The effects of bradykinin on electrobiological phenomena in isolated right atrium of the rat.

Bradykinin induces or accelerates the already present electrobiological activity in isolated right atrium of rats. Acceleration of the electrobiological activity induced by bradykinin decreases with increase of initial activity. Bradykinin disturbs transiently the course of the repolarization period in action potential. It may be one of the mechanisms of arrhythmia development caused by bradykinin.     

Effects of bradykinin on DNA synthesis in resting NIL8 hamster cells and human fibroblasts

Bradykinin stimulates [3H]thymidine incorporation and DNA synthesis in resting, serum-deprived NIL8 hamster cells. The ED50 for this stimulation is 4.52 +/- 2.91 nM. Other kinin peptides including lys-bradykinin (kallidin) and met-lys-bradykinin also stimulate [3H]thymidine incorporation in the NIL8 cells, whereas desarg9-bradykinin is without effect, suggesting action of the kinin peptides through type B2 receptors. Bradykinin also stimulates DNA synthesis in IMR-90 human fibroblasts; however, this effect is observed only in the presence of indomethacin, which blocks prostaglandin synthesis. These results suggest that prostaglandins act as negative modulators of the growth-stimulatory effects of bradykinin in the fibroblasts. This conclusion is supported by the observation that exogenously added PGE1, PGE2, PGA1, PGA2, PGB1, and PGB2 strongly inhibit [3H]thymidine incorporation in the human fibroblasts. The direct effect of bradykinin observed in the NIL8 cells may be attributable to the relative resistance of these cells to growth inhibition by prostaglandins.     

Is the C-terminal region of bradykinin the binding site of polyphenols?

Bradykinin is a bioactive hormone involved in a variety of physiological processes. In various solvents, this peptide adopts beta-turn structures. The C-terminal turn is a structural feature for the receptor affinity of agonists and antagonists while the N-terminal turn might be important for antagonistic activities. Polyphenols like dimeric proanthocyanidin B3 interact with the peptide. Thus to investigate the effects of polyphenols on bradykinin activity and structure, we studied the interaction in the structuring solvent DMSO which can be a close mimic of aqueous physiological environments like receptor-binding sites. Bradykinin alone presented a folded structure with two turns. B3 interacted with the peptide C-terminus and involved the loss of the bend structure of this region, while the N-terminus turn was maintained. Numerous studies have shown that polyphenolic molecules can act upon various biological targets, and the formation of this type of complex might be one of the possible modes of action.     

The effect of potentiating factors on the bradykinine effect in vitro]

Bradykinin potentiating factors from the venom of Bothrops jajaraca and Agkistrodon halys blomhoffii potentiate the action of bradykinin at several smooth muscles. This potentiation is specific for bradykinin and has to be distinguished from an unspecific potentiation. The potentiation induced by BPF is not due to an indirect cholinergic mechanism or to a kininase inhibition in vitro. The results suggest that there would be an allosteric transition of the bradykinin receptor.     

Homology Modeling and Docking Studies of Human Bcl-2L10 Protein

Abstract

Bradykinin is a bioactive hormone involved in a variety of physiological processes. In various solvents, this peptide adopts β-turn structures. The C-terminal turn is a structural feature for the receptor affinity of agonists and antagonists while the N-terminal turn might be important for antagonistic activities. Polyphenols like dimeric proanthocyanidin B3 interact with the peptide. Thus to investigate the effects of polyphenols on bradykinin activity and structure, we studied the interaction in the structuring solvent DMSO which can be a close mimic of aqueous physiological environments like receptor-binding sites. Bradykinin alone presented a folded structure with two turns. B3 interacted with the peptide C-terminus and involved the loss of the bend structure of this region, while the N-ter-minus turn was maintained. Numerous studies have shown that polyphenolic molecules can act upon various biological targets, and the formation of this type of complex might be one of the possible modes of action.     

Effect of bradykinin on membrane properties of guinea pig bronchial parasympathetic ganglion neurons

The effect of bradykinin on membrane properties of parasympathetic ganglion neurons in isolated guinea pig bronchial tissue was studied using intracellular recording techniques. Bradykinin (1-100 nM) caused a reversible membrane potential depolarization of ganglion neurons that was not associated with a change in input resistance. The selective bradykinin B(2) receptor antagonist HOE-140 inhibited bradykinin-induced membrane depolarizations. Furthermore, the cyclooxygenase inhibitor indomethacin attenuated bradykinin-induced membrane depolarizations to a similar magnitude ( approximately 70%) as HOE-140. However, neurokinin-1 and -3 receptor antagonists did not have similar inhibitory effects. The ability of bradykinin to directly alter active properties of parasympathetic ganglion neurons was also examined. Bradykinin (100 nM) significantly reduced the duration of the afterhyperpolarization (AHP) that followed four consecutive action potentials. The inhibitory effect of bradykinin on the AHP response was reversed by HOE-140 but not by indomethacin. These results indicate that bradykinin can stimulate airway parasympathetic ganglion neurons independent of sensory nerve activation and provide an alternative mechanism for regulating airway parasympathetic tone.     

Bradykinin stimulates the production of prostaglandin E2 and interleukin-6 in human osteoblast-like cells.

The effect of bradykinin (BK) on proteinase activity, prostaglandin synthesis, and the production of interleukin-6 (IL-6) was investigated in cultures of human osteoblast-like cells. Bradykinin had no effect on stromelysin activity and plasminogen activator activity produced by human osteoblast-like cells. However, BK stimulated the production of prostaglandin E2, an effect that was markedly enhanced by pre-incubation with recombinant interleukin-1 alpha (rhIL-1 alpha), but was apparently unaffected by BK receptor antagonists types 1 and 2. Bradykinin stimulated the intracellular accumulation of total inositol phosphates suggesting that its effects were mediated by stimulation of phosphoinositide metabolism. Bradykinin within the dose range of 10(-11)-10(-5) M also significantly stimulated the production of IL-6. Bradykinin may, therefore, mediate a variety of responses in bone under both physiological and pathological conditions.     

Effect of inflammatory mediators on respiration in rat liver mitochondria

Some inflammatory mediators have been studied for their influence on the energy reactions of the liver mitochondria. Mediators were injected intraperitoneally to rats 15 min before decapitation in the following doses (per 100 g of the body) weight: histamine--0.5 mg, serotonin--0.5 mg, bradykinin--0.2 mg, andekalin--0.5 units. Histamine action in the body is connected with modification of the respiratory mitochondria chain and, like the oligomycin action, is directed to attended oxidation and phosphorylation points. Serotonin increases the mitochondria sensitivity to separating agents in succinate oxidation. It is supposed that serotonin-induced inhibition of oxidation of NAD-dependent substances is connected with NADH2 dehydrogenase inhibition or transhydrogenase reaction activation. Bradykinin has activated NAD-dependent substance oxidation and increased respiratory chain sensitivity on the SoQ link to 2,4-dinitrophenol action. Andekalin exerts an analogous effect intensifying ADP-, DNP- and Ca-stimulated respiration of mitochondria during succinate oxidation. Mechanism of the inflammatory mediators influence on the energy metabolism is discussed.     

Bradykinin elicits "second window" myocardial protection in rat heart through an NO-dependent mechanism

Bradykinin is an important endogenous mediator exerting acute protective effects in the ischemic myocardium. The aims of this study were to investigate whether exogenously administered bradykinin could evoke delayed myocardial protection and to determine whether any protection observed might be dependent on nitric oxide (NO) generation. Conscious rats received bradykinin (40 microg/kg iv) or saline, preceded 15-20 min earlier by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg ip) or saline. Twenty-four hours later, hearts were Langendorff perfused and subjected to 35 min of regional ischemia and 120 min of reperfusion. Infarct size was assessed using tetrazolium staining and expressed as a percentage of the risk zone. Bradykinin pretreatment reduced the infarct-to-risk ratio from 53.5 +/- 3.2% to 29.1 +/- 4.7% (P < 0.01). The administration of L-NAME before bradykinin abrogated the delayed protection (infarct size 52.3 +/- 5.0%) but alone did not influence infarct size (53.5 +/- 4.8%). These results are the first to demonstrate that bradykinin can evoke a delayed ("second window") enhancement of myocardial tolerance to ischemia, an action that is dependent on the early generation of NO.     

Bradykinin stimulates prolactin release in vitro

Bradykinin (BK) is a nonpeptide, originally discovered in blood; recently BK has been localized in neurons and fibers of the hypothalamus. BK is a vasoactive substance which is involved in pain, inflammation and oedema. The present study demonstrates that BK is also a potent stimulator of prolactin (PRL) release from anterior pituitary cells in vitro. A significant enhancement of the release of PRL is observed at 1 nM BK. The stimulation of PRL release by BK is dose-dependent. This work shows that anterior pituitary cells in culture may serve as a useful model system in which to study the mechanism of action of BK.     

Effect of Bradykinin on Murrah buffalo (Bubalus bubalis) semen cryopreservation

Keeping in view the poor freezability of bubaline semen in conventionally used extenders, this study was conducted on three Murrah bulls to improve semen cryopreservation with the incorporation of Bradykinin (0.5, 1.0 and 2.0 ng ml(-1)) in routinely used egg yolk tris-glycerol (EYTG) extender. Bradykinin (2.0 ng ml(-1)) had significant (P<0.05) beneficial effect on live sperm % (81.6+/-1.8) and hypo osmotic swelling (HOS) % (63.0+/-1.3) as compared to their respective control values of 73.4+/-2.1 and 56.3+/-2.0 at 0 h post freezing. The post-thaw progressive sperm motility in semen samples diluted with EYTG containing 2.0 ng ml(-1) Bradykinin (65.5+/-1.4) was also significantly (P<0.01) higher than control (60.3+/-1.9) at 0 h post freezing. Thus incorporation of 2 ng ml(-1) Bradykinin in buffalo semen diluted in EYTG extender may be useful in improving the quality of cryopreserved bubaline semen.     

The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold

The Bradykinin B2 receptor antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg) has been used as a template for the de novo design and synthesis of a small number of non-peptide lead compounds based on the 1,4-benzodiazepin-2-one framework. Two of the compounds have been found to exhibit moderate K(i) values of 8.9 and 9.2 microM at the human Bradykinin B2 receptor.     

Activation of bradykinin B2 receptors increases calcium entry and intracellular mobilization in C9 liver cells.

In C9 rat liver cells bradykinin and kallidin increased (approximately 2-fold) the intracellular concentration of calcium, but the B1 agonist, des-Arg9-bradykinin did not. The effect of bradykinin was inhibited by the B2 antagonists, Hoe 140 and N-alpha-adamantaneacetyl-D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin, but not by the B1 antagonist, des-Arg9-[Leu8]-bradykinin. The action of bradykinin was diminished, but not abolished, in medium without calcium. The peptide was able to increase intracellular calcium concentration in cells treated with thapsigargin. Bradykinin action was not observed in cells previously stimulated with this local mediator: however, under the same conditions, angiotensin II induced a clear increase in intracellular calcium concentration. Our data indicate that activation of bradykinin B2 receptors increase intracellular calcium concentrations by inducing both gating of the cation and intracellular mobilization in C9 liver cells. In addition, homologous desensitization was observed.     

Mechanisms of regulation of the capillary bed in the human chorionic villi

The purpose of the present researches was to confirm the hypothesis that in the human placenta the microcirculation is subjected to humoral control, because of the absence of innervation in the chorionic villi and the ability of the capillaries to contract themselves. Chorionic villi were incubated in presence of vasoactive substances, Histamine, Serotonin, Bradykinin, Dopamine, Enkephalin Prostaglandins. After incubation, the specimens were fixed and embedded in resin. Semithin sections were submitted to a computerized analysis for the evaluation of the ratio between surface of capillaries and surface of the villus. The results confirmed that in the control of capillaries in the human placenta most of the tested substances show a specific action, dose- or time-dependent.     

Action of rat liver cathepsin B on bradykinin and on the oxidized insulin A-chain

Rat liver cathepsin B was tested for its peptide-bond specificity against bradykinin and the oxidized insulin A-chain. Bradykinin was shown to be resistant to the action of cathepsin B. One possible reason for this resistance is the proline content of the peptide and the discrimination against proline residues at three or four subsites of cathepsin B. Oxidized insulin A-chain was degraded by a peptidyl dipeptidase activity. Three dipeptides were cleaved from the C-terminal part of the insulin A-chain after having been incubated for 2 h (molar ration E:S = 1:2800) and six dipeptides were released after a longer digestion (10 h, E:S = 1:575).     

Bradykinin, morphine and naloxone interaction on the sensorimotor cortical neuron level

In experiments on awake rabbits the effect of bradykinin, morphine and naloxone (applied by means of microiontophoresis) on sensomotor cortical neurons was studied. Bradykinin increased the discharge frequency in the majority of neurons. Morphine inhibited the neuronal activity. Bradykinin had no activating effect in the presence of morphine. Naloxone eliminated morphine depressing effect and restored the neuronal reaction to bradykinin. According to the data obtained it is suggested that bradykinin interacts with opiate receptors in the brain.     

Bradykinin suppresses endothelin-induced contraction of coronary artery through its B2-receptor on the endothelium.

Bradykinin (BK), a powerful vasodilating peptide, has been known to be one of the factors regulating vascular contractility mainly through its action on the endothelium. The effects of BK on vascular contraction induced by endothelin-1 (ET-1), a potent vasoconstrictor peptide produced in endothelium, were investigated in vitro using the canine coronary ringed artery. ET-1 at concentrations of 10(-10) to 10(-7) M induced strong and persistent contraction dose-dependently. The ET-1-induced contraction was inhibited by BK at concentrations of 10(-7) and 10(-6) M only in the presence of endothelium. A B1-receptor agonist (des-Arg9-BK) and a B1-receptor antagonist (des-Arg9-[Leu8]-BK) did not affect these effects of BK, whereas a B2-receptor antagonist ([D-Arg0,Hyp3,Thi5,8,D-Phe7]-BK) inhibited the effect of BK on the ET-1-induced contraction. These results indicate that BK may be a potent counter-factor for the ET-1-induced coronary vasoconstriction through its B2-receptors on the endothelium.     

Bradykinin stimulates tumor necrosis factor and interleukin-1 release from macrophages

Bradykinin and related kinins have been implicated in the initiation and maintenance of inflammation. Cytokines appear to be the primary mediators of many inflammatory diseases. The potential ability of bradykinin to stimulate release of tumor necrosis factor and interleukin-1 from macrophages was examined. Bradykinin stimulated release of both cytokines from P388-D1 and RAW264.7 murine macrophages. Studies with selective agonists and antagonists suggest that cytokine release is mediated by a B1 kinin receptor.     

Synergism in cytosolic Ca2+ mobilization between bradykinin and agonists for pertussis toxin-sensitive G-protein-coupled receptors in NG 108-15 cells.

Bradykinin (BK) induced a transient and pertussis toxin (PT)-insensitive increase in cytosolic Ca2+ ([Ca2+]i) in NG 108-15 neuroblastoma x glioma hybrid cells, whereas leucine-enkephalin (EK), somatostatin, norepinephrine or carbachol showed a weak but PT-sensitive action. When any one of the latter agonists was applied to the cells treated with low doses of BK, however, the level of [Ca2+]i rise caused by the agonist was remarkably increased in a PT-sensitive manner. The decreasing of extracellular Ca2+ only slightly influenced the actions of these agonists. Thus, synergism between a BK receptor and PT-sensitive G-protein-coupled receptors results in marked intracellular Ca2+ mobilization by the latter agonists.     

Kallikrein-kinin system in hepatic experimental models

The purpose of this brief review is to describe some characteristics of the kallikrein-kinin system (KKS) in the liver. The liver synthesizes kininogens and prekallikrein and the synthesis of both proteins is increased in rats during the acute phase reaction. It is also the main organ to clear tissue as well as plasma kallikrein from the circulation in normal and pathological conditions. Bradykinin (BK), yielded by the kallikrein-kinin system, is a potent arterial hypotensive peptide, but in the liver it induces a portal hypertensive response. The portal hypertensive action of bradykinin is mediated by B2 receptors located on sinusoidal cells of the periportal region and is followed by its hydrolysis by angiotensin-converting enzyme, which is primarily present in the perivenous (centrolobular) region.