Effect Of Kallikrein Research Articles

Effect of kallikrein and ozagrel on hemorheology in the treatment of patients with acute cerebral infarction

Objective To observe the effect of kallikrein and ozagrel on hemorheology in the treatment of patients with acute cerebral infarction, provide a theoretical basis for clinical treatment. Methods 100 patients with acute cerebral infarction met the inclusion criteria were randomly divided into 50 cases of observation group and 50 cases of control group, the control group were received conventional drug therapy,the observation group were given kallikrein and ozagrel on the basis of the control group, kallikrein 0.15PNA/times,ozagrel 80mg one time,bid,14d for a course of treatment. The symptoms improvement were observed,the NIHSS score and ADL score were calculated after treatment, then the blood were extraced for detecting high shear viscosity of whole blood, red blood cell aggregation index, hematocrit, fibrinogen, erythrocyte sedimentation rate, and the clinical efficacy were judged. Results The total effective rate of the observation group were 96%(48/50),which of the control group were 66%(33/50),the total effective of the observation group was significantly higher than the control group(χ2=16.105,P<0.01);The high shear viscosity of whole blood,red blood cell aggregation index,hematocrit, fibrinogen, erythrocyte sedimentation rate,NHISS of the observation group and the control group after treatment were lower than before treatment(t=6.589 and 3.762,6.204 and 3.661,8.112 and 5.774,5.542 and 3.529,9.429 and 3.962,9.621 and 6.586,all P<0.05), the ADL score was significantly higher than before treatment(t=7.673 and 5.446,all P<0.05),the high shear viscosity of whole blood,red blood cell aggregation index,hematocrit,fibrinogen,erythrocyte sedimentation rate,NHISS of the observation group after treatment were lower than those of the control group(t=3.387,3.545,3.525,3.288,3.302,4.988,all P<0.05),the ADL score was significantly higher than the control group(t=3.446,P<0.05). Conclusion The method containing kallikrein and ozagrel has exact clinical efficacy, can effectively improve blood rheology and cerebral blood perfusion ischemic area, promote neurological deficits and recover the ability of daily life, and its security is good, which is worthy of promotion. Key words: Cerebral infarction; Neurological deficits; Hemorheology; Kallikrein; Ozagrel

Congenital prekallikrein deficiency

The congenital deficiency of prekallikrein (PK) is a rare condition in which there is a peculiar discrepancy between a severe in vitro defect and absence of bleeding. The gene controlling PK synthesis is located on chromosome 4 and consists of 14 exons and 15 introns. Only approximately 80 cases of PK deficiency have been described in the literature. Owing to the lack of bleeding, most cases go undetected or, if detected, go unreported. Occasional bleeding or thrombosis have been reported in a few patients but this was only due to the presence of associated risk factors. It is certain that the defect does not protect from thrombosis. Diagnosis is based on the presence of a great prolongation of partial thromboplastin time and normal prothrombin time and thrombin time. The long partial thromboplastin time is fully corrected by the addition of normal plasma or normal serum and presents the unusual feature of shortening on long incubation times. Platelet and vascular tests are normal. Immunological studies allow differentiation into two types, namely cases of true deficiency, which are approximately 70% of the total, and cases with abnormal forms. PK is a glycoprotein synthesized in the liver as a single-chain peptide of 88000 Da. It mostly circulates (∼75%) as a complex with high-molecular-weight kininogen. It is cleaved by FXIIa into a heavy chain and a light chain (catalytic domain), held together by disulfide bonds. Molecular biology techniques have so far only been applied to eleven families, and these studies do not yet allow definite phenotype/genotype conclusions. The exons involved are 5, 8, 11, 14 and 15. The noncoagulative effects of PK, mainly based on the effect of kallikrein, have been studied less, since they appear to be the result of the involvement of other components of the contact phase. Kallikrein can mainly affect the formation of bradykinin from high-molecular-weight kininogen and the activation of pro-urokinase to urokinase. Bradykinin causes inflammation, vasodilatation and an increase in vessel permeability. The activation of pro-urokinase results in enhanced fibrinolysis. However, fibrinolysis has been reported to be normal or defective in these patients.

Nitric oxide mediates cardiac protection of tissue kallikrein by reducing inflammation and ventricular remodeling after myocardial ischemia/reperfusion

We assessed the role of nitric oxide (NO) and the kinin B2 receptor in mediating tissue kallikrein's actions in intramyocardial inflammation and cardiac remodeling after ischemia/reperfusion (I/R) injury. Adenovirus carrying the human tissue kallikrein gene was delivered locally into rat hearts 4 days prior to 30-minute ischemia followed by 24-hour or 7-day reperfusion with or without administration of icatibant, a kinin B2 receptor antagonist, or N(ω)–nitro–L–arginine methyl ester (L–NAME), a nitric oxide synthase inhibitor. Kallikrein gene delivery improved cardiac contractility and diastolic function, reduced infarct size at 1 day after I/R without affecting mean arterial pressure. Kallikrein treatment reduced macrophage/monocyte and neutrophil accumulation in the infarcted myocardium in association with reduced intercellular adhesion molecule-1 levels. Kallikrein increased cardiac endothelial nitric oxide synthase phosphorylation and NO levels and decreased superoxide formation, TGF–β1 levels and Smad2 phosphorylation. Furthermore, kallikrein reduced I/R-induced JNK, p38MAPK, IκB-α phosphorylation and nuclear NF–κB activation. In addition, kallikrein improved cardiac performance, reduced infarct size and prevented ventricular wall thinning at 7 days after I/R. The effects of kallikrein on cardiac function, inflammation and signaling mediators were all blocked by icatibant and L–NAME. These results indicate that tissue kallikrein through kinin B2 receptor and NO formation improves cardiac function, prevents inflammation and limits left ventricular remodeling after myocardial I/R by suppression of oxidative stress, TGF–β1/Smad2 and JNK/p38MAPK signaling pathways and NF–κB activation.

Tissue Kallikrein and Kinin Infusion Rescues Failing Myocardium After Myocardial Infarction

Background Tissue kallikrein is a serine proteinase that generates the vasoactive kinin peptide, which produces vasodilatory, angiogenic, and antiapoptotic effects. In this study, we investigated the effect of a stable supply of kallikrein and kinin on ventricular remodeling and blood vessel growth in rats after myocardial infarction. Methods and Results At 1 week after coronary artery ligation, tissue kallikrein or kinin was infused through a minipump for 4 weeks. At 5 weeks after myocardial infarction, kallikrein and kinin infusion significantly improved cardiac contractility and reduced diastolic dysfunction without affecting systolic blood pressure. Kallikrein and kinin infusion significantly increased capillary density in the noninfarcted region. Kallikrein and kinin infusion also reduced heart weight/body weight ratio, cardiomyocyte size, and atrial natriuretic peptide and brain natriuretic peptide expression in the noninfarcted area. Moreover, kallikrein and kinin infusion inhibited interstitial collagen deposition, collagen fraction volume, and collagen I and collagen III mRNA levels, transforming growth factor (TGF)-β1 and plasminogen activator inhibitor-1 expression, and Smad2 phosphorylation. The effects of kallikrein and kinin on cardiac remodeling were associated with increased nitric oxide levels and reduced NADPH oxidase expression and activity, superoxide formation, and malondialdehyde levels. Furthermore, in cultured cardiac fibroblasts, kinin inhibited angiotensin II-stimulated TGF-β1 production, and the effect was blocked by icatibant. Conclusion These results indicate that a subdepressor dose of kallikrein or kinin can restore impaired cardiac function in rats with postinfarction heart failure by inhibiting hypertrophy and fibrosis and promoting angiogenesis through increased nitric oxide formation and suppression of oxidative stress and TGF-β1 expression.

Kallikrein–kinin in stroke, cardiovascular and renal disease

Tissue kallikrein, a serine proteinase, produces the potent vasodilator kinin peptide from kininogen substrate. The levels of tissue kallikrein are reduced in humans and animal models with hypertension, cardiovascular and renal disease. Using transgenic and somatic gene transfer approaches, we investigated the role of the tissue kallikrein-kinin system in cardiovascular, renal and central nervous systems. A single injection of the human tissue kallikrein gene in plasmid DNA or an adenoviral vector resulted in a prolonged reduction of blood pressure and attenuation of hypertrophy and fibrosis in the heart and kidney of several hypertensive animal models. Furthermore, enhanced kallikrein-kinin levels after gene transfer exerted beneficial effects, with protection against cardiac remodelling, renal injuries, restenosis, cerebral infarction and neurological deficits in normotensive animal models without haemodynamic effects, indicating direct actions of kallikrein independent of its ability to lower blood pressure. The effects of kallikrein were mediated by the kinin B2 receptor, as the specific B2 receptor antagonist icatibant abolished the actions of kallikrein. Moreover, kallikrein-kinin exhibited pleiotropic effects by inhibiting apoptosis, inflammation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in the heart, kidney, brain and blood vessel. Exogenous administration of kallikrein also led to increased nitric oxide (NO)/cGMP and cAMP levels, and reduced NAD(P)H oxidase activities, superoxide formation and pro-inflammatory cytokine levels. These results indicate a novel role of kallikrein-kinin through the kinin B2 receptor as an antioxidant and anti-inflammatory agent in protection against stroke, cardiovascular and renal disease, and may uncover new drug targets for the prevention and treatment of heart failure, vascular injury, end-stage renal disease and stroke in humans.

Tissue kallikrein attenuates salt-induced renal fibrosis by inhibition of oxidative stress

High salt intake induces hypertension, cardiac hypertrophy, and progressive renal damage. Progressive renal injury is the consequence of a process of destructive fibrosis. Using gene transfer approach, we have shown that the tissue kallikrein-kinin system (KKS) plays an important role in protection against renal injury in several hypertensive rat models. In this study, we further investigated the effect and potential mechanisms mediated by kallikrein on salt-induced renal fibrosis. Adenovirus harboring the human tissue kallikrein gene was delivered intravenously into Dahl salt-sensitive (DSS) rats on a high salt diet for 4 weeks. Two weeks after gene delivery, the effect of kallikrein on renal fibrosis was examined by biochemical and histologic analysis. Kallikrein gene delivery resulted in reduced blood urea nitrogen (BUN), urinary protein and albumin levels in DSS rats on a high salt diet. Expression of recombinant human tissue kallikrein was detected in the sera and urine of rats injected with the kallikrein gene. Histologic investigation showed that kallikrein gene delivery significantly reduced glomerular and tubular fibrosis scores and collagen deposition, as well as renal cell proliferation, compared to rats on a high salt diet injected with control virus. Kallikrein gene transfer significantly increased nitric oxide and cyclic guanosine monophosphate (cGMP) levels in conjunction with reduced salt-induced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase activity, superoxide production, transforming growth factor-beta1 (TGF-beta1) mRNA and protein levels, and TGF-beta1 immunostaining. These results indicate that tissue kallikrein protects against renal fibrosis in hypertensive DSS rats through increased nitric oxide bioavailability and suppression of oxidative stress and TGF-beta expression.

Structure and signalling pathways of kinin receptors.

Kinins are peptide hormones that transmit their biological effects via G protein-coupled receptors. They are generated by kallikrein-mediated proteolysis of their precursors, the kininogens. Kinins have been implicated in the regulation of blood pressure, pain sensation and cell growth. Interestingly, all components of the kallikrein-kinin system have also been localized in testis. Effects of kallikrein and bradykinin on pre-spermatogonial cell proliferation and on sperm motility suggest a regulatory function of kinins and their cognate receptors in the male reproductive system. This review is dedicated to summarize the current knowledge about structure, signal transduction and regulation of kinin receptors. Particular emphasis will be given to the kinin-induced activation of the mitogen-activated protein kinase cascade which might represent an important signalling pathway involved in regulation of spermatogenesis and sperm function.

Thrombin‐stimulated platelet aggregation is inhibited by kallikrein in a time‐ and concentration‐dependent manner

Many in vitro studies have shown that activation of prekallikrein (PK) to kallikrein (KAL) in normal plasma triggers rapid activation of the coagulation cascade. In agreement, the coagulation activation is impaired in PK‐deficient plasma. Paradoxically, PK‐deficient patients show a tendency to thrombosis. To investigate the discrepancy between the in vitro and in vivo findings, we analyzed the effect of KAL on the rate of platelet aggregation. For this research, physiologic concentrations of washed human platelets were incubated for 5 and/or 10 min with ∼2.2 to 88 nM human plasma KAL (<1/100 to ∼1/3 of PK concentrations in plasma) prior to the addition of high concentrations of α‐thrombin (54 nM) or fibrinogen plus ADP. KAL concentrations were arbitrarily selected on the assumption that concentrations of free KAL (the enzymatically active species) were minute in normal plasma and higher when KAL production was enhanced, and/or inhibitors were depleted. Full platelet aggregation was that seen in the absence of KAL or PK. Inhibition of platelet aggregation stimulated by thrombin was markedly increased with increased KAL concentrations and incubation times. The degree of inhibition by KAL was smaller when ADP was the agonist. The data suggest that KAL may play a role in the modulation of platelet aggregation in vivo under normal conditions as well as when prolonged, high concentrations of KAL occur in blood. The data may also help to explain the intriguing observation that PK‐deficient patients show a tendency to thrombotic episodes and myocardial infarction whereas in vitro assays predict bleeding.

Kallikreins when activating bradykinin B 2 receptor induce its redistribution on plasma membrane

The bradykinin (BK) B 2 receptor (R) is directly activated by kallikreins and other serine proteases independent of BK release. Both the G αi and G αq proteins are involved, shown by the release of arachidonic acid and [Ca 2+] i elevation. Site-directed mutagenesis of the receptor and the lack of heterogenous desensitization of the human B 2R by the BK and kallikrein emphasize among others the differences between activation by the proteases and the peptide. To characterize further the mechanism thereby kallikreins activate and desensitize the B 2R, we investigated the distribution of the human B 2R tagged with the green fluorescent protein (B 2-GFP Ct) on the plasma membrane of stably transfected Chinese hamster ovary (CHO) cells. We visualized the movement of B 2-GFP Ct R with confocal fluorescence microscopy after activation by BK or a by serine protease. Continued exposure of the cells to BK led to B 2R internalization within 15–20 min. Porcine pancreatic and human recombinant tissue kallikreins induced a rapid definite redistribution of receptors on the plasma membrane within 5 min, prior to internalization. These effects of kallikrein were blocked by the B 2R antagonist HOE 140 and by the kallikrein inhibitor, aprotinin. The B 2R was also activated by endoproteinases LysC and ArgC and trypsin, but these enzymes did not induce redistribution, only internalization. In control experiments, kallikrein had no effect on cells transfected to stably express the angiotensin-converting enzyme—green fluorescent protein (GFP). Thus, kallikreins when activating the BK B 2R also trigger its redistribution on plasma membrane.

Human Tissue Kallikrein Attenuates Hypertension and Secretes into Circulation and Urine After Intramuscular Gene Delivery in Hypertensive Rats

Systemic delivery of the human tissue kallikrein transgene has been shown to markedly delay the increase of blood pressure in hypertensive rat models. To demonstrate potential hypotensive effects of kallikrein via local delivery, adenovirus carrying the human tissue kallikrein gene was inoculated into quadriceps of spontaneously hypertensive rats (SHR). A single intramuscular injection of the kallikrein gene caused a significant delay of blood pressure increase for 5 weeks. The expression of human tissue kallikrein and its mRNA was identified solely in injected muscle. Immunoreactive human tissue kallikrein was detected in the muscle as well as in the circulation and urine of adult and newborn rats. Urinary kinin and cGMP levels increased significantly in rats receiving kallikrein gene delivery as compared with rats receiving control virus containing the LacZ gene. The detection of human tissue kallikrein in rat urine after local gene delivery into the muscle provides direct evidence that circulatory kallikrein can be secreted into the urine.

Immunolocalization of Bradykinin B2 Receptors on Skeletal Muscle Cells

The kallikrein-kinin system has been implicated in the inflammatory process, blood pressure regulation, renal homeostasis, and glucose utilization. The effects of kallikrein and kinin on glucose uptake by the skeletal muscle are well established; however, the occurrence and the cellular distribution of the kinin receptor(s) mediating these effects in the striated muscle are unknown. Using anti-peptide antibodies raised against the predicted intra- and extracellular domains of the B2 receptor and the peroxidase/antiperoxidase system, we have been able to detect the B2 receptor on the plasma membrane of striated skeletal muscle cells of the rat hindlimb. A strong immunostaining appeared as a rim of immunoreactive material located on the periphery of striated muscle cells. Cross-sectioned and longitudinally sectioned cells revealed a similar staining pattern. Alternatively, the immunostaining with specific antibodies to tissue kallikrein and to T-kininogen did not yield a significant staining of the striated muscle cells. Localization of the B2 receptor on the surface of striated muscle cells provides a structural basis for the hypothesized physiological functions of the kinin system in the skeletal muscle.

Monoclonal Antibody F1 Binds To the Kringle Domain of Factor XII and Induces Enhanced Susceptibility for Cleavage by Kallikrein

In a previous study we have shown that monoclonal antibody F1 (MoAb F1), directed against an epitope on the heavy chain of factor XII distinct from the binding site for anionic surfaces, is able to activate factor XII in plasma (Nuijens JH, et al: J Biol Chem 264; 12941, 1989). Here, we studied in detail the mechanism underlying the activation of factor XII by MoAb F1 using purified proteins. Formation of factor XIIa was assessed by measuring its amidolytic activity towards the chromogenic substrate H-D-Pro-Phe-Arg-pNA (S-2302) in the presence of soybean trypsin inhibitor and by assessing cleavage on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Upon incubation with MoAb F1 alone, factor XII was auto-activated in a time-dependent fashion, activation being maximal after 30 hours. Factor XII incubated in the absence of MoAb F1 was hardly activated by kallikrein, whereas in the presence of MoAb F1, but not in that of a control MoAb, the rate of factor XII activation by kallikrein was promoted at least 60-fold. Maximal activation of factor XII with kallikrein in the presence of MoAb F1 was reached within 1 hour. This effect of kallikrein on the cleavage of factor XII bound to MoAb F1 was specific because the fibrinolytic enzymes plasmin, urokinase, and tissue-type plasminogen activator could not substitute for kallikrein. Also, trypsin could easily activate factor XII, but in contrast to kallikrein, this activation was independent of MoAb F1. SDS-PAGE analysis showed that the appearance of amidolytic activity correlated well with cleavage of factor XII. MoAb F1-induced activation of factor XII in this purified system was not dependent on the presence of high-molecular-weight kininogen (HK), in contrast to the activation of the contact system in plasma by MoAb F1. Experiments with deletion mutants revealed that the epitopic region for MoAb F1 on factor XII is located on the kringle domain. Thus, this study shows that binding of ligands to the kringle domain, which does not contribute to the proposed binding site for negatively charged surfaces, may induce activation of factor XII. Therefore, these findings point to the existence of multiple mechanisms of activation of factor XII.

The myostimulating effect of tissue kallikrein on rat uterus

The mechanism of the myostimulating activity of rat tissue kallikrein on rat uterus was re-examined using uterus from kininogen-deficient rats and HOE 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]bradykinin), a specific bradykinin receptor-B2 antagonist. The uterus from kininogen-deficient rats was 50 times less sensitive to rat kallikrein than that from normal rats. HOE 140 (6 to 60 nM) inhibited the contracting effects of bradykinin and of rat kallikrein. Porcine kallikrein had no effect on rat uterus. Bradykinin and rat kallikrein induced a relaxation of rat duodenum. The duodenum from kininogen-deficient rats was 100 times less sensitive to rat kallikrein than the duodenum from normal rats. HOE 140 (0.6 to 3 nM) inhibited the relaxing effects of bradykinin and of kallikrein. Preincubation of rat kallikrein with aprotinin (Trasylol) abolished the effects of kallikrein on smooth muscles. HOE 140 inhibited the amidolytic activity of tissue kallikrein with a Ki value of 220 microM. HOE 140, at micromolar concentrations, suppressed the kininogenase activity of tissue kallikrein. Plasma of deficient rats contained 0.7% of the normal levels of kininogens. After washing the blood vessels with saline, kininogens were present in uterine homogenates but not in duodenal homogenates from both rat strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes of sperm tail morphology after kallikrein treatment.

Kallikrein has been reported to act positively on sperm motility. Because sperm motility must be analyzed with regard to sperm tail morphology, this study examined whether changes of sperm motility after kallikrein treatment were accompanied by structural alterations of the midpieces and tails of spermatozoa. In 60 andrologic outpatients in whom a significant improvement of sperm motility was noted after treatment with kallikrein (600 U daily for 3 mo), sperm tail morphology was analyzed according to a recently proposed classification. The effect of kallikrein could be clearly attributed to a decrease of tail disturbances characteristic of epididymal dysfunction. Besides possible effects on spermatogenesis, kallikrein may influence the epididymal maturation of spermatozoa, leading to increased progressive motility.

The Effect of Kallikrein on Human Sperm Membrane Function.

To illustrate the influence of kallikrein on the hypoosmotic swelling test, 84 human semen samples were classified into 4 groups: normospermia (n = 34, group A), oligospermia (n = 18, group B), asthenospermia (n = 8, group C), and oligoasthenospermia (n = 24, group D). Two aliquots of 0.45 ml were prepared from each specimen in all the groups: one was incubated for 3 hr in a glass tube containing kallikrein and the other was incubated without kallikrein (control). Quantitative and qualitative assessment of sperm motility and the hypoosmotic swelling test (HOST) were subsequently performed in each pair of samples. Percentage of motile spermatozoa, speed of forward progression of motile spermatozoa and the percentage of swollen sperm were significantly lower in the control samples than in samples treated with kallikrein in all the groups. Kallikrein was also proved effective in increasing the outcome of the HOST, the percentage of motile spermatozoa and the speed of forward progression of washed spermatozoa received from normospermic men (n = 15). It seems that kallikrein has a direct effect on sperm membrane and improves its properties and functions.

Effects of Kallikrein on Sperm Motility, Capillary Tube Test, and Pregnancy Rate in an Aih Program

From 1984 to 1986, 172 couples were enrolled in an artificial insemination homologous (AIH) program, because of negative postcoital test, fair PT, positive PT with unexplained infertility, and impotentia coeundi. Patients were randomly assigned to the following procedures: AIH with native semen (N, n = 68), washed sperm (V, n = 50), semen mixed with kallikrein (K, 5 IE/ml semen, n = 45), and timed intercourse. The overall pregnancy rate (PR) was 22% per couple (13% inseminations, 9% spontaneous). PR from insemination (spontaneous) was 13% (8), 13% (13), 23% (0) in PT negative, fair, and positive patients, respectively, and 18% (9), 13% (7), and 11% (9) in AIH groups N, V, and K. Among in vitro studies with K added semen, an improvement of sperm motility was demonstrated in half of the specimens. In the capillary tube test (CTT), with wives' cervical mucus, a deterioration was more frequently seen than an improvement after 2 h, independent of the early effect of K in semen, K induced changes of CTT were less pronounced when donors' cervical mucus was used. The results of the in vitro studies offer an explanation for the low PR in the AIH program with K.

Metabolic Effects of Kinins

In 1928, Frey and co-workers discovered kallikrein in human urine and described its prolonged hypotensive effect in the dog. Four years later, the same authors first reported a blood glucose-lowering effect of orally administered kallikrein in diabetic patients. However, the observed blood glucose-lowering effect of kallikrein appeared to fade with repeated administration, and therefore its possible metabolic role was not further investigated and fell into disregard. One decade ago, experimental data yielded indirect evidence that the regulation of local skeletal muscle blood flow and glucose uptake during work was mediated by proteolytically cleaved kinins. Further experiments demonstrated that in insulin-resistant states such as postoperative stress and type II diabetes, reduced muscular insulin sensitivity was increased and partly restored by continuous low-dose infusion of synthetic bradykinin. Recent work showing that tissue kallikrein is present in a number of different tissue sites, including skeletal muscle and our own observation of local kinin overflow after muscle work in healthy subjects, but not in type II diabetics, support the concept of a skeletal muscle kallikrein-kinin system (KKS) that is locally activated upon contraction. Moreover, in isolated perfused rat heart preparations, favorable effects of kinins on myocardial glucose uptake, oxidation, and glycolytic flux have been reported. Most interestingly, cardioprotective effects of kinins have been observed and attributed to improved energy and substrate metabolism in ischemic hearts. Taken together, these data gave rise to the concept that tissue KKS might be involved in the local modulation of skeletal muscle and myocardial tissue blood flow and substrate metabolism, and that activation of the KKS is defective in insulin-resistant states.

Conformation of high molecular weight kininogen: Effects of kallikrein and factor XIa cleavage

The effect of kallikrein and factor XIa proteolysis of high molecular weight kininogen (HK) was investigated. Circular dichroism (CD) spectroscopy showed that cleavage of HK by plasma kallikrein or urinary kallikrein, both of which result in an active cofactor (HKa), results in conformational change that is characterized by increase in CD ellipticity at 222 nm. This suggests an increase in organized secondary structures. By contrast, cleavage of HK by factor XIa which results in an inactive cofactor (HKi) is characterized by a dramatic decrease in CD ellipticity at 222 nm suggesting an entirely different type of conformational change. The intrinsic fluorescence of HK is enhanced after cleavage by all three proteases. These conformational changes may play a role in determining the structure and function of HKa and HKi.

Effect of kallikrein on the Sertoli cell function.

The effect of kallikrein on the Sertoli cells was investigated to determine the rat testicular androgen binding component (ABC = androgen binding protein + androgen receptor) concentration using the dextran-coated charcoal method. The results showed that the concentrations of testicular ABC were increased significantly by the administration of kallikrein to levels approaching those seen after stimulation by LH-RH or FSH. Therefore, it is suggested that kallikrein has an effect that influences the Sertoli cells directly or indirectly.

Circulatory effect of kallikrein; with special reference to cerebral circulation.

Circulatory effect of kallikrein; with special reference to cerebral circulation.