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)

The purpose of this research was to obtain further information about the role of polymorphonuclear leukocytes in essential hypertension. These cells could be involved in the pathogenesis of organ injury. Thirty subjects (14 men and 16 women) with essential hypertension were enrolled. In these subjects we determined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate and N:-formyl-methionyl-leucyl-phenylalanine, the polymorphonuclear leukocyte membrane fluidity, obtained by labeling the cells with 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3, 5-hexatriene, cytosolic Ca(2+) concentration, obtained by marking the cells with Fura 2-AM, and integrin pattern (CD11a, CD11b, CD11c, and CD18), by using the indirect immunofluorescence with a flow cytometer. At baseline there was no difference in membrane fluidity between normal subjects and hypertensives, whereas hypertensives showed an increase in cytosolic Ca(2+) content and an increase of the phenotypical expression of CD11a, CD11b, and CD18. In normal subjects and in hypertensives, after activation, no variation was found in membrane fluidity and cytosolic Ca(2+) content. In normal subjects, after activation, we observed a significant increase of the expression of all adhesion molecules, whereas in hypertensives we found an increase of the expression of CD11b, CD11c, and CD18 but also a decrease of CD11a. The behavior of the polymorphonuclear leukocyte integrin profile may have several explanations, and in particular, the trend of CD11a after chemotactic activation may be related to its cleavage or to an altered integrin phosphorylation/dephosphorylation balance hypothetically present in this clinical condition.
Hypertension 2000 Nov
PMID:Polymorphonuclear integrins, membrane fluidity, and cytosolic Ca(2+) content after activation in essential hypertension. 1108 48

A peptide fraction having activity against angiotensin I-converting enzyme (ACE) was separated from the peptic digest of protein prepared from wakame (Undaria pinnatifida) by ion-exchange chromatographies and gel-filtration. Fractions with high ACE inhibitory activity were combined and further chromatographed on a reverse-phase column to yield four tetrapeptides with ACE inhibitory properties. These tetrapeptides were identified by sequence analysis and fast atom bombardment mass spectrometry as Ala-Ile-Tyr-Lys (IC(50): 213 microM), Tyr-Lys-Tyr-Tyr (64.2 microM), Lys-Phe-Tyr-Gly (90.5 microM), and Tyr-Asn-Lys-Leu (21 microM). Each tetrapeptide was synthesized and its antihypertensive activity was determined after oral administration in spontaneously hypertensive rats. The blood pressure significantly decreased after tetrapeptide ingestion. The present study demonstrated that dietary wakame may have beneficial effects on hypertension.
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PMID:Identification of an antihypertensive peptide from peptic digest of wakame (Undaria pinnatifida). 1109 Nov

The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) has high affinity for BRS-3 and using this ligand showed BRS-3 has a unique pharmacology with high affinity for no known natural Bn peptides. However, use of this ligand is limited because it has high affinity for all known Bn receptors. In the present study we have attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) or its d-Phe(6) analogue. Each of the 22 peptides synthesized had binding affinities determined for hBRS-3, hGRPR, and hNMBR, and hBRS-3 selective ligands were tested for their ability to activate phospholipase C and increase inositol phosphates ([(3)H]inositol phosphate). Using this approach we have identified a number of BRS-3 selective ligands. These ligands functioned as receptor agonists and their binding affinities were reflected in their potencies for altering [(3)H]inositol phosphate. Two peptides with an (R)- or (S)-amino-3-phenylpropionic acid substitution for beta-Ala(11) in the prototype ligand had the highest selectivity for the hBRS-3 over the mammalian Bn receptors and did not interact with receptors for other gastrointestinal hormones/neurotransmitters. Molecular modeling demonstrated these two selective BRS-3 ligands had a unique conformation of the position 11 beta-amino acid. This selectivity was of sufficient magnitude that these should be useful in explaining the role of hBRS-3 activation in obesity, glucose homeostasis, hypertension, and other physiological or pathological processes.
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PMID:Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3. 1111 77

Vascular resistance and arterial pressure are reduced during normal pregnancy, but dangerously elevated during pregnancy-induced hypertension (PIH), and changes in nitric oxide (NO) synthesis have been hypothesized as one potential cause. In support of this hypothesis, chronic inhibition of NO synthesis in pregnant rats has been shown to cause significant increases in renal vascular resistance and hypertension; however, the cellular mechanisms involved are unclear. We tested the hypothesis that the pregnancy-associated changes in renal vascular resistance reflect changes in contractility and intracellular Ca(2+) concentration ([Ca(2+)](i)) of renal arterial smooth muscle. Smooth muscle cells were isolated from renal interlobular arteries of virgin and pregnant Sprague-Dawley rats untreated or treated with the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 4 mg. kg(-1). day(-1) for 5 days), then loaded with fura 2. In cells of virgin rats incubated in Hanks' solution (1 mM Ca(2+)), the basal [Ca(2+)](i) was 86 +/- 6 nM. Phenylephrine (Phe, 10(-5) M) caused a transient increase in [Ca(2+)](i) to 417 +/- 11 nM and maintained an increase to 183 +/- 8 nM and 32 +/- 3% cell contraction. Membrane depolarization by 51 mM KCl, which stimulates Ca(2+) entry from the extracellular space, caused maintained increase in [Ca(2+)](i) to 292 +/- 12 nM and 31 +/- 2% contraction. The maintained Phe- and KCl-induced [Ca(2+)](i) and contractions were reduced in pregnant rats but significantly enhanced in pregnant rats treated with L-NAME. Phe- and KCl-induced contraction and [Ca(2+)](i) were not significantly different between untreated and L-NAME-treated virgin rats or between untreated and L-NAME + L-arginine treated pregnant rats. In Ca(2+)-free Hanks', application of Phe or caffeine (10 mM), to stimulate Ca(2+) release from the intracellular stores, caused a transient increase in [Ca(2+)](i) and a small cell contraction that were not significantly different among the different groups. Thus renal interlobular smooth muscle of normal pregnant rats exhibits reduction in [Ca(2+)](i) signaling that involves Ca(2+) entry from the extracellular space but not Ca(2+) release from the intracellular stores. The reduced renal smooth muscle cell contraction and [Ca(2+)](i) in pregnant rats may explain the decreased renal vascular resistance associated with normal pregnancy, whereas the enhanced cell contraction and [Ca(2+)](i) during inhibition of NO synthesis in pregnant rats may, in part, explain the increased renal vascular resistance associated with PIH.
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PMID:[Ca(2+)](i) signaling in renal arterial smooth muscle cells of pregnant rat is enhanced during inhibition of NOS. 1112 38

Changes in tissue protein synthesis in hypertension have usually been measured in vitro in heart from acutely hypertensive rats without consideration of changes in atrial or pulmonary tissue or changes occurring in long-standing hypertension. The objective of the study was to investigate the in vivo changes in cardiopulmonary protein synthesis in three different rat models of chronic hypertension. Hypertension in aortic constriction, the Goldblatt model, and the bromoethylamine model were induced in rats for 30 days. At the end of the experimental period, in vivo rates of protein synthesis were measured with a flooding dose of [3H]phenylalanine (a method which effectively considers precursor pools). Concomitant measurements included quantification of contractile protein and RNA and DNA contents. Indices of protein breakdown were also assessed by selective measurement of protease activities. At the end of 30 days, aortic constriction induced marked increases in protein contents of the left ventricle, septum, left atria, and lungs. Accompanying changes included concomitant increases in RNA and DNA contents. Left ventricular myofibrillary, sarcoplasmic, and stromal protein contents increased in the aortic constriction model. Less marked changes occurred in the Goldblatt model, though the left atria were not significantly affected. In contrast, the bromoethylamine model had no effect on the protein or RNA contents of any region. In all cardiac regions of all three models, fractional rates of protein synthesis were not significantly affected. However, protein synthesis increased in the lungs of both the Goldblatt and bromoethylamine models at 30 days. Protease activities were decreased in the left ventricles of all three models at 30 days, with lysosomal protease activities declining in the aortic constriction model and cytoplasmic protease activities declining in the other two models. The failure of chronic hypertension to increase ventricular synthesis rates may represent inherent limitations in the time frame for measuring protein synthesis in vivo. However, at earlier time points (i.e., 10 days), the aortic constriction model was characterized by marked increases in left ventricular and atrial protein contents, RNA contents, and fractional rates of protein synthesis. This was consistent with the supposition that, in acute phases of hypertrophy, rates of protein synthesis increase, whereas in established hypertrophy, synthesis rates remain unchanged or decrease. The applicability of the aortic constriction model was investigated by examining the effects of the angiotensin converting enzyme inhibitor lisinopril (5 mg/kg/day). After 30 days treatment, lisinopril impeded the increase in left ventricular mixed and myofibrillar proteins. This effect was accompanied by an apparent increase in protein synthesis. In conclusion, although all three chronic models are able to induce hypertension, varying degrees of hypertrophy develop, which are more pronounced in the aortic constriction model. Accompanying changes include hypertrophy in the atria, reduced rates of ventricular proteolytic activity, and altered rates of protein metabolism in the lungs.
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PMID:In vivo protein synthetic rates of atrial, ventricular, and pulmonary tissue proteins in aortic constriction, goldblatt, and bromoethylamine models of hypertension. 1117 Jul 87

High salt diet is often associated with increases in blood pressure, and the state of activation of endothelium-dependent vascular relaxation pathways is critical under these conditions. Basal activation of endothelial endothelin B (ET(B)) receptors by endothelin has been suggested to stimulate the release of factors that promote vascular relaxation. However, whether ET(B) receptors play a role in enhancing endothelium-dependent vascular relaxation during high salt diet is unclear. In this study, we investigated whether chronic treatment with an ET(B) receptor antagonist is associated with impaired endothelium-dependent vascular relaxation and enhanced vascular reactivity particularly during high salt diet. Isometric contraction was measured in aortic strips isolated from male Sprague-Dawley rats on normal sodium (NS, 1%) and high sodium diet (HS, 8%) for 7 days and untreated or treated with the ET(B) receptor antagonist A-192621 (30 mg/kg per day) for 5 days. The mean arterial pressure was (in mm Hg) 122+/-3 in NS, 132+/-3 in HS, 144+/-2 in NS/ET(B) antagonist, and 171+/-12 in HS/ET(B) antagonist rats. In endothelium-intact strips, phenylephrine (Phe, 10(-5) mol/L) increased active stress to 7.6+/-1.0x10(3)N/m(2) in NS rats and 8.2+/-0.9x10(3)N/m(2) in HS rats. Phe (10(-5) mol/L) -induced stress was significantly greater in NS/ET(B) antagonist (11.3+/-0.9x10(3)N/m(2)) than NS and far greater in HS/ET(B) antagonist (14.1+/-0.1.2x10(3)N/m(2)) than HS rats. Also, Phe was more potent in NS/ET(B) antagonist and HS/ET(B) antagonist rats (ED(50)=0.3x10(-7) and 0.15x10(-7) mol/L) than in NS and HS rats (ED(50)=0.8x10(-7) and 0.7x10(-7) mol/L). Removal of the endothelium enhanced Phe-induced contraction significantly in NS and to a greater extent in HS, but not in NS/ET(B) antagonist or HS/ET(B) antagonist rats. In endothelium-intact strips, acetylcholine (ACh) caused relaxation of Phe contraction that was less in NS/ET(B) antagonist than NS and far less in HS/ET(B) antagonist than HS rats. Pretreatment of endothelium-intact strips with L-NAME (10(-4) mol/L), to inhibit nitric oxide (NO) synthase, or with methylene blue (10(-5) mol/L) or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10(-6) mol/L), to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced contraction significantly in NS and HS, slightly in NS/ET(B) antagonist, but not in HS/ET(B) antagonist rats. Measurement of basal and ACh-induced nitrite/nitrate production from aortic strips showed a significant reduction in NS/ET(B) antagonist compared with NS, and a greater reduction in HS/ET(B) antagonist compared with HS rats. Relaxation of Phe contraction with sodium nitroprusside was not significantly different among the different groups of rats. Thus, an endothelial ET(B) receptor-mediated pathway of vascular relaxation involving release of NO seems to be active under basal conditions and may protect against excessive vasoconstriction and increased blood pressure particularly during high salt diet.
Hypertension 2001 Feb
PMID:Role of endothelin B receptors in enhancing endothelium-dependent nitric oxide-mediated vascular relaxation during high salt diet. 1123 Mar 28

Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratified by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusion of mixed amino acids. Before and during amino acid administration, we measured glomerular filtration rate (GFR), putative second messengers of amino acids (nitric oxide [NO.] metabolites and cGMP), serum insulin and amino acid concentrations, and the FE(Li)+ as an index of renal proximal tubular reabsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43+/-8.16% versus 31.0+/-13.4% rise, P:=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P:<0.01) with the change in urinary NO. metabolite excretion; a diminished rise in urinary NO. metabolite excretion in the FH+ group (P:=0.0105) suggested a biochemical mechanism for the different GFR responses between FH groups: a relative inability to convert arginine to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol. h(-1)/1.73 m(2), P:=0.001), although cGMP did not change during the amino acid infusion (P:=0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (P:=0.0013), accounting for approximately 45% of the variance in GFR response. Decline in FE(Li)+, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (r=-0.506, P:=0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FH+ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO. in the kidney. Corresponding changes in GFR and fractional excretion of Li(+) suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension.
Hypertension 2001 Mar
PMID:Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: mechanisms and consequences. 1124 15

The potentiation of kinin actions represents a cardioprotective property of ACE inhibitors. Although a clear contribution to this effect is related to the inhibition of bradykinin (BK) breakdown, the high efficacy of potentiation and the ability of ACE inhibitors to provoke a B(2)-receptor-mediated response even after receptor desensitization has also triggered hypotheses concerning additional mechanisms of kinin potentiation. The application of kinin analogues with enhanced metabolic stability for the demonstration of degradation-independent mechanisms of potentiation, however, has yielded inconsistent results. Therefore, the relation between the susceptibility of B(2)-agonists to ACE and the potentiation of their actions by ACE inhibitors was investigated with the use of minimally modified kinin derivatives that varied in their degree of ACE resistance. The B(2)-agonists BK, D-Arg-[Hyp(3)]-BK, [Hyp,(3) Tyr(Me)(8)]-BK, [DeltaPhe(5)]-BK, [D-NMF(7)]-BK, and [Phe(8)psi(CH(2)-NH)Arg(9)]-BK were tested for degradation by purified rabbit ACE and for their potency in contracting the endothelium-denuded rabbit jugular vein in the absence and presence of ramiprilat. Purified ACE degraded D-Arg-[Hyp(3)]-BK and [Hyp,(3) Tyr(Me)(8)]-BK at 81% and 71% of BK degradation activity, respectively, whereas other peptides were highly ([DeltaPhe(5)]-BK) or completely ([D-NMF(7)]-BK, [Phe(8)psi(CH(2)-NH)Arg(9)]-BK) resistant. The EC(50) of BK-induced venoconstriction (1.15+/-0.2 nmol/L) was reduced by a factor of 5.7 in the presence of ramiprilat. Likewise, D-Arg-[Hyp(3)]-BK and [Hyp,(3) Tyr(Me)(8)]-BK were both significantly potentiated by a factor of 4.4, whereas the activities of the other agonists were not affected. Ramiprilat exerted no influence on the maximum contraction induced by any of the agonists. It is concluded that the potentiation of kinin analogues during ACE inhibition correlates quantitatively with the susceptibility of each substance to degradation by ACE. As such, no evidence of degradation-independent potentiating actions of ACE inhibitors could be obtained.
Hypertension 2001 Jul
PMID:Potentiation of kinin analogues by ramiprilat is exclusively related to their degradation. 1146 75

Ouabain increases vascular resistance and may induce hypertension by inhibiting the Na+ pump. The effects of 0.18 and 18 microg/kg, and 1.8 mg/kg ouabain pretreatment on the phenylephrine (PHE; 0.1, 0.25 and 0.5 microg, in bolus)-evoked pressor responses were investigated using anesthetized normotensive (control and uninephrectomized) and hypertensive (1K1C and DOCA-salt treated) rats. Treatment with 18 microg/kg ouabain increased systolic and diastolic blood pressure in all groups studied. However, the magnitude of this increase was larger for the hypertensive 1K1C and DOCA-salt rats than for normotensive animals, while the pressor effect of 0.18 microg/kg ouabain was greater only in DOCA-salt rats. A very large dose (1.8 mg/kg) produced toxic effects on the normotensive control but not on uninephrectomized or 1K1C rats. Rat tail vascular beds were perfused to analyze the effects of 10 nM ouabain on the pressor response to PHE. In all animals, 10 nM ouabain increased the PHE pressor response, but this increase was larger in hypertensive DOCA-salt rats than in normotensive and 1K1C rats. Results suggested that a) increases in diastolic blood pressure induced by 18 microg/kg ouabain were larger in hypertensive than normotensive rats; b) in DOCA-salt rats, smaller ouabain doses had a stronger effect than in other groups; c) hypertensive and uninephrectomized rats were less sensitive to toxic doses of ouabain, and d) after treatment with 10 nM ouabain isolated tail vascular beds from DOCA-salt rats were more sensitive to the pressor effect of PHE than those from normotensive and 1K1C hypertensive rats. These data suggest that very small doses of ouabain, which might produce nanomolar plasma concentrations, enhance pressor reactivity in DOCA-salt hypertensive rats, supporting the idea that endogenous ouabain may contribute to the increase and maintenance of vascular tone in hypertension.
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PMID:Effects of small doses of ouabain on the arterial blood pressure of anesthetized hypertensive and normotensive rats. 1147 Oct 47

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 micromol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours, P<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of (3)H-phenylalanine (1.4-fold by ET and 1.5-fold by PE, P<0.01), cell size (2.3-fold and 2.5-fold, P<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold, P<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold, P<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of (3)H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.
Hypertension 2002 Jan
PMID:Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine. 1179 83


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