UMLS:C0432222 - FACTA Search

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The normal metabolic turnover of plasma kininogens was studied by measuring the disappearance of intravenously administered radiolabeled human and monkey plasma kininogens from the circulation of healthy adult rhesus monkeys. Curves obtained by plotting log radioactivity against time could be expressed as double exponential equations, with the first term representing diffusion, and the second, catabolism. No significant difference between the turnovers of human and monkey kininogens was observed. The difference between the t1/2 of high molecular weight kininogen (25.95 +/- 1.60 h) (mean +/- SEM) and that of low molecular weight kininogen (18.94 +/- 1.93 h) was only marginally significant (P less than 0.05). In contrast, a highly significant (P less than 0.001) difference in their mean catabolic rates (1.12 +/- 0.08 d-1 for high molecular weight kininogen vs. 2.07 +/- 0.09 d-1 for low molecular weight kininogen) was observed. These differences between the two kininogens were attributed to differences in their distribution between the intra- and extravascular pools. Studies of kininogen turnover will be useful in elucidating the in vivo functions of the various kininogens in health as well as during clinical illness.
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PMID:Turnover of human and monkey plasma kininogens in rhesus monkeys. 10 15

We have established a simplified assay system for the measurement of urinary kallikrein activity by utilizing the sensitive and specific radioimmunoassay system of kinins previously reported from our laboratory. Kinins were generated by incubating urine samples (50 microliter) with kininogen (1500 ng) in the presence of kininase inhibitors, and the generated kinins were measured by radioimmunoassay. Since the cross reactivity of kininogen in the kinin radioimmunoassay system was not recognized at dose up to 1.0 microgram, the amount of untreated kininogen in the radioimmunoassay samples did not interfere with the measurement of kinins. This eliminated the necessity for a kininogen extraction procedure. A good linear correlation (r = 0.939, p less than 0.001) was observed between the urinary kallikrein activity determined by this assay system (kininogenase activity) and that by esterolytic acitvity. Urinary kallikrein activity was 3.3 +/- 0.9 microgram/min/24 hour urine (mean +/- SEM), 1.4 +/- 0.4 microgram/min/24 hour urine and 0.25 +/- 0.06 microgram/min/24 hour urine in 6 normal subjects, 7 patients with non-complicated essential hypertension and 4 patients with chronic renal failure, respectively. Thus, urinary kallikrein activity was significantly lower in the patients with essential hypertension (p less than 0.05) and the patients with chronic renal failure (p less than 0.01) than in the normal subjects.
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PMID:Measurement of urinary kallikrein acitvity by kinin radioimmunoassay. 10 45

The possibility that bradykinin, a potent vasodilator, might be a physiological antagonist of the renin-angiotensin system was investigated. 11 norman subjects, ranging in age from 21 to 33 yr were studied. Seven of the subjects were given a 10 meq sodium, 100 meq potassium, 2500 ml isocaloric diet. After metabolic balance was achieved, they were infused with either 1 liter of 5 per cent glucose over 2 h or 2 liters of 0.9 per cent saline over 4 h. During the infusions, plasma renin activity (PRA), angiotensin II (A II), prekallikrein, bradykinin, and aldosterone levels were frequently determined. Plasma prekallikrein and kallikrein inhibitor did not change during the infusion of either glucose or saline. In subjects receiving saline, plasma bradykinin fell from 3.9 plus or minus 1.5 (SEM) ng/ml at 0 min to 0.93 plus or minus 0.2 at 30 min and 0.95 plus or minus 0.3 at 120 min. These changes paralleled the decrease in PRA over the same period (7.9 plus or minus 1.3 ng/ml/h to 5.6 plus or minus 0.8 at 30 min and 3.5 plus or minus 0.7 at 120 min). Similarly, A II fell from 113 plus or minus 12 pg/ml to 62 plus or minus 10 and 48 plus or minus 5, respectively, at 30 and 120 min. In contrast, the control group infused with glucose showed no change in bradykinin, A II, or PRA. Another four subjects were given a constant 200 meq sodium/100 meq potassium isocaloric diet. After metabolic balance was achieved, they were kept supine and fasting overnight. At 9 a.m. they assumed an upright position and began walking a fixed distance (200 ft) at a normal rate (3-4 ft/s). Plasma prekallikrein and kallikrein inhibitor did not change during the posture study. The plasma bradykinin rose from a base line of 0.54 plus or minus 0.01 (SEM) ng/ml to 0.96 plus or minus 0.13 at 20 min. 0.77 plus or minus 0.18 at 60 min, and 0.96 plus or minus 0.07 at 120 min. These changes parallel the increase in PRA over the same period (1.65 plus or minus 3.3 ng/ml/h to 3.6 plus or minus 0.85 at 20 min, 5.3 plus or minus 0.9 at 60 min, and 5.35 plus or minus 0.55 at 120 min). Likewise, the A II rose from 32.5 plus or minus 1.82 pg/ml to 50.8 plus or minus 3.6 at 20 min, 54.3 plus or minus 3.2 at 60 min, and 61.3 plus or minus 5.9 at 120 min. Thus, in sodium-depleted individuals, saline infusion produces a rapid fall of plasma bradykinin at a rate similar to that observed for a II and PRA. Conversely, in sodium-loaded individuals, assumption of upright posture leads to a parallel rise in A II, TPRA, and bradykinin. These studies indicate that there is a close correlation of bradykinin levels with renin activity and angiotensin II, in both acute sodium loading and assumption of upright posture, suggesting that these two systems may be physiologically interrelated.
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PMID:Response of the kallikrein-kinin and renin-angiotensin systems to saline infusion and upright posture. 23 59

We determined kinin-generating activity (kininogenase) in the thoracic aorta of spontaneously hypertensive rats (SHRs) at age 5 and 15 weeks and in appropriately age-matched Wistar-Kyoto (WKY) rats. Aorta homogenates were incubated with partially purified dog kininogen, and the resulting kinins were extracted with ethanol. The kinins were determined by a sensitive kinin radioimmunoassay (RIA). Kininogenase activity was expressed as mean +/- SEM, picogram kinin generated/mg x protein/h. Active kininogenase in SHR was approximately one-third in 5-week-old and about one-fifth in 15-week-old rats when compared with their normotensive controls. Total kininogenase activity in SHRs was approximately 80% and 58% of the normotensive controls at ages 5 weeks and 15 weeks, respectively. Active enzyme was 14% of the total in 5-week-old SHRs, and it was only 5% of the total in 15-week-old SHRs. It seems unlikely that the changes in kininogenase are secondary to hypertension because blood pressor is only marginally elevated at 5 weeks according to the literature. We hypothesize that genetic hypertensive rats may suffer from an inherent deficiency in the kininogenase activity of the vascular wall. The deficiency may also be in the mechanism of activation of precursor enzyme.
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PMID:Kininogenase of the aortic wall in spontaneously hypertensive rats. 128 21

Hemodynamic forces influence many endothelial cell functions. The coupling between hemodynamic forces and cell function could be mediated by mechano-sensitive ion channels present in the plasma membrane of endothelial cells. Because one of these channels is permeable to Ca2+, we tested whether hemodynamic forces influence endothelial cell Ca2+ ([Ca2+]i). Bovine aortic endothelial cells were grown inside cylindrical glass tubes, loaded with fura-2, and perfused at different pressures and flow rates on the stage of a fluorescence microscope. Decreasing flow from 110 to 2 ml.min-1 raised [Ca2+]i from 57 +/- 11 to 186 +/- 29 nM (mean +/- SEM, p less than 0.01) by increasing the entry of extracellular Ca2+ into the cytoplasm. Increasing flow from 2 to 110 ml.min-1 transiently decreased [Ca2+]i from 62 +/- 3 to 33 +/- 5 nM (p less than 0.01) apparently due to reduced Ca2+ entry and concomitant extrusion by the plasma membrane Ca(2+)-ATPase. The rise in [Ca2+]i induced by bradykinin was magnified during a decrease in flow; in control cells, 10(-7) M bradykinin increased [Ca2+]i by 162 +/- 26 nM, whereas [Ca2+]i increased 350 +/- 67 nM (p less than 0.05) in cells previously exposed to 110 ml.min-1. These observations suggest that flow-induced changes in [Ca2+]i might be a signal-transduction mechanism for endothelial functions responsive to hemodynamic forces and may also modulate the magnitude of hormonally mediated increases in [Ca2+]i.
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PMID:Changes in luminal flow rate modulate basal and bradykinin-stimulated cell [Ca2+] in aortic endothelium. 131 20

The purpose of this study was to examine whether neutral endopeptidase and angiotensin I-converting enzyme, two membrane-bound metalloenzymes that are widely distributed in the microcirculation, play a role in bradykinin-induced increase in vascular permeability in the hamster cheek pouch. Changes in vascular permeability were quantified by counting the number of leaky sites and by calculating the clearance of fluorescein isothiocyanate (FITC)-dextran (molecular mass, 70,000 d) during suffusion of the cheek pouch with bradykinin. Bradykinin produced a concentration- and time-dependent increase in the number of leaky sites and clearance of FITC-dextran. The selective, active site-directed neutral endopeptidase inhibitors phosphoramidon (1.0 microM) and thiorphan (10.0 microM) and the selective angiotensin I-converting enzyme inhibitor captopril (10.0 microM) each shifted the concentration-response curve to bradykinin significantly to the left. During suffusion with bradykinin (1.0 microM) and phosphoramidon, the number of leaky sites increased significantly from 17 +/- 2 to 27 +/- 4 sites per 0.11 cm2 (mean +/- SEM, p less than 0.05), and FITC-dextran clearance increased significantly from 1.0 +/- 0.2 to 2.1 +/- 0.3 ml/sex x 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of peptidases in bradykinin-induced increase in vascular permeability in vivo. 131 17

We examined the effects of the tyrosine kinase (TK) inhibitors, genistein, and tyrphostin (RG-50864) on the contractile action of epidermal growth factor - urogastrone (EGF-URO), transforming growth factor-alpha (TGF-alpha), and other agonists in two smooth muscle bioassay systems (guinea pig gastric longitudinal muscle, LM, and circular muscle, CM). We also studied the inhibition by tyrphostin of EGF-URO stimulated protein phosphorylation in identical smooth muscle strips. The selective inhibition by genistein and tyrphostin of EGF-URO and TGF-alpha induced contraction, but not of carbachol- and bradykinin-mediated contraction, occurred at much lower concentrations (genistein, less than 7.4 microM (2 micrograms/mL); tyrphostin, less than 20 microM (4 micrograms/mL)) than those used in previously published studies with these TK inhibitors. In LM tissue, the IC50 values were for genistein 1.1 +/- 0.1 microM (0.30 micrograms/mL; mean +/- SEM) and 3.6 +/- 0.5 microM (0.74 micrograms/mL) for tyrphostin, yielding a molar potency ratio (GS: TP) of 1:3 in the longitudinal preparation. In CM tissue, the IC50 values were 3.0 +/- 0.3 microM (0.81 micrograms/mL) for genistein and 2.4 +/- 0.2 microM (0.49 micrograms/mL) for tyrphostin, yielding a molar potency ratio (GS:TP) of 1.0:0.8 in the circular strips. The inhibition by genistein and tyrphostin of EGF-URO and TGF-alpha mediated contraction was rapid (beginning within minutes) and was reversible upon washing the preparations free from the enzyme inhibitors. In intact tissue strips studied under bioassay conditions, tyrphostin (40 microM) also blocked EGF-URO triggered phosphorylation of substrates detected on Western blots using monoclonal antiphosphotyrosine antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tyrosine kinase inhibitors and the contractile action of epidermal growth factor-urogastrone and other agonists in gastric smooth muscle. 131 19

The endogenous peptide bradykinin is found in plasma and inflammatory exudates and has been implicated as a chemical mediator of inflammatory pain and hyperalgesia. Two subtypes of bradykinin receptors, B1 and B2, have been described, and antagonists for the receptor subtypes have been synthesized. The bradykinin analogs [desArg9,Leu8]BK and DArg[Hyp3,DPhe7]BK have been reported to have antagonist activity at the B1 and B2 bradykinin receptors in smooth muscle, respectively. Behavioral studies in rats indicate that the bradykinin analogs can block the algesic effects of bradykinin. We wished to determine the effects of bradykinin and the bradykinin analogs (B1 and B2 analogs, respectively) on cutaneous nociceptors in the monkey. In addition, we wished to determine the type of bradykinin receptor that mediates the sensitizing effects of bradykinin. Recordings were made from single C-fiber and A-fiber nociceptive afferents (CMHs and AMHs) that innervated hairy skin. Heat sensitivity before and after the injections was determined with a heat test sequence consisting of stimuli that ranged, in 1 degree C increments, from 41 degrees to 49 degrees C. Intradermal injections of vehicle (neutral normal saline) failed to alter the heat response of CMHs. Bradykinin (10 nmol in 10 microliters) evoked activity in 6 of 10 CMHs and sensitized all the fibers to heat stimuli. After the bradykinin injection, the mean heat threshold of the CMHs decreased from 44 +/- 0.5 degrees to 42.7 +/- 0.5 degrees C (mean +/- SEM, p less than 0.02), and the total response to the heat test sequence increased by 87% (p less than 0.002). In a related psychophysical study in human volunteers, the same dose of bradykinin resulted in a comparable (115%) increase in ratings of pain (Manning et al., 1991). Bradykinin also evoked activity in 10 of 17 AMHs and sensitized 8 AMHs to heat stimuli. Bradykinin failed to alter the threshold for activation of CMHs to mechanical stimuli as measured by application of von Frey hairs to the receptive field. In contrast to bradykinin, intradermal injection of the B1 and B2 analogs (10 nmol in 10 microliters) evoked activity in 2 of 6 and 0 of 5 CMHs, respectively. A noteworthy finding was that both analogs enhanced the response of CMHs to heat stimuli by 50% (B1 analog, 1.5 +/- 0.1; B2 analog, 1.5 +/- 0.2). The B1 (n = 10) and B2 (n = 5) analogs did not evoke activity in any of the 15 AMHs tested.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effects of bradykinin and sequence-related analogs on the response properties of cutaneous nociceptors in monkeys. 132 2

To determine whether endothelium-derived relaxing factor (EDRF) contributes to the regulation of endothelial permeability, the transendothelial flux of 14C-sucrose, a marker for the paracellular pathway across endothelial monolayers (Oliver, J. Cell. Physiol. 145:536-548, 1990), was examined in monolayers of bovine aortic endothelial cells grown on collagen-coated filters. The permeability coefficient of 14C-sucrose was significantly decreased by 10(-3) M 8-Bromoguanosine 3',5'-cyclic monophosphate or by 5 x 10(-6) M glyceryl trinitrate, an activator of soluble guanylate cyclase. Depletion of L-arginine from endothelial monolayers increased 14C-sucrose permeability from 3.21 +/- 0.59 to 3.88 +/- 0.50 x 10(-5) cm.sec-1 (mean +/- SEM; n = 6; P < 0.05). The acute administration of 5 x 10(-4) M L-arginine to monolayers depleted of this amino acid decreased 14C-sucrose permeability from 2.91 +/- 0.27 to 2.52 +/- 0.26 x 10(-5) cm.sec-1 (n = 11; P < 0.05). 14C-sucrose permeability was increased by 10(-7) M bradykinin and this effect was enhanced by the presence of each one of the following compounds: 10(-5) M methylene blue, 4 x 10(-6) M oxyhemoglobin, 5 x 10(-4) M NG-methyl-L-arginine or 5 x 10(-4) M N omega-nitro-L-arginine. These results suggest that EDRF contributes to the sealing of the endothelial monolayer and that EDRF released by bradykinin acts as a feedback inhibitor attenuating the increase in endothelial permeability induced by this peptide. Because endothelial cells have the ability to contract and relax and possess guanylate cyclase responsive to nitric oxide, our results suggest that EDRF decreases 14C-sucrose permeability by relaxing endothelial cells, thereby narrowing the width of endothelial junctions.
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PMID:Endothelium-derived relaxing factor contributes to the regulation of endothelial permeability. 136 53

The unstimulated platelet surface contains a specific and saturable binding site for high molecular weight kininogen (HK) and low molecular weight kininogen (LK). Investigations were performed with purified heavy and light chains of HK to determine which portion(s) of the HK molecule binds to the platelet surface. Purified 64-Kd heavy chain of HK and 56-Kd light chain of HK, independently, inhibited 125I-HK binding to unstimulated platelets with a 50% inhibitory concentration (IC50) of 84 nmol/L (apparent Ki, 30 nmol/L) and 30 nmol/L (apparent Ki, 11 nM), respectively. The ability of each of the purified chains of HK to independently inhibit 125I-HK binding was not due to cleavage, reduction, and alkylation of the protein, because two-chain HK, produced by treating HK the same way as purifying the separate chains, inhibited binding similarly to intact HK. Further, purified LK alone inhibited 125I-HK binding to platelets (Ki, 17 +/- 1 nmol/L, n = 7). The 64-Kd heavy chain of HK was a competitive inhibitor on a reciprocal plot of 125I-HK-platelet binding with an apparent Ki of 28 +/- 6 nmol/L (n = 4). Independently, purified 56-Kd light chain of HK was also found to be a competitive inhibitor of 125I-HK-platelet binding, with an apparent Ki of 11 +/- 3 nmol/L (mean +/- SEM, n = 4). These indirect studies indicated that HK binds to platelets by two portions of the molecule, one on the heavy chain and another on the light chain. Studies with 125I-light chain of HK showed that it specifically bound directly to platelets in the presence of zinc, since it was blocked by HK, light chain of HK, or EDTA, but not by LK, C1s, C1 inhibitor, plasmin, factor XIII, or fibrinogen. Purified light chain of HK did not inhibit direct 125I-LK binding to platelets. HK was found to bind to platelets in an unmodified form. HK bound to platelets was cleaved by plasma or urinary kallikrein at a slower rate than the same concentration of soluble HK or HK bound and subsequently eluted from the platelet surface. Cleavage of platelet-bound HK correlated with bradykinin liberation. These studies indicate that HK has two domains on its molecule that bind to platelets. Further, platelet-bound HK is protected from kallikreins' proteolysis. This latter finding suggests that cell binding may modify the rate of bradykinin liberation from HK.
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PMID:High molecular weight kininogen binds to platelets by its heavy and light chains and when bound has altered susceptibility to kallikrein cleavage. 153 48

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