysiological consequences of changes in the coupling ratio of Na,K-ATPase for renal sodium reabsorption and its implications for hypertension. 856 44

In order to investigate the changes of endogenous opiate systems in hypertension and their possible role in the pathogenesis in hypertension, we measured plasma concentrations of beta-endorphin, leucine-enkephalin, neurotension, arginine vasopressin, plasma renin activity and angiotensin II by radioimmunoassay in 60 normal persons and 120 patients with essential hypertension. The results showed that the patient group had lower levels of beta-endorphin and leucine enkephalin (P < 0.001), higher levels of arginine vasopressin, plasma renin activity and angiotensin II (P < 0.01, P < 0.05 and P < 0.05, respectively), and normal level of neurotensin, as compared with those in normal group. Plasma levels of leucine-enkephalin was correlated negatively to the mean artery pressure (r = -0.196, P < 0.05). Plasma level of arginine vasopressin was correlated to the duration of the hypertension (r = 0.216, P < 0.05). After 150 min and 14 days of treatment with clonidine, plasma levels of beta-endorphin, leucine-enkephalin increased significantly (< 0.01) and correlated negatively with the decrease of the mean artery pressure (r = -0.340 and r = -0.436 at 150 min, r = -0.369 and r = -0.441 on the 14th day, respectively, P < 0.01). Plasma renin activity and angiotensin II decreased significantly (P < 0.05 and P < 0.01). Arginine vasopressin and neurotensin did not change significantly. After intravenous administration of opiate antagonist-naloxone, the blood pressure and heart rate increased significantly (P < 0.01). The results suggested that the changes of endogenous opioids may be involved in the pathogenesis of hypertension and in the antihypertensive action of clonidine.
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PMID:Plasma levels of beta-endorphin, leucine enkephalin and arginine vasopressin in patients with essential hypertension and the effects of clonidine. 858 72

The factors responsible for predisposition to progressive organ injury and vascular complications in arterial hypertension are uncertain. Recent evidence shows that leukocytes participate in cardiovascular conditions for which hypertension is a risk factor. Therefore, there is a need to define the properties of circulating leukocytes in hypertensives. There are about twice as many circulating leukocytes in spontaneous hypertensive rats (SHRs) compared with their normotensive controls, the Wistar-Kyoto rats (WKYs). The SHR neutrophils are viscoelastic and similar to neutrophils in WKYs but exhibit lower deformability in short-term elastic deformation. Mature SHRs have elevated levels of spontaneous pseudopod formation. Mild stimulation with N-formyl-Met-Leu-Phe or platelet-activating factor (10(-8) M) results in a significantly enhanced level of neutrophil pseudopod formation in SHRs but not in WKYs. SHRs exhibit higher levels of spontaneous superoxide formation. Alkaline phosphatase content of individual circulating neutrophils in SHRs is on average lower while plasma levels of alkaline phosphatase in the same samples are elevated in the SHRs. Spontaneous degranulation of SHR neutrophils is also detectable with myeloperoxidase measurements. Such activity of circulating leukocytes poses a significant risk for vascular cytotoxicity in the hypertensive rats.
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PMID:Properties of circulating leukocytes in spontaneously hypertensive rats. 870 19

The effects of the endothelin receptor antagonist TAK-044 (cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-ala nyl-L-alpha-aspartyl-D-2-(2-thienyl)glycyl-L-leucyl-D-tryptophyl]+ ++disodiu m salt) and BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) were studied in the rat heart to characterize the receptor subtypes responsible for the cardiovascular actions of endothelin-1. Endothelin-1 induced a transient decrease and subsequent increase in perfusion pressure in perfused rat hearts, and increased left ventricular developed pressure. TAK-044 diminished these endothelin-1-induced responses (100 pmol/heart) with IC50 values of 140, 57 and 1.3 nM, respectively. BQ-123 (1-30 mu M) partially inhibited the endothelin-1-induced hypertension (30-40%) in the rat heart, and failed to inhibit the hypotension. The positive inotropic effect of endothelin-1 was abolished by BQ-123. Neither indomethacin (10 mu M) nor Nomega-nitro-L-arginine methyl ester (100 mu M) attenuated the endothelin-1-induced hypotension. TAK-044 and BQ-123 attenuated the positive inotropic effect of endothelin-1 in rat papillary muscles. In rat cardiac membrane fractions, TAK-044 and BQ-123 inhibited [125I]endothelin-1 binding to endothelin ET(A) receptors with IC50 values of 0.39 +/- 0.6 and 36 +/- 9 nM, respectively, whereas only TAK-044 potently blocked the endothelin ET(B) receptor subtype (IC50 value: 370 +/- 180 nM). These results suggest that endothelin-1 modulates cardiovascular functions in the rat heart by activating both endothelin ET(A) and endothelin ET(B) receptors, all of which are sensitive to TAK-044.
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PMID:Pharmacological characterization of cardiovascular responses induced by endothelin-1 in the perfused rat heart. 872 Apr 78

The growth response of aortic vascular smooth muscle cells (VSMCs) to chronic hypertension includes vascular hypertrophy. We have shown previously that angiotensin II positively regulates the expression of the human vascular smooth muscle (SM) alpha-actin gene. To further expand our understanding of vasoactive peptide-induced vascular hypertrophy, we studied endothelin-1 (ET-1) regulation of total protein synthesis and cytoskeletal gene expression in VSMCs. In a concentration-dependent manner ET-1 increased [3H] leucine incorporation by VSMCs (122.4 +/- 5.5%, mean +/- SEM, n = 5). ET-1 (0.1 microM) induced expression of SM alpha-actin mRNA as detected by Northern blot analysis. Also, ET-1 in a concentration-dependent manner (0.1 nM-0.1 microM) induced expression of the chloramphenicol acetyl transferase gene driven by 896 bp of the human SM alpha-actin promoter when transiently transfected into rat aortic VSMCs by the calcium phosphate method (141.2 +/- 9.8%, mean +/- SEM, n = 10). These data suggest that part of ET-1-induced increase in protein synthesis is achieved through transcriptional regulation of the SM alpha-actin gene via activation of cis-acting element(s) in the promoter. Such findings help elucidate the role of ET-1 in regulation of vascular growth.
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PMID:Endothelin-1 induces an increase in total protein synthesis and expression of the smooth muscle alpha-actin gene in vascular smooth muscle cells. 876 40

We compared the ability of angiotensin II (Ang II) to induce hypertrophy of neonatal rat ventricular myocytes with that of endothelin-1. Over 72 hours, Ang II (1 mumol/L) increased the ratio of protein to DNA by less than 10%, whereas endothelin-1 (100 nmol/L) produced a 28% increase. The growth effects of either agonist occurred independently of chronotropic actions. Radioligand binding studies showed that myocytes have nearly 300-fold more receptors for endothelin-1 than Ang II, and type 1 and type 2 Ang II receptor subtypes (AT1 and AT2) are present in near equal proportions. Cotreatment with a 10-fold molar excess of AT2 antagonists (PD 123177 or CGP 42112) for 72 hours augmented the Ang II-induced increase in the protein-to-DNA ratio to levels nearly as high (23%) as those with endothelin-1 (28%). AT2 antagonists enhanced Ang II stimulation of protein synthesis, as indexed by [3H]leucine incorporation, whereas an AT1 antagonist blocked Ang II-induced incorporation. An AT2 antagonist also prevented Ang II-induced protein degradation. In conclusion, Ang II-induced myocyte growth is tempered because of low AT1 levels and an antigrowth effect of AT2. These findings have potential clinical significance in that regression of hypertension-induced cardiac hypertrophy by AT1 antagonists may be in part due to an unopposed antigrowth effect of Ang II mediated via AT2.
Hypertension 1996 Oct
PMID:Role of type 1 and type 2 angiotensin receptors in angiotensin II-induced cardiomyocyte hypertrophy. 884 90

Serum angiotensin-converting enzyme was measured in 60 patients with endemic nephropathy and in 30 healthy individuals. According to the arterial blood pressure, the patients with endemic nephropathy were further divided into groups with arterial hypertension (n = 30) and without arterial hypertension (n = 30). The activity of angiotensin-converting enzyme was determined by a spectrophotometric method using hippuryl-l-histidyl-l-leucine as a substrate. The serum activity of angiotensin-converting enzyme was significantly increased in the patients with endemic nephropathy (28.51 +/- 1.64 U/l) as compared with healthy individuals (20.83 +/- 1.33 U/l). The level of the enzyme was further increased if the endemic nephropathy was accompanied by arterial hypertension (37.09 +/- 1.45 U/l). The possible mechanisms of the increase in the angiotensin-converting enzyme activity are discussed.
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PMID:Serum angiotensin-converting enzyme activity in patients with endemic nephropathy. 888 29

We tested several peptides related to des-Arg9-bradykinin as stimulants or inhibitors of B1 (rabbit aorta, human umbilical vein) and B2 (rabbit jugular vein, guinea pig ileum, human umbilical vein) receptors. We also incubated the compounds with purified angiotensin-converting enzyme from rabbit lung to test their resistance to degradation. We evaluated apparent affinities (in terms of the affinity constant pA2) of compounds and their potential residual agonistic activities (alpha E). Bradykinin and des-Arg9-bradykinin were used as agonists for the B2 and B1 receptors, respectively. Degradation of peptides by the angiotensin-converting enzyme was prevented in the presence of a D-residue in position 7 of des-Arg9-bradykinin. Replacement of Pro7 with D-Tic combined with Leu, Ile, Ala, or D-Tic in position 8 led to weak B1 receptor antagonists, some of which had strong residual agonistic activities on the B2 receptor preparations. The use of D-beta Nal in position 7, combined with Ile in position 8 and AcLys at the N-terminal (eg, AcLys[D-beta Nal7, Ile8]des-Arg9-bradykinin) gave the most active B1 receptor antagonist (pA2 of 8.5 on rabbit aorta and human umbilical vein), which is also partially resistant to enzymatic degradation. Extension of the N-terminal end by Sar-Tyr-epsilon Ahx (used for labeling purposes) and even cold-labeling of Tyr with iodine were compatible with high, selective, and specific antagonism of the B1 receptors. We compared some compounds with some already known B1 receptor antagonists to underline the novelty of new peptidic compounds.
Hypertension 1996 Nov
PMID:Structure-activity studies of B1 receptor-related peptides. Antagonists. 890 31

This study was designed to characterize the hemodynamic and biochemical properties of the abdominal aorta in four genetically related inbred rat strains that express genetic hypertension and hyperactive behavior in varying combinations. These include (1) the spontaneously hypertensive rat (SHR), which is hypertensive, hyperactive, and hyperreactive to stress; (2) Wistar-Kyoto (WKY) rats, which express none of these traits; (3) WKHT rats, which are hypertensive but not hyperactive; and (4) WKHA rats, which are hyperactive and hyperreactive to stress, but normotensive. Together, these four strains allowed us to examine the structural and functional changes in the aorta in the hypertensive SHR, the most widely used animal model of genetic hypertension, while controlling for the variables of hyperactivity and hyperreactivity that are also expressed in the SHR. Four groups of animals of both sexes were studied: (1) WKY, n = 101, (2) WKHA, n = 33, (3) WKHT, n = 91, and (4) SHR, n = 28. Blood pressure (BP) was determined by tail plethysmography as well as direct intraarterial monitoring under anesthesia. Fixed specimens were prepared for histologic analysis and the wall thickness determined morphometrically. Quantification of soluble tissue protein, elastin, and collagen in the aortic tissue was determined by measuring leucine (leu), hydroxyproline (HP/leu), and desmosine (DES/leu). The hypertensive strains (SHR and WKHT) had significantly higher tail BP than the normotensive strains (WKY and WKHA)-WKY: 128.7 +/- 22.3; WKHA: 126.7 +/- 14.6; WKHT: 162.8 +/- 21.2; SHR: 164.2 +/- 36.1 (p < 0.0001). Additionally, intraaortic diastolic BP and mean BP were higher in SHR rats than in WKHT. Morphometric studies showed the media thickness in the SHR rats was significantly greater than in the WKY and WKHA rats and no different than in the WKHT rats. Significantly less of the aortic wall protein was present as elastin in the hypertensive rats (SHR and WKHT), as well as the hyperactive rats (WKHA), compared to rats that had neither trait (WKY). These studies provide new information regarding aortic structure and function in genetic hypertension using inbred strains to control for the hyperactivity/hyperreactivity traits that coexist with hypertension in the SHR. They reveal that hypertensive aortas have altered matrix proteins that cannot be explained simply on the basis of blood pressure alone.
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PMID:Hemodynamic and biochemical characteristics of the aorta in the WKY, SHR, WKHT, and WKHA rat strains. 895 87


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