Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clearance of exogenous plasma kallikrein, its uptake by liver, spleen, kidneys, lungs and its extravasation in the paws were determined in normal Wistar rats, normal and kininogen-deficient Brown Norway rats. Kallikrein was purified from rat plasma and labelled with 125I. After intravenous injection of 125I-kallikrein, the disappearance of acid-precipitable kallikrein from the blood fits a biexponential curve similar in the three groups of rats: a rapid initial clearance (T1/2 around 3 min) followed by a phase of slower elimination (T1/2 around 50 min). Removal of kallikrein from the blood was associated with a large uptake of radioactivity by the liver: 67% of the 125I-kallikrein cleared from the blood at 10 min. The kidneys and the spleen accumulated small amounts of the radioactivity. The uptake of kallikrein by the spleen was slightly reduced in kininogen-deficient rats. The kininogen deficiency in Brown Norway rats from the strain BN/May Pfd was confirmed by the low levels of kinins released by tissue kallikrein and by a prolongation of activated thromboplastin times in the plasma of these animals. We concluded that plasma kallikrein is rapidly cleared from the circulation of the rat. The liver is the main clearing organ of plasma kallikrein. The disappearance of kallikrein from the circulation is not affected by the lack of high molecular weight kininogen, except in the case of the uptake of the enzyme performed by the cells of the spleen, which is reduced.
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PMID:The fate of plasma kallikrein in normal and kininogen-deficient rats. 978 57

Tissue kallikrein and low molecular weight kininogen are localized in the particular cells of the connecting tubules, indicating that kinin is immediately generated in the lumina of the lower nephrons. The role of the renal kallikreinkinin system was studied using mutant kininogen-deficient Brown NorwayKatholiek (BN-Ka) rats, and compared with that in normal BN-Kitasato rats of the same strain. Mutant BN-Ka rats showed no visible changes, but they were very sensitive to excess sodium ingestion and to the tendency of sodium to accumulate in the body by aldosterone released by angiotensin II, so that sodium was accumulated in erythrocytes and cerebrospinal fluid in BN-Ka rats and hypertension was induced. After four days infusion of 0.3 M NaCl solution to conscious and unrestrained mutant BN-Ka rats, the sensitivity of the vascular smooth muscle to norepinephrine and angiotensin II increased 30-fold and 10-fold, respectively. Bradykinin was degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like exopeptidase (CPY) in rat and human urine. Daily oral administration of a selective inhibitor of CPY, ebelactone B, or that of NEP, BP1O2, prevented development of deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats. These results indicate that: 1) the renal kallikrein-kinin system allows excretion of excess sodium in the body, 2) decreased sodium excretion due to reduced excretion of urinary kallikrein in patients with essential hypertension or in genetically hypertensive rats may cause hypertension, and 3) urine kininase inhibitors such as ebelactone B may emerge as a new antihypertensive drug.
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PMID:Crucial suppressive role of renal kallikrein-kinin system in development of salt-sensitive hypertension. 983 May 1

We have previously reported on the identification of T-kininogen (T-KG) as a gene whose expression is increased during senescence in male Sprague-Dawley (S-D) rats. Serum T-KG levels increase 2.5-4 months before the time of death for any given animal, irrespective of the actual age of the animal at the time of this event. Furthermore, dietary restriction (DR) delays, but does not prevent, the increase in serum T-KG levels. In the present study, we have assessed whether or not the age-related increase in T-KG is a common feature of senescence in other strains of rat. We have analyzed hepatic T-KG mRNA levels in male Fischer 344 rats (F344), as well as in male and female (Fischer 344 x Brown Norway)F1 rats (F1). In both of these strains, we observed a dramatic increase in hepatic T-KG mRNA levels when male rats approach senescence. The mRNA levels behave similarly in F1 and S-D rats, in that the increase occurs late in life, and it is either repressed or delayed by DR. In contrast, the increase in T-KG mRNA levels in F344 rats occurs earlier in life, and is not significantly affected by DR. Young female F1 rats fed ad libitum (AL) show a statistically significant (P = 0.0009) 2.6-fold higher level of T-KG mRNA, as compared to their male counterparts. Thus, while we still observe an age-related increase in this parameter in both AL and DR female F1 rats, the difference is statistically significant (P = 0.0001) only in DR animals. We conclude that the increase in T-KG gene expression is a common feature of senescence and that, at least in males of these commonly used rat strains, T-KG can be used as a reliable biomarker of aging. Since the increase in T-KG gene expression does not appear to correlate with inflammatory processes, and since different strains of animals succumb to different pathologies, these results further suggest that the increase in T-KG expression might be related to the process of aging per se, rather than to any given age-related pathology.
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PMID:T-kininogen is a biomarker of senescence in rats. 988 78

1. Subcutaneous injection of sodium deoxycholic acid into the anterior of the back of male ddY mice elicited dose-dependent scratching of the injected site with the forepaws and hindpaws. 2. Up to 100 microg of sodium deoxycholic acid induced no significant increase in vascular permeability at the injection site as assessed by a dye leakage method. 3. Bradykinin (BK) B2 receptor antagonists, FR173657 and Hoe140, significantly decreased the frequency of scratching induced by sodium deoxycholic acid. 4. Treatment with aprotinin to inhibit tissue kallikrein reduced the scratching behaviour induced by sodium deoxycholic acid, whereas treatment with soybean trypsin inhibitor to inhibit plasma kallikrein did not. 5. Although injection of kininase II inhibitor, lisinopril together with sodium deoxycholic acid did not alter the scratching behaviour, phosphoramidon, a neutral endopeptidase inhibitor, significantly increased the frequency of scratching. 6. Homogenates of the skin excised from the backs of mice were subjected to gel-filtration column chromatography followed by an assay of kinin release by trypsin from each fraction separated. Less kinin release from the fractions containing kininogen of low molecular weight was observed in the skin injected with sodium deoxycholic acid than in normal skin. 7. The frequency of scratching after the injection of sodium deoxycholic acid in plasma kininogen-deficient Brown Norway Katholiek rats was significantly lower than that in normal rats of the same strain, Brown Norway Kitasato rats. 8. These results indicate that BK released from low-molecular-weight kininogen by tissue kallikrein, but not from high-molecular-weight kininogen by plasma kallikrein, may be involved in the scratching behaviour induced by the injection of sodium deoxycholic acid in the rodent.
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PMID:Reduction of sodium deoxycholic acid-induced scratching behaviour by bradykinin B2 receptor antagonists. 1005 Nov 36

Kininogens have recently been shown to possess antiadhesive, anticoagulant, and profibrinolytic properties and can inhibit platelet activation at low thrombin concentrations. To test whether kininogens have antithrombotic properties in vivo, we devised a model of limited arterial injury confined to removal of the endothelium. Brown-Norway Katholiek strain rats with an absence of low- and high-molecular-weight kininogen due to a single point mutation, A163T, were compared in the thrombosis model to the wild-type animals, which were otherwise genetically identical. Despite an equivalent vascular injury, the mean time (+/-SEM) for a 90% decrease in flow measured by laser Doppler was 38.4+/-17 minutes in the kininogen-deficient rats compared with 194+/-29 minutes in the wild-type animals (P<0.002). The degree of vascular injury was the same. No evidence for disseminated intravascular coagulation (decrease in factor V, antithrombin, or fibrinogen) or excessive fibrinolysis (elevation of fibrinogen degradation products) was found in either group of animals. The results suggest that kininogens have antithrombotic properties at low concentrations of thrombin and that inhibitory peptides derived from kininogen may constitute a new antithrombotic strategy.
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PMID:Kininogens are antithrombotic proteins In vivo. 1047 69

Bradykinin (BK) is a peptide mediator generated at sites of inflammation and its effects are mediated through constitutively expressed B(2) receptor or through induction of B(1) receptors. We examined the role of these receptors in bronchial hyperresponsiveness (BHR). Brown-Norway rats sensitized with ovalbumin (OA) and Al(OH)(3) intraperitoneally, were exposed 3 wk later to either saline or OA aerosol. B(1) receptor antagonist desArg(10)[Hoe140] (200 nmol/kg or 1 micromol/kg, intraperitoneally) or B(2) receptor antagonist Hoe140 (200 nmol/kg, intraperitoneally) was administered 30 min before allergen exposure. Hoe140 had no effect on OA-induced BHR to acetylcholine (ACh) and bronchoalveolar lavage fluid (BALF) cellular profiles, but inhibited bronchoconstriction to BK (p < 0.04). At both doses, desArg(10)[Hoe140] dose-dependently inhibited allergen-induced BHR to ACh (p < 0.01), but had no effect on bronchoconstriction to BK or baseline ACh responsiveness. The inflammatory cells in BALF were not affected apart from reduced lymphocyte numbers at the highest dose. B(1) receptor mRNA expression measured by Northern analysis was increased after allergen exposure in sensitized lungs, with a peak at 2 to 6 h after exposure, whereas B(2) receptor mRNA expression remained unchanged. Newly induced BK B(1) receptors may be involved in allergen-induced BHR to ACh, whereas constitutive B(2) receptors mediate BK-induced bronchoconstriction.
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PMID:Contribution of bradykinin B(1) and B(2) receptors in allergen-induced bronchial hyperresponsiveness. 1055 46

Recent studies indicate that during early phases of life the kallikrein-kinin system (KKS) plays a role in kidney development. In the rat kidney, the spatial and temporal pattern of expression of the genes encoding for kallikrein or bradykinin (BK) B2-receptors parallels postnatal nephrogenesis and blood flow redistribution from the inner to the outer renal cortex. Animal models with genetic dysfunction of the renal KKS show alterations in the functional maturation of the kidney, and ultimately develop salt-sensitive hypertension. Kininogen-deficient Brown Norway Katholiek rats have undetectable urinary kinin levels and show an exaggerated blood pressure sensitivity to chronic excess of salt or mineralocorticoids. Another rat model with genetic reduction in urinary kallikrein excretion is characterized by an altered pressure-natriuresis relationship, with this defect being corrected by infusion of purified rat tissue kallikrein. Knockout mice lacking the BK B2-receptor gene show elevated blood pressure and heart rate under basal conditions and enhanced blood pressure sensitivity to salt. In rats, prenatal blockade of the BK B2-receptor by icatibant leads to a cardiovascular phenotype similar to that of animals with genetic defects of the KKS. Delayed renal maturation is observed when high salt intake is associated with icatibant. Collectively, these findings indicate a relevant role of the KKS in the physiologic maturation of renal and cardiovascular phenotypes. Genetic or environmental factors, able to potentiate the activity of the renal KKS, could protect against the development of arterial hypertension.
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PMID:Role of the kallikrein-kinin system in the maturation of cardiovascular phenotype. 1056 Jul 85

We have previously reported that the renal kallikrein-kinin system suppressed the development of hypertension, using kininogen deficient Brown Norway Katholiek rats. Kinins were degraded in urine mainly by carboxypeptidase Y-like kininase (CPY). Blockade of renal kinin degradation may prevent the experimental hypertension through the facilitation of the renal kallikrein-kinin system. Daily administration of ebelactone B (EB), which is isolated from Actinomycetes and strongly inhibits CPY, from the first day of deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks completely blocked hypertension in Sprague-Dawley rats. This treatment reduced sodium levels in erythrocytes and cerebrospinal fluids (CSF) significantly. By contrast, an ACE inhibitor, lisinopril did not prevent hypertension. The development of hypertension in young spontaneously hypertensive rats was also blunted by EB with reductions in sodium levels in erythrocytes and in CSF. The arterial kinin levels in rats undergoing DOCA-salt treatment were 2.2 +/- 0.2 pg/ml, which were increased significantly to 4.6 +/- 0.4 pg/ml with captopril (10 mg/kg, s.c.). The increased kinin levels were less than those to show hypotension. EB did not increase the arterial kinin levels, with significant increase in urinary kinin secretion. These results suggested that facilitation of the renal kallikrein-kinin system by inhibition of kinin degradation on the luminal side of the renal tubules may effectively prevent hypertension.
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PMID:Facilitation of renal kallikrein-kinin system prevents the development of hypertension by inhibition of sodium retention. 1060 38

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B(2) receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B(2) kinin receptor antagonist in BN rats.
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PMID:Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats. 1066 82

1. To determine whether the antihypertensive response in deoxycorticosterone acetate (DOCA) salt-treated rats was mediated by kinins on the luminal side of renal tubules or in the circulation, selective urinary kininase inhibitors were administered to normal Brown Norway Kitasato (BN-Ki) rats and kininogen-deficient Brown Norway Katholiek (BN-Ka) rats. 2. Kinins were degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like kininase (CPY) in urine, but were inactivated mainly by angiotensin-converting enzyme (ACE) in the plasma. 3. Ebelactone B inhibited CPY, while poststatin inhibited CPY and NEP. 4. Daily administration of poststatin (5 mg/kg per day, s.c.) for 3 days reduced blood pressure (BP) in DOCA salt-treated BN-Ki rats, but not in BN-Ka rats. 5. Ebelactone B (5 mg/kg per day, s.c.) also reduced BP in BN-Ki rats, which was accompanied by increased urinary sodium excretion, but had no effect on BP in BN-Ka rats. 6. Lisinopril (5 mg/kg per day, s.c.) had no effect on BP in either rat strain. 7. Arterial kinin levels in BN-Ki rats increased significantly (2.2-4.6 pg/mL) with captopril (10 mg/kg, s.c.). However, arterial kinin levels that induced hypotension following the infusion of bradykinin (1000 ng/kg per min, i.v.) were 110-fold higher than endogenous arterial kinin levels attained following captopril. 8. These results suggest that inhibition of kinin degradation on the luminal side of the renal tubules may effectively attenuate hypertension.
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PMID:Inhibition of kinin degradation on the luminal side of renal tubules reduces high blood pressure in deoxycorticosterone acetate salt-treated rats. 1069 33


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