Kallikrein System Research Articles

Anatomical relationship between kallikrein-containing tubules and the juxtaglomerular apparatus in the human kidney.

Current evidence suggests a functional and biochemical link between the renin and the kallikrein systems. The purpose of this work was to study the localization of kallikrein along the human nephron to elucidate whether there exists an anatomical base for such interrelation. Serial sections of human kidney tissue were stained by immunocytochemical methods with antisera against kallikrein. Kallikrein immunostaining was observed exclusively in segments of the distal nephron lying in the cortical labyrinths and forming arcades in its distal portion. Consistently the tubules containing kallikrein established a close anatomical relationship with the afferent arteriole of the juxtaglomerular apparatus providing an anatomical base for an interaction between the renin and kallikrein systems in the human kidney.

Effect of bromelain on kaolin-induced inflammation in rats

The effects of stem bromelain on the plasma kallikrein system, bradykinin levels and plasma exudation at the inflammatory site were examined in rats with a kaolin-induced inflammation of an air pouch. Bromelain (5, 7.5 mg/kg) caused a dose-dependent decrease of bradykinin levels at the inflammatory site and a parallel decrease of the prekallikrein levels in sera. Plasma exudation was also reduced dose dependently. Bradykinin-degrading activity in sera was elevated after treatment with bromelain, although it was unchanged in the pouch fluid. These data indicate that bromelain inhibits plasma exudation through inhibiting the generation of bradykinin at the inflammatory site via depletion of the plasma kallikrein system.

Kinin formation: mechanisms and role in inflammatory disorders.

Although considerable progress has been made in elucidating the molecular events occurring during kinin generation by both the plasma kinin-forming system and the tissue kallikrein system, it is only in recent years that we have come to appreciate their potential role in inflammation in a wide variety of diseases. The importance of the tissue kallikrein system depends upon secretion of the active form of the requisite enzyme in the presence of a source of kininogen. Since tissue kallikreins are widely distributed in tissues, and since lymph and interstitial fluid contains kininogen (271), a local milieu for potential kinin formation is always present. The plasma system will be activated secondary to inflammation initiated by some other process. There may be endothelial or epithelial damage exposing connective tissue. Plasma leakage caused by release of some other permeability factor (including kinin made by tissue kallikrein) would thus lead to activation of the plasma cascade in many forms of inflammation. As with all mediators, however, the contribution of kinins to an inflammatory response can only be definitively evaluated if their actions can be selectively antagonized. Competitive receptor antagonists have recently been synthesized (228) and will, we hope, soon be available for administration to humans. Should these compounds prove effective in vivo, they could be used in conjunction with currently available assays for kallikreins, kininogens, kinins, and their various inactivated or degraded products, to provide new insights into the role of these systems in the pathogeneses of inflammatory diseases.

Changes in blood coagulation and fibrinolysis in patients on different treatment regimens for prostatic cancer. - predictors for cardiovascular complications?

An analysis of haemostatic variables was done in 31 prostate cancer patients treated with oestrogens ( 13 pts), estramustine phosphate (7 pts) or orchidectomy (11 pts) before, at about 7 weeks and 6 months of treatment. Six patients treated with either of the drugs developed venous thromboembolism or ischemic vascular disease. Already before treatment there were changes indicating some activation of blood coagulation, fibrinolysis and kallikrein systems. The drug treated group showed significant changes in several variables: i.e. increase in factor VII, plasminogen and prekallikrein but also a decrease in antithrombin and in inhibitors to the fibrinolytic and kallikrein system. Significant difference between the drug treated groups was found in circulating platelet aggregates and in kallikrein inhibiting activity. Tissue plasminogen activator capacity was significantly lower in the drug treated patients with complications than in those without. The study also showed that in addition to the assay of the tissue plasminogen activator capacity during the first weeks of therapy it might be helpful in predicting cardiovascular complications to investigate platelet aggregates, prothrombin complex, factor X, von Willebrand factor antigen, fibrinogen, antithrombin, fibrinopeptide A, and the inhibitors of fibrinolysis as well as C 1-esterase inhibitor.

401 Kallikrein, FXII and plasma defence systems in intensive care patients with and without ards

401 Kallikrein, FXII and plasma defence systems in intensive care patients with and without ards

Role of renal kallikrein in modulating the antihypertensive effect of a single oral dose of captopril in normal- and low-renin essential hypertensives.

The antihypertensive efficacy of angiotensin converting enzyme (ACE) inhibitors may result from the blockade of angiotensin II formation but also, theoretically, from the inhibition of kinin breakdown. To test whether a blunted activity of the kallikrein-kinin system might account for the failure of ACE inhibitors in lowering blood pressure (BP) in patients in whom the renin-angiotensin system (RAS) is not enhanced, 31 essential hypertensives with normal or low plasma renin activity (PRA) were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall, in both systolic and diastolic BP, was obtained in the subgroup of patients who were classified as 'normal-kallikrein hypertensives' according to whether their pretreatment urinary kallikrein excretion was within the normal range, while no significant change in BP was observed in 'low-kallikrein hypertensives'. Furthermore, the mean percentage fall in mean BP, throughout the 2 h following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47, P less than 0.05) in all the patients. Our results suggest that blunted activity of the kallikrein system might be responsible for failure of captopril to lower BP in some hypertensive patients.

The Effects of Aprotinin, a Kallikrein Inhibitor, on Renin Release and Urinary Sodium Excretion in Mild Essential Hypertensives

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.

Renal Hemodynamics and Natriuresis Induced by the Dopamine-1 Agonist, SKF 82526

The intrarenal infusion of dopamine (DA) during alpha- and beta-adrenergic blockade has been reported to increase renal blood flow (RBF) and sodium excretion by occupation of DA-1 receptors. In addition, DA may potentially influence renal function by occupation of DA-2 receptor subtypes. This study was designed to examine the hemodynamic and/or tubular mechanisms of the natriuretic effect of DA-1 in dogs anesthetized with pentobarbital. The intrarenal infusion of the DA-1 agonist, SKF 82526 (10−9, 10−8, 10−7M), resulted in dose related increases in RBF and absolute and fractional sodium excretion. These changes were not associated with alterations in urinary prostaglandin E2, F2 alpha, or kallikrein excretion. To determine the role of RBF in the natriuresis due to SKF 82526 infusion (10−7M), the renal artery was constricted to return RBF to control levels during continued SKF 82526 infusion. Although absolute and fractional sodium excretion decreased during this maneuver, they remained higher than control. These studies support both a hemodynamic and a tubular mechanism for the natriuretic effect of the DA-1 agonist, SKF 82526. These effects do not appear to be mediated by the renal prostaglandin or kallikrein systems.

ハイドロキシアパタイト（Ｈ‐ＡＰ）ｃｏｌｕｍｎのＰｌｇ．Ａｃｔ．吸着性について

Purification and function of blood Plg. Act. have not been studied sufficiently. Therefore, we evaluated the separation of blood Plg. Act. using by chromatography of hydroxyapatite (H-AP). H-AP varies in each characteristics according to the size and the degree of production by heat and large particle of H-AP calcined by 1200°C are selected for the open column.Blood Plg. Act. are adsorbed on H-AP column smoosely from human plasma instead of activation of coagulation and kallikrein system. Plg. Act. was eluted out by 0.05M phosphate buffer containing 0.2M Argine and 0.3M Nacl. H-AP column adsorbed blood Plg. Act. more effective than Fibrin Celite column or Lysine Sepharose column.This method is considered an effective application in the separation and purification of blood Plg. Act. as an affinity column.

Activation of cascade systems by hip arthroplasty: No difference between fixation with and without cement

The acrylic bone cement has been regarded as a very potent activator of the hemostatic mechanisms. A battery of coagulation, fibrinolytic, and kallikrein variables were studied perioperatively in 21 patients undergoing hip arthroplasty with fixation of the prosthesis either with (Charnley) or without (HP-Garches) cement. Epidural analgesia was used and dextran 6 per cent as thromboprophylaxis. The HP-Garches procedure was shorter and caused less blood loss. No differences were found between the two surgical procedures regarding the activation of the cascade systems. The coagulation and fibrinolytic systems were activated early, but a week postoperatively the latter seems to predominate. A marked activation of the kallikrein system was apparent. Our study shows that despite thromboprophylaxis a marked activation of the coagulation, fibrinolytic, and kallikrein systems occurs in relation to hip arthroplasty irrespective of the use or nonuse of cement and irrespective of the volume of blood loss during surgery. It may be the reaming of the bone marrow that initiates the activation of the cascade systems.

Urinary kallikrein excretion can predict the blood pressure response to a single oral dose of captopril.

The antihypertensive efficacy of ACE inhibitors depends in theory from the blockade of the angiotensin II formation but also from the inhibition of kinin breakdown. To test whether a blunted activity of the kallikrein-kinin system might account for the failure of ACE inhibitors in lowering BP in patients in whom the renin-angiotensin system is not enhanced, thirty-one essential hypertensives with normal or low PRA were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall both in systolic and diastolic blood pressure (BP) was obtained in the subgroup of patients who were classified as "normal kallikrein hypertensives" according to whether their pretreatment urinary kallikrein excretion was within the normal range, while no significant change in BP was observed in "low kallikrein hypertensives". Furthermore the mean percentage fall in mean BP, throughout the 2 hours following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47, p less than 0.05) in the entire group of patients. Our results suggest that a blunted activity of the kallikrein system might be responsible for failure of captopril in lowering BP in patients in whom the renin-angiotensin system is not pathogenetically implicated.

Relation between urinary kallikrein excretion and blood pressure response to a single oral dose of captopril.

Thirty-one essential hypertensives with normal or low PRA were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall both in systolic and diastolic blood pressure (BP) was obtained in the subgroup of patients who were classified as "normal kallikrein hypertensives", while no significant change in BP was observed in "low kallikrein hypertensives". Furthermore the mean percentage fall in mean BP, throughout the 2 hours following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47 p less than 0.05) in the entire group of patients. Our results suggest that a blunted activity of the kallikrein system might be responsible for failure of captopril in lowering BP in patients in whom the renin-angiotensin system is not pathogenetically implicated.

Thiazide induced hypotension: the role of plasma volume reduction and the urinary kallikrein system.

The hypotensive response the thiazide diuretics was studied in 15 males with moderate essential hypertension and correlated with serial changes in plasma volume, weight, plasma renin activity, urinary aldosterone, and urinary kallikrein, both total and activity. A greater than 10 mmHg fall in mean arterial pressure after four weeks of treatment defined the responders to therapy (n = 10) while all others were considered non-responders (n = 5). In responders, the fall in mean arterial pressure was accompanied by sustained reduction in plasma volume and weight. No sustained fall in plasma volume was noted in non-responders. Plasma renin activity and urinary aldosterone excretion increased in responders but not in non-responders. Urinary kallikrein, both total and active, increased in the responders but remained unchanged in the non-responders. The results are consistent with the hypothesis that a sustained reduction in plasma volume is necessary for the maintenance of a hypotensive response to thiazides. Stimulation of the renal kallikrein-kinin system may be necessary to balance the antinatriuretic and pressor effects of the renin-angiotensin-aldosterone system. If unopposed, this system would return plasma volume and blood pressure to pretreatment levels.

Effects of dopamine on renal function in the rat isolated perfused kidney.

The renal effects of dopamine, the dopamine antagonist spiperone and the combination of dopamine and spiperone were examined in the isolated perfused rat kidney preparation. Studies were carried out at constant perfusion pressure and the following were measured at 10 min intervals for 1 h: perfusate flow; GFR (3H-inulin); urine flow rate; sodium, potassium and kallikrein excretion; perfusate renin concentration; perfusate and urinary-dopamine levels. Low-dose dopamine infusion (6 X 10(-10) mol/min) resulted in significant diuresis, natriuresis and kaluresis but little change in GFR. These effects were blocked by spiperone (10(-10) mol/min) which had no significant effects when infused alone. At a higher dose (10(-8) mol/min) dopamine significantly increased urine flow alone; this too was reversed by spiperone. Dopamine had no significant effects on perfusate flow, renin release or kallikrein excretion. Perfused control kidneys excreted amounts of dopamine (328 pmol/h, s.e.m. = 57, n = 6) far in excess of kidney dopamine content (49 pmol/g, s.e.m. = 6, n = 32). Renal handling of infused dopamine was dose-related; the fraction of the administered dose taken up and/or metabolized by the kidney on the higher dose infusion was considerably less than on the lower dose (40%, s.e.m. = 3 vs. 82%, s.e.m. = 6) while more was excreted (13%, s.e.m. = 3 vs. 2%, s.e.m. = 1). These studies indicate that dopamine at low doses can produce diuresis, natriuresis and kaluresis independently of extrarenal or haemodynamic influences and not mediated by renal renin or kallikrein systems. The kidney also exhibits a saturable capacity for dopamine uptake and/or metabolism.

Increased urinary kallikrein-like activity during ADH-induced hyponatremia in rats.

The urinary kallikrein system was studied during hyponatremia associated with water and vasopressin administration in rats. Two groups of animals were studied. In the experimental group (n = 5), vasopressin (0.4 U/day) was injected intramuscularly for 7 days, and water (15%-20% body weight per day) was given via a stomach tube. The control group (n = 6) received only vasopressin. In the experimental group, plasma sodium concentration (PNa) decreased from 143.2 +/- 0.5 to 130.8 +/- 1.8 (m +/- SEM) mmol/liter (5th day, p less than 0.01) along with plasma osmolality. Urinary kallikrein-like activities (UkaV) increased from 99.1 +/- 7.5 to 172.6 +/- 23.5 mumol X min/day (100 g body weight) (5th day, p less than 0.05; 6th day, p less than 0.05; and 7th day, p less than 0.05) after the administration of vasopressin. Uric acid clearance (Cua) increased from 0.153 +/- 0.014 to 0.275 +/- 0.041 ml/min (5th day, p less than 0.05; 7th day, p less than 0.05). No change was observed in urinary aldosterone excretion (UAldV), creatinine clearance, or blood pressure. UkaV correlated with Cua (r = 0.81, p less than 0.01) and with the degree of change of PNa (r = --0.79, p less than 0.01), respectively. In the control group, no change was observed in the above parameters. A significant relationship between UkaV and fractional Na clearance (r = 0.60, p less than 0.01) was observed. We conclude that the urinary kallikrein system in rats may be stimulated during hyponatremia when induced by water and vasopressin. This increased activity is probably the result of volume expansion associated with water and vasopressin and may have some relationship to fractional Na clearance in the kidney.

Hypertension: Physiopathology and Treatment

This outstanding book appears in a second edition six years after the appearance of<i>Hypertension: Physiopathology and Treatment</i>in 1977, edited by Jacques Genest and associates. In their preface, the authors point out the necessity for updating the first edition of the book, particularly because of advances in the measurement of human plasma renin and catecholamines, improved understanding of the roles of dopamine, of renal prostaglandins and the kallikrein system, and increased awareness of the importance of defective permeability to sodium in the cellular membrane in hypertension. In the area of drug therapy they pay particular attention to the development of oral converting enzyme inhibitors. The imposing list of 135 authors is international in scope and includes a large number of names that are familiar to all who have an interest in hypertension because of their leadership both in basic research and in the clinical aspects of the subject. Happily,

Activation of Blood Coagulation, Fibrinolytic and Kallikrein Systems during Storage of Plasma

Activation of Blood Coagulation, Fibrinolytic and Kallikrein Systems during Storage of Plasma

急性すい炎における凝固線溶，カリクレイン，ＴＸＡ２，ＰＧＩ２の動態

The disturbance of micro-circulation on several organs may contribute to the pathologic features of acute pancreatitis. The coagulo-fibrinolysis, platelets, kallikrein-kinin and prostaglandins are the most important factors of micro-circulation. Although changes in coagulation, fibriolysis and the plasma kallikrein system have been reported individually, already in pancreatitis, to our knowledge, no detailed comparison of these systems has been published, espacially no information has been received on the prostaglandin in acute pancreatitis.The coagulation system (PT, APTT, fibrinogen and AT-III), the fibrinolysis system (plaminogen, α2-PI, FDP and ECLT), kallikrein-kinin system (prekallikrein) and prostaglandins (TXA2 and PGI2) were investigated in the 49 patients with acute pancreatitis in the course of time.Results; On the coagulation system, the shortened APTT, the elavated fibrinogen and the decreased AT-III level were recognized. On the fibrinolysis system, although plasminogin and α2PI level were low and FDP level elevated on the onset, they recovered in the normal level gradually, and ECLT prolonged more than normal. β-TG increased already on the onset. The plasma prekallikrein level was lower than normal significantly. This low level of prekallikein should be due to the consumption and the several inhibitors (α2M., α1AT. etc.). PGI2 was almost normal, though in a few patients this level became high slightly on the early phase. However, the high TXB2 level were observed in all patients.Conclusion; The micro-circulation disturbance and an increased tendency of thrombosis have occured from the onset in acute pancreatitis. This situation should contribute to the disturbance of several organ functions, finally, DIC may be happened.

Hereditary angioneurotic oedema and blood-coagulation: interaction between C1-esterase-inhibitor and the activation factors of the proteolytic enzyme systems.

C-1-inactivator (C-1-INA) does not only exert its important inhibitory functions in the complement system but also in the first step in the activation of the coagulation, fibrinolytic and kallikrein system. We therefore determined in nine patients with hereditary angioneurotic oedema (HANE) with obvious quantitative or functional defects of C-1-INA, and one further patient with Quincke-type oedema of different origin, the coagulation factors of the initial phase such as Hageman factor, plasma thromboplastin antecedent (PTA) and high molecular weight kininogen (HMWK). These factors were further correlated with the concentration as well as functional activity of C-1-INA. Nine of ten patients showed a significant, sometimes even excessive, increase in the levels of factor XII (mean +/- SD = 146% +/- 63), HMWK (mean +/- SD = 126% +/- 56) and PTA (mean +/- SD = 289% +/- 294), and a decrease of C1-esterase inhibitor (C-1-inactivator), which was measured with a immunologic method (mean +/- SD = 9.6 mg/dl +/- 6.6) for its concentration as well as being measured for its activity (mean +/- SD = 30.4% +/- 24.9).

Effects of cyclooxygenase inhibitors on plasma and urinary kallikrein.

In vitro studies were performed to investigate the direct effects of the cyclooxygenase inhibitors (COI), meclofenamate, imidazol, acetylsalicylic acid (ASA), indomethacin, and acetaminophen on the plasma kallikrein system and on urinary kallikrein excretion. Biological (guinea pig ileum) and colorimetric (synthetic substrate) methods were used. Results showed that all COIs except ASA affected both the activation of pre-kallikrein in plasma and the direct activity of plasma kallikrein, but none of the COIs tested was able to alter the urinary kallikrein excretion. Additionally, in Wistar rats we studied the effects of chronic administration of ASA, meclofenamate, and indomethacin on the plasma kallikrein system and urinary kallikrein excretion. In contrast to the in vitro studies, administration of these COIs reduced the amount of total 24-hour urinary kallikrein excretion. Moreover, the pre-plasma kallikrein and total plasma kallikrein levels were diminished in all experimental groups. However, only ASA and meclofenamate increased the free-plasma kallikrein levels despite the fact the three COIs used reduced the high molecular weight kininogen. Thus, in vitro data suggest an important and direct effect of meclofenamate, imidazol, indomethacin, and acetaminophen on the plasma kallikrein system, without any effect on urinary secretion. ASA was the only COI that showed no direct effect in these experiments. Chronic COI administration in Wistar rats suggests that ASA, meclofenamate, and indomethacin affect both the plasma kallikrein-kinin system and kallikrein excretion. When these drugs are used to evaluate the interactions between prostaglandins and the kallikrein-kinin system, their possible effects through both mechanisms, directly or via prostaglandin inhibition, should be considered.