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PubMed1999

Inhibition of kinin action and kinin generation compared to dexamethasone pretreatment with respect to vascular effects and pancreatic enzymes in experimental acute pancreatitis.

It was determined earlier that inhibition of the action of endogenous kinins by the bradykinin B2 antagonist, icatibant (Hoe-140; D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), prevents pancreatic oedema formation during caerulein-induced acute pancreatitis, and simultaneously improves the egress of activated pancreatic enzymes from the pancreas. We have now investigated whether inhibition of increases in vascular permeability by another approach, i.e., pretreatment with dexamethasone, would have comparable effects. In addition, preliminary data are presented on the effects of the selective low molecular weight inhibitor of tissue kallikrein, H-(4-Cl)-D-Phe-1Nal-(3-aminopropyl)-guanidine (CH-2856). Icatibant abolished plasma extravasation into the pancreatic tissue and prevented the development of hypovolaemia. Caerulein-induced increases of amylase activity in the pancreas were significantly reduced by icatibant, while amylase activity in blood was augmented. Inhibition of kinin generation by CH-2856 had similar effects, as oedema formation was inhibited and enzyme activities were reduced in the pancreas and augmented in the blood serum. Dexamethasone completely abolished oedema formation, but only partially inhibited the development of hypovolaemia and haemoconcentration. Amylase activities in the pancreas and in blood remained completely unaffected by dexamethasone. The results suggest that retention of activated enzymes in the pancreatic tissue during acute pancreatitis involves a B2 receptor-mediated, but glucocorticoid-insensitive mechanism.

Acute Disease↗
PubMed1959

The extraction of human urinary kinin (substance Z) and its relation to the plasma kinins.

Human urinary kinin (substance Z) has been extracted by modifications of the methods previously described by Gomes (1955) and Jensen (1958). The separation of two oxytocic fractions from such extracts by paper pulp chromatography (Walaszek, 1957; Jensen, 1958) could not be confirmed. Substance Z could not be distinguished from kallidin, bradykinin or glass-activated kinin by parallel quantitative assays, thus confirming that these four substances are very closely related.

Biological Assay↗
PubMed1981

The renal kallikrein-kinin system in Brattleboro rats with hereditary hypothalamic diabetes insipidus. Missing relationship between antidiuretic hormone and the renal kallikrein-kinin system.

The activity of the renal kallikrein-kinin system was investigated in male Brattleboro rats homozygous for hypothalamic diabetes insipidus (DI); Long-Evans rats (LE) were taken as controls. In the rats with DI, urinary kallikrein excretion was lower (P less than 0.05) than in the LE rats. However, when related to total renal mass or to body weight, there was no difference between the two strains. Kallikrein activity in the renal cortex was similar in the Brattleboro and the LE rats. Antidiuretic hormone (vasopressin tannate) in a dose of 100 mU given once daily for 3 days had no effect on urinary kallikrein excretion in either of the strains. Water deprivation for 24 h resulted, also in both strains, in a similar reduction in urinary kallikrein excretion. The renal kallikrein-kinin system of LE rats and that of DI rats does not principally differ in basic activity, nor in response to the administration of vasopressin, nor to water deprivation.

Angiotensin II↗
PubMed1990

Kinin- and non-kinin-mediated interactions of converting enzyme inhibitors with vasoactive hormones.

The antihypertensive effect of inhibitors of the angiotensin I-converting enzyme (ACE = kininase II) results from their vasodilatory and natriuretic effects as well as their effect on baroreceptor function. In addition to the inhibition of systemic and local angiotensin II formation, other local hormonal systems may also be involved in this effect at multiple target sites. Thus, potentiation of the vasodilator and natriuretic kinin system following inhibition of kininase II is thought to contribute to the persistent hypotensive effect of ACE inhibitors despite normalization of circulating ACE activity. Although increased plasma bradykinin levels cannot be detected, we found that the enhanced kinin-dependent local vascular prostacyclin production can be blunted in vitro by aprotinin, a kallikrein inhibitor. ACE inhibition may affect the atrial natriuretic peptide (ANP) system as the renin-angiotensin system and ANP appear to play antagonistic roles at the peripheral and central nervous system levels. Inhibition of kallikrein or of kininase II were both shown to modulate the natriuretic and vasorelaxant effects of ANP. In hypertensive subjects, we found that ACE inhibition with blood pressure normalization reduces basal and stimulated plasma ANP and blunts the renal sodium excretion in response to saline loading. In contrast, we did not observe effects of acute ACE inhibition in healthy sodium-depleted volunteers on plasma vasopressin under basal conditions or in response to passive tilt. Finally, we investigated the interaction of ACE inhibition with substance P, a powerful endogenous diuretic and natriuretic peptide that may have a transmitter function in the baroreceptor reflex arch.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin.

Hereditary angioedema (HAE) is due to a functional deficiency of the inhibitor of the activated first component of complement (C1 INH). This abnormality is thought to be responsible for the generation of a kininlike peptide in HAE plasma that is derived from the second component of complement (C2). Specifically, a combination of C2 cleavage by C1s and C2 fragment cleavage by plasmin has been reported to generate a kinin that is distinguishable from bradykinin. We have attempted to generate this peptide by activating the classical complement pathway by incubation of plasma with immune complexes and then adding plasmin or by incubating purified C1s with C4 and C2 and then adding either plasmin or trypsin. We performed a total of 13 experiments, and in no case was a kininlike molecule generated as assessed by contraction of the estrus rat uterus. However, incubation of EDTA-treated HAE plasma at 37 degrees C for time intervals up to 1 hr progressively generated a smooth muscle-contracting activity. This activity was resistant to tryptic digestion but was destroyed after incubation with carboxypeptidase B, an inhibition profile consistent with that of bradykinin. We therefore propose that bradykinin alone, or in combination with other factors heretofore unrecognized, might be responsible for the swelling that is characteristic of hereditary angioedema.

Angioedema↗
PubMed1981

Biological activities of photoaffinity labeling analogues of kinins and their irreversible effects on kinin receptors.

Several analogues of bradykinin and [des-Arg9]bradykinin with potentially reactive groups have been tested for their biological activities. In these analogues, phenylalanine was replaced by the aromatic amino acid (4'-nitro)Phe, (4'-amino)Phe, (4'-azido)Phe, and (4'-diazonium)Phe, as well as with other residues. [Des-Arg9]bradykinin and the octapeptide analogues were tested on rabbit aorta strips, an assay organ containing the B1 receptor which is activated by the octapeptide [des-Arg9]bradykinin. Strips of rabbit jugular vein served as bioassays for bradykinin and the nonapeptide analogues, because the rabbit jugular vein bears the receptor B2 which is sensitive to bradykinin nonapeptides. The biological findings support the interpretation that kinins act on two different receptor types, since the potency orders of the analogues in the two bioassays are different. All potential photolabels retained reasonable affinities in the dark, except [(4'-azido)Phe8,des-Arg9]bradykinin, which, however, proved to be a weak and competitive antagonist of [des-Arg9]bradykinin on the rabbit aorta. Inactivation experiments with the unstable (4'-diazonium)Phe-containing peptides did not show any irreversible effect in the two bioassays. Photoaffinity labeling experiments with the azido and the nitro peptides gave irreversible and specific effects on both the rabbit aorta and the jugular vein. [(4'-Azido)Phe8,des-Arg9]bradykinin photolyzed at 365 nm on the rabbit aorta reduced the sensitivity of this tissue against [des-Arg9]bradykinin specifically to about one-third of its initial value. [(4'-Azido)Phe5]bradykinin reduced the sensitivity of the rabbit jugular vein to bradykinin by more than 50%. The observed irreversible effects were always loss of myotropic activity and never permanent contraction.

Affinity Labels↗
PubMed1988

Effect of intravenous enkephalin administration on kallikrein-kinin system in experimental hemorrhagic shock. Evidence for activation of kallikrein-kinin system by naloxone.

The effects of enkephalin derivates with different opioid receptor subtype specificity and naloxone on cardiovascular responses and kallikrein-kinin system (KKS) were studied in anesthetized rats exposed to 30% hemorrhage. Administration of a mu-receptor agonist (DAGO) in early hemorrhage improved mean arterial blood pressure (MAP) responses to hemorrhage. This effect could be abolished by naloxone pretreatment. Moreover, a delayed MAP recovery after hemorrhage could be observed. Treatment with a delta-agonist (DADL) resulted in transient depression of MAP and heart rate (HR). Hemorrhage by itself caused only a slight activation of KKS as indicated by decreased plasma kallikreinogen concentration and reduced kallikrein inhibitor capacity after 20% blood loss. Enkephalin administration did not exert significant effects on KKS. Naloxone pretreatment, in contrast, induced prehemorrhagic activation of KKS, which was potentiated by subsequent hemorrhage. Naloxone-induced activation of KKS could be confirmed by an in vitro study. Taken together these results suggest that the KKS is not involved in MAP and HR responses to enkephalin administration during hemorrhage, whereas it might be implicated in naloxone-induced delayed posthemorrhagic MAP recovery.

Animals↗
PubMed1978

Plasma-kinin-forming enzyme in human skin: extraction and column chromatographic separation of plasma-kinin-forming enzyme and its inhibitor.

The optimal salt concentration for extraction of plasma-kinin-forming enzyme from the human skin was investigated. It was confirmed that a salt concentration higher than 1.5 M in the extraction buffer was required for optimal extraction of this enzyme. An inhibitor of this enzyme was detected in the extract with buffer alone, and the coexistence of this enzyme with the inhibitor in buffer extract was also confirmed by using G-200 gel chromatography.

Bradykinin↗
PubMed1976

The influence of kinins on the action of circulatory drugs. I. The influence of kinins on hypertensive and hypotensive effects of selected drugs.

The influence of bradykinin and kallikrein on the action of norepinephrine, epinephrine, isoprenaline, phentolamine, propranolol, aminophylline and theophylline on blood pressure was studied. The kinins potentiated the hypertensive action of norepinephrine and epinephrine, weakened the hypotensive action of isoprenaline, potentiated the hypotensive action of propranolol, and had no effect on the action of phentolamine, aminophylline and theophylline.

Aminophylline↗
PubMed1979

Kinin-forming enzyme in human skin: the purification and characterization of a kinin-forming enzyme.

A kinin-forming-enzyme in human skin extract was further purified by successive column chromatography on DEAE-cellulose, Hydroxylapatite-cellulose and Sepharose-4B. By these procedures, 2.7 mg of purified enzyme was obtained from 10 gm of original skin. The purified material was homogeneous as ascertained by cellulose acetate membrane electrophoresis, sodium dodecyl sulfate polyacrylamide gel disc electrophoresis and ultracentrifugation. It had an S20,w value of 4.3 and an apparent molecular weight of 104,000 as measured by gel filtration on Sephadex G-200. The purified enzyme was comparatively heat-stable, but was unstable below pH values of 5 and above pH 9. It possessed arginine or lysine esterolytic activity, but not tyrosine or tryptophane esterolytic activity and denatured proteolytic activity. This enzyme was not affected by metal ion, cystein, glutathion or rho-chloromercuribenzoate, but was strongly inhibited by alpha-N-rho-tosyl-L-lysine chloromethyl ketone or soybean-trypsin inhibitor. It was also inhibited by alpha 1-antitrypsin, but not by alpha 2-macroglobulin. This enzyme was confirmed to be immunologically distinct from human plasma, urinary or pancreas kallikrein.

Animals↗
PubMed1985

Assessment of histamine release and kinin formation in man: identification of kinin degradation products and characterization of a lymphocyte-dependent histamine releasing factor.

Factors traditionally associated with histamine release include IgE antibody plus antigen and the anaphylatoxins C3a, C4a, and C5a. Yet histamine release is thought to occur in disorders such as chronic urticaria, atopic dermatitis, and contact dermatitis in which the above mechanisms do not appear operative. We have partially purified a factor from stimulated human mononuclear cells which causes basophil histamine release. It is homogeneous by gel filtration with a molecular weight of about 35,000 daltons and has two molecular forms when assessed by ion exchange chromatography, isoelectrofocusing in gels and chromatofocusing. The purified material, when radiolabeled, gives a single band upon two-dimensional gel electrophoresis and radioautography. This factor may therefore represent one mechanism in which delayed hypersensitivity and histamine release are linked. We are also developing methods to better assess the kinin-forming system in allergic diseases. Assays for enzyme inhibitor complexes are the most sensitive and specific methods for inferring activation in plasma. These include quantitation of activated Hageman factor-C1 INH complexes and kallikrein-C1 INH complexes each of which appears elevated in cutaneous late-phase reactions. However, bradykinin assessment is fraught with difficulties including spurious generation and rapid inactivation. Using high performance liquid chromatography we have separated bradykinin from kallidin, des-Arg9-bradykinin (the degradation product of carboxypeptidase N) as well as the fragments Arg-Pro-Pro-Gly-Phe, Ser-Pro, and Phe-Arg, the degradation products formed by angiotensin-converting enzyme. These can be assayed in purified mixtures, can be detected upon addition of bradykinin to human plasma and are formed by kaolin treatment of plasma.

Basophils↗
PubMedDate not supplied

Participation of prostaglandins in the action of kinins on the central dopaminergic system in the rat. I. The action of kinins on the central dopaminergic system after pretreatment with indomethacin.

The effect of intraventricularly (ivc) administered bradykinin (BRS) and activation of kininogenic enzymes of the cerebral tissue by kallikrein on dopaminergic system was investigated in tests of amphetamine (AMPH) and apomorphine (APO)-induced stereotypy and haloperidol (HAL)-induced catalepsy in rats receiving an inhibitor of prostaglandin synthetase, indomethacin (IND). The cerebral content of dopamine (DA), noradrenaline (NA) and homovanillic acid (HVA) was determined after some dosage schedules. In rats pretreated with IND the action of AMPH was potentiated and modulated by kinins (depending on the dose). IND prolonged the duration of APO-induced stereotypy and antagonized the action of low dose (1 mu g) of BRS, but potentiated the action of high doses (2 and 4 mu g) of BRS. IND potentiated the action of BRS on catalepsy induced by a low dose of HAL (0.75 mg/kg) but abolished the action of BRS on the catalepsy produced by a high dose of HAL (1.25 mg/kg). The results of biochemical investigation do not explain in full the behavioral changes.

Animals↗
PubMedDate not supplied

The participation of prostaglandins in the action of kinins on the central dopaminergic system in the rat. III. Participation of PGE1 in the action of kinins on the central dopaminergic system.

Prostaglandin E1 (PGE1) slightly inhibited the amphetamine (AMPH) induced stereotypy after administration of bradykinin (BRS) or stimulation the activity of kininogenic enzymes of the cerebral tissue by kallikrein administration. After administration of PGE1, BRS did not affect the apomorphine (APO)-induced stereotypy. The effect of kinins on catalepsy induced by haloperidol (HAL) was changed depending on the dose of PGE1. PGE1 given in combination with BRS increased the NA turnover in the rat striatum in comparison with the group receiving BRS, and given together with BRS and APO depressed the NA turnover in comparison with the group BRS and APO. A combined administration of PGE1 and BRS did not change the DA and HVA content under the experimental conditions used.

Animals↗
PubMed1979

High concentrations of free kinins and kinin system components in abdominal transudate of a patient with nephrotic syndrome.

High levels of bradykinin (60--80 ng/ml) were found in abdominal transudate from a patient with nephrotic syndrome caused by chronic glomerulonephritis. The abdominal transudate contained neutral kininogenase and its precursor, identified with plasma kallikrein and prekallikrein, respectively, as well as both forms of kininogen, the low-molecular-weight form predominating. The abdominal transudate was characterized also by very low kininase activity and low levels of alpha 1-antitrypsin (0.46 g/l) and alpha 2-macroglobulin. Large amounts of very low density lipoproteins were present in the transudate. Despite the difference in total protein content between the abdominal transudate and the patient's serum (4.3 g/l and 48 g/l, respectively) their protein fraction composition was similar. The data obtained suggest that bradykinin is important in maintenance of long-lasting blood vessel hyperpermeability, which, in turn, is a driving force in the pathogenesis of refractory nephrotic edema.

Adolescent↗