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)

Brown Norway Katholiek rats, which have very low levels of plasma kininogens, excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats fed low (0.3%) NaCl diets (131 +/- 4 mm Hg, n = 12) was not different from that in normal rats. Two percent NaCl diets given from 7 weeks of age for 4 weeks caused rapid increases in blood pressure (167 +/- 4 mm Hg, n = 12, 9 weeks old) in deficient rats, although the same diets induced no blood pressure increase in normal rats. Urinary excretion of active kallikrein and prokallikrein remained constant in both rat groups throughout NaCl loading. During this period, the deficient rats secreted less urine (9 weeks old, P < .05) and less urinary sodium (11 weeks old, P < .05). Serum levels of sodium in deficient rats were higher (P < .05) than in normal rats at 9 weeks of age. Intracellular concentrations of sodium in the erythrocytes of deficient rats were higher (P < .05) than in normal rats throughout NaCl loading. Subcutaneous infusion of bovine low molecular weight kininogen with an osmotic pump in NaCl-loaded deficient rats induced a reduction (P < .01) in blood pressure and increases (P < .05) in urine volume and urinary sodium and kinin levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 or of aprotinin in NaCl-loaded normal rats induced a hypertensive response. This antagonist treatment reduced urine volume and urinary sodium. These results indicate that the lack of kinin generation observed in the kininogen-deficient rats was related through sodium retention to the hypertensive response to NaCl loading.
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PMID:High sensitivity to salt in kininogen-deficient brown Norway Katholiek rats. 769 88

1. The Brown Norway (B/N) Katholiek rat is a mutant strain of plasma kininogen deficiency. The plasma of B/N-Katholiek rats was shown to contain only 3-5% of high-molecular-weight and low-molecular-weight kininogens (HK and LK) of the normal level by specific RIA, and 30% of prekallikrein was detected by amidase activity. However, HK antigen in the liver microsomal fraction of B/N-Katholiek rats was about 60% of that of normal rats. 2. In this paper we compare and discuss synthesis and secretion of HK and LK by primary cultures of livers of deficient and normal rats. The deficient hepatocytes could synthesize HK and LK in the same way as normal cells but could not secrete mature forms of HK and LK in the medium. Examination of the subcellular localization of the mutant HK in the hepatocytes showed that a larger amount of mutant HK antigen, compared to normal rats, was found in the 10,000 g fraction, which is rich in lysosomes, suggesting that the mutant HK may be transported to the lysosomes. 3. We also analyzed sequence of the HK cDNA of B/N-Katholiek and B/N-Kitasato rats and found a point mutation of G to A at nucleotide 487, which locates at the heavy chain region of HK and LK. 4. We constructed five expression plasmids to transfect COS-1 cells to examine HK secretion. COS-1 cells transfected with the plasmids containing the G to A transition could not secrete and retained HK, while those cells transfected with the plasmids containing normal G released HK into the medium. 5. These results indicate that a point mutation G to A at nucleotide 487, resulting in an amino acid transition from alanine (163) to threonine, is responsible for the defective secretion of HK and LK by the liver of B/N-Katholiek rats. We also discuss other cases of secretion defect of plasma proteins reported in the literature.
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PMID:Molecular mechanism of kininogen deficiency in brown Norway Katholiek rats. 774 70

A hypotensive effect of intravenously injected des-Arg9-bradykinin was found in Brown/Norway strain young male rats which were pretreated with a small amount of endotoxin 24 h before the experiment, whereas the hypotensive effect of bradykinin was unaffected by the endotoxin. The potency of des-Arg9-bradykinin for the hypotensive effect was comparable to that of bradykinin. On the other hand, in endotoxin-pretreated aged rats, this effect of des-Arg9-bradykinin was not observed. Only during the intravenous infusion of des-Arg9[Leu8]bradykinin, a bradykinin B1 receptor antagonist, was the hypotensive effect of des-Arg9-bradykinin inhibited, whereas that of bradykinin was potentiated. After the end of infusion of des-Arg9[Leu8]bradykinin, the response to des-Arg9-bradykinin rapidly recovered. The results suggest the possibility that des-Arg9-bradykinin might play a role in inflammatory diseases.
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PMID:A hypotensive response induced by des-Arg9-bradykinin in young brown/Norway rats pretreated with endotoxin. 776 75

We investigated the role of reactive oxygen species in ozone-induced airway hyperresponsiveness (AHR) in Brown Norway rats. Airway responsiveness to inhaled acetylcholine (ACh) and bradykinin (BK) and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were measured in vivo. Neutral endopeptidase (NEP) activity assay and measurement of BK-receptor binding sites in Brown Norway rat lungs were carried out in vitro. Apocynin (5 mg/kg), an inhibitor of superoxide anion-generating NADPH oxidase, was administered perorally 30 min before a 3- or 6-h exposure to 3 ppm of ozone, and the animals were studied 18-24 h postexposure. Ozone induced increases in airway responsiveness to ACh and BK and in neutrophil counts in BALF. Apocynin inhibited the increase in airway responsiveness to BK but not to ACh without affecting the neutrophil counts in BALF. The antioxidants allopurinol and deferoxamine prevented ozone-induced AHR to both ACh and BK but did not reduce neutrophil counts. To further examine the mechanisms of ozone-induced AHR to BK, we measured NEP activity and the density of BK receptors in vitro after ozone exposure. Ozone exposure had no significant effect either on NEP activity or on the affinity and the number of BK receptors in lungs from rats treated with or without apocynin. We conclude that superoxide anions released from inflammatory cells in the airway may be involved in ozone-induced AHR. Inactivation of NEP or upregulation of BK receptors do not appear to be involved, but the possibility of localized changes cannot be excluded.
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PMID:Ozone-induced airway hyperresponsiveness: role of superoxide anions, NEP, and BK receptors. 777 93

Brown Norway Katholiek (B/N-Ka) is a mutant rat strain deficient in plasma high-molecular-weight (HK) and low-molecular-weight kininogen (LK). It has been reported that the deficiency, caused by defective secretion of HK and LK by the liver, is associated with a point mutation of alanine (163) to threonine in the common heavy chain. In this report we demonstrate by specific radioimmunoassay that the amount of immunoreactive HK antigen in the B/N-Ka kidney was almost the same as that found in the normal Brown Norway rat (Brown Norway Kitasato, B/N-Ki). HK antigen in the kidneys of both strains was immunohistochemically localized at distal tubules with similar intensity in both strains. Among the subcellular fractions of the kidney homogenates, HK antigen was predominantly found in the microsomal fraction of both strains. To see whether this HK antigen is derived from plasma HK or is synthesized in the kidneys, we examined uptake of HK by the tubular cells after incubation with 125I-HK. Only 0.6% of the radioactivity of added 125I-HK was found in the tubular cells of both strains after a 60-min incubation. Messages of HK mRNA from both strains of rats were visualized by PCR at almost the same intensity. These results suggest that HK antigen found in the kidney may be derived mainly from biosynthesis in the kidney itself and partly from uptake of HK from blood. There was no difference in these features of HK between the kidneys of the deficient and the normal B/N rats.
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PMID:Demonstration of high-molecular-weight kininogen in kininogen-deficient rat kidneys. 779 87

We investigated the role of endogenous nitric oxide (NO) and superoxide anions in recombinant human interleukin-1 beta (rhIL-1 beta)-induced bronchial hyperresponsiveness (BHR) and neutrophilia in Brown-Norway rats. Aminoguanidine (100 mg/kg/d) administered subcutaneously for 3 d, an inhibitor of inducible NO synthase, L-arginine (100 mg/kg/d administered subcutaneously for 3 d, a specific precursor for the synthesis of NO, and apocynin (5 mg/kg/orally), an inhibitor of superoxide anion (O2-)-generating NADPH oxidase in macrophages and neutrophils, were administered prior to administration of rhIL-1 beta (500 U) intratracheally. Aminoguanidine in addition to another inhibitor of NO synthase, NW-nitro-L-arginine methyl ester (L-NAME) 100 mg kg/d administered subcutaneously for 3 d augmented bronchial responsiveness to inhaled bradykinin (BK) but not to acetylcholine (ACh), an effect reversed by L-arginine. rhIL-1 beta-treated rats also demonstrated BHR to BK but not to ACh, associated with neutrophilia in bronchoalveolar lavage fluid (BALF). rhIL-1 beta-induced BHR and neutrophilia were neither further increased by aminoguanidine nor inhibited by L-arginine. Apocynin, however, significantly inhibited rhIL-1 beta-induced BHR but not the BALF neutrophilia. Suppression of NO generation and generation of O2- from macrophages and infiltrating neutrophils may be important in rhIL-1 beta-induced airway hyperresponsiveness to bradykinin.
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PMID:Role of nitric oxide and superoxide anions in interleukin-1 beta-induced airway hyperresponsiveness to bradykinin. 792 31

Brown Norway Katholiek rats with very low levels of plasma kininogens excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats (132 +/- 2 mmHg, n = 7) was not different from that of normal rats. Angiotensin II (Ang II) (20 micrograms/d SC) from 7 weeks of age for 2 weeks with a micro-osmotic pump caused significant increases in blood pressure (181 +/- 5 mm Hg, n = 7, 9 weeks old) in the deficient rats, although the same treatment induced no blood pressure increase in the normal rats. Also during this period, the deficient rats had significantly higher heart rates, tended to excrete less urinary sodium, and showed significantly higher sodium levels in serum, erythrocytes, and cerebrospinal fluid compared with the normal rats. Ang II increased urinary excretion of aldosterone in both deficient and normal rats (P < .05). Spironolactone treatment (50 mg/kg per day) for 7 days in deficient rats restored blood pressure and heart rate to normal levels and significantly reduced sodium levels in erythrocytes and cerebrospinal fluid. Subcutaneous infusion of bovine low-molecular-weight kininogen with an osmotic pump in Ang II-treated deficient rats induced significant reductions in blood pressure, heart rate, and erythrocyte sodium levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 in Ang II-treated normal rats induced a hypertensive response in parallel with significant increases in heart rate and erythrocyte sodium level. These results suggest that the lack of kinin generation observed in the kininogen-deficient rats may cause the hypertensive response during the administration of a nonpressor dose of Ang II mainly through sodium retention probably caused by aldosterone release.
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PMID:Hypertension induced by a nonpressor dose of angiotensin II in kininogen-deficient rats. 802 Sep 99

Airway responsiveness (AR) to inhaled acetylcholine and bradykinin and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were studied in inbred male Brown-Norway rats actively sensitized to ovalbumin and later given 500 U interleukin-1 beta (IL-1 beta) intratracheally. We examined animals 14 to 21 days after initial sensitization at 18 to 24 hours after the intratracheal administration of IL-1 beta. We evaluated AR to acetylcholine as -log PC200, which is -log10 transformation of provocative concentration of acetylcholine producing 200% increase in lung resistance, and to bradykinin as percent increase in lung resistance. BALF was examined as an index of inflammatory changes within the lung. Although there was no significant difference in baseline lung resistance, nonsensitized and sensitized animals that were given IL-1 beta demonstrated a significant increase of AR to bradykinin at 18 to 24 hours and a significant increase of neutrophil counts in BALF, which was already observed by 4 to 6 hours. There was a significant correlation between AR to bradykinin and neutrophil counts in BALF in all animals (r = 0.644; p < 0.0005). We conclude that intratracheal administration of IL-1 beta induces the inflammatory changes, which are characterized by an increase in neutrophil counts in BALF, and increased AR to bradykinin, and that active sensitization per se does not potentiate the effect of IL-1 beta on AR to acetylcholine or bradykinin or on airway inflammation.
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PMID:Effect of interleukin-1 beta on airway hyperresponsiveness and inflammation in sensitized and nonsensitized Brown-Norway rats. 812 Feb 73

To clarify the mechanism of plasma kininogen deficiency of Brown Norway Katholiek strain (B/N-Katholiek) rats, we compared synthesis and secretion of kininogens by primary cultures of hepatocytes from B/N-Katholiek and B/N-Kitasato (normal strain) rats. Pulse-and-chase experiments using [35S]methionine demonstrated that kininogen antigens with molecular masses of 100 and 66 kDa, corresponding to high- and low-molecular-weight kininogens (HK and LK), respectively, were detected in the hepatocytes of both strains. These proteins were then processed to 108- and 71-kDa forms, respectively, and secreted by the normal hepatocytes, while the latter forms were hardly secreted in the culture media of the deficient hepatocytes. However in the deficient cells, 100- and 66-kDa forms were accumulated, but 108- and 71-kDa bands were faint. A subcellular fractionation study showed that a relatively higher amount of the kininogen antigens was present in the lysosomal fraction of B/N-Katholiek hepatocytes than in that of B/N-Kitasato hepatocytes. From these results we postulate the cause of the secretion defect of B/N-Katholiek liver to be as follows. (i) B/N-Katholiek liver could synthesize the mature secretable forms of HK and LK, but they are too rapidly transported to the lysosomes, or (ii) the mature forms in B/N-Katholiek hepatocytes might be synthesized much more slowly than those in the normal cells. T-Kininogen was normally synthesized and secreted by the hepatocytes of B/N-Katholiek, suggesting that the secretion defect could be limited to HK and LK, at a common site.
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PMID:Plasma kininogen deficiency: associated defective secretion of kininogens by primary cultures of hepatocytes from brown Norway Katholiek rats. 834 Mar 46

To clarify the mechanism of the secretion defect of high molecular weight kininogen (HK) and low molecular weight kininogen (LK) by the liver of Brown Norway (B/N) Katholiek rats causing plasma kininogen deficiency, we cloned cDNAs for HK from cDNA libraries of the livers of B/N Katholiek and B/N Kitasato rats. A point mutation of G to A at nucleotide 487 was found in the cDNA of B/N Katholiek rats by sequence analysis of the cDNAs (including the entire HK-coding region) obtained from both strains. Both B/N Katholiek and B/N Kitasato rat cDNA fragments were introduced into a eukaryotic vector, pRc/CMV, to construct their respective expression plasmid, which was used to transfect COS-1 cells. At 24 h of incubation, the culture medium of COS-1 cells transfected with the B/N Katholiek rat cDNA contained only 10% of the HK antigen that was found in COS-1 cells transfected with the B/N Kitasato rat cDNA. More HK antigen was retained in the former cells. Moreover, cells transfected with B/N Katholiek rat cDNA, in which the A at nucleotide 487 was artificially replaced by G, secreted a significant amount of HK into the medium. These results suggest that a point mutation of G to A at nucleotide 487, which causes a substitution of Ala163 to Thr in the heavy chain of HK and LK, is responsible for the defective secretion of HK and LK by the liver of B/N Katholiek rats.
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PMID:A point mutation of alanine 163 to threonine is responsible for the defective secretion of high molecular weight kininogen by the liver of brown Norway Katholiek rats. 834 7


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