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PubMed1986

Studies of the digestion of bradykinin, Lys-bradykinin, and des-Arg9-bradykinin by angiotensin converting enzyme.

We have studied the degradation of bradykinin, lysyl bradykinin and des-Arg9-bradykinin by the angiotensin converting enzyme. Bradykinin was cleaved at two sites to produce the pentapeptide Arg-Pro-Pro-Gly-Phe plus dipeptides Ser-Pro and Phe-Arg. Lysyl bradykinin was cleaved similarly to release the same dipeptides plus the hexapeptide Lys-Arg-Pro-Pro-Gly-Phe. The tripeptidase activity of ACE was observed when des-Arg9-bradykinin was digested. A single cleavage yielded the above pentapeptide plus Ser-Pro-Phe. Although des-Arg9-bradykinin was the most rapidly digested, when mixtures of des-Arg9-bradykinin and bradykinin or lysyl bradykinin were tested, virtually all of the bradykinin and most of the lysyl bradykinin was digested prior to the onset of digestion of des-Arg9-bradykinin. This was shown to be due to inhibition of des-Arg9-bradykinin cleavage by kinins and kinin-degradation products. The order in terms of potency was bradykinin greater than lysyl bradykinin greater than Ser-Pro much greater than Phe-Arg greater than Arg-Pro-Pro-Gly-Phe. The concentration of chloride ion was an important parameter which affected the rate of digestion of each substrate examined. des-Arg9-bradykinin was not digested by ACE in the absence of sodium chloride and the rate of digestion increased as the chloride concentration was increased to 100-150 mM. On the other hand, increasing NaCl concentration was inhibitory for bradykinin digestion. The rate of Lys-bradykinin digestion was increased from 0 to 1 mM NaCl and decreased thereafter up to physiologic concentration. A half-maximal rate was seen at 100-150 mM NaCl compared to no salt. Of the divalent cations examined, cupric ion inhibited further digestion of des-Arg9-bradykinin at physiologic concentrations. Our data indicate that the rate of degradation of kinins and the nature of the stable final cleavage products in plasma or serum (studied in vitro) are dependent upon the effects of chloride ion, metal ions, and the kinetic effects of multiple metabolites produced by at least two kininases.

Bradykinin↗

PubMed1997

Bradykinin-induced knee joint incapacitation involves bradykinin B2 receptor mediated hyperalgesia and bradykinin B1 receptor-mediated nociception.

The participation of B1 and B2 types of bradykinin receptors was studied in the rat knee-joint incapacitation test. Five intra-articular successive hourly administrations of bradykinin produced progressive incapacitation, thus indicating that bradykinin induced sensitization to its own nociceptive effect. Four co-injections of bradykinin with the bradykinin B1 receptor antagonist des-Arg9-[Leu8]bradykinin were without nociceptive effect. However, a 5th injection of bradykinin alone produced intense incapacitation. The bradykinin B2 receptor antagonist HOE-140 ([D-Arg)[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), or indomethacin, prevented the bradykinin-induced incapacitation. However, successive co-injections of bradykinin with prostaglandin E2, in contrast to bradykinin alone, did induce incapacitation in animals pretreated with indomethacin or HOE-140. The injection of the bradykinin B1 receptor agonist des-Arg9-bradykinin into prostaglandin E2-treated joints did induce incapacitation, although administration of the bradykinin B1 receptor agonist or prostaglandin E2 alone did not induce incapacitation. In conclusion, in ongoing articular inflammation, it is suggested that the bradykinin B1 receptor is particularly involved with nociceptor activation, while the bradykinin B2 receptor is related to nociceptor sensitization.

Animals↗

PubMed1990

[Hyp3]-bradykinin and [Hyp3]-Lys-bradykinin interact with B2-bradykinin receptors and stimulate inositol phosphate production in cultured human fibroblasts.

The recently isolated, naturally occurring peptide hormones [Hyp3]-bradykinin and [Hyp3]-Lys-bradykinin were investigated for their agonist activity on solubilized binding sites from human fibroblasts. Both ligands competed with [3H]bradykinin binding in a dose-dependent fashion with potencies similar to bradykinin (BK) and Lys-BK. Biological activity was assessed by determination of inositol phosphate accumulation and cyclic 3',5'-adenosine monophosphate synthesis in intact cultured cells. Stimulation by the hydroxylated peptides resulted in a pronounced accumulation of both parameters with similar effectiveness as BK and Lys-BK. These results indicate that [Hyp3]-BK and [Hyp3]-Lys-BK are agonists at the bradykinin receptor system with properties comparable to their non-hydroxylated analogues. This suggests that hydroxylation of kinins does not alter receptor interaction or signal transduction in cultured human fibroblasts.

Bradykinin↗

PubMed1988

Effect of des arginine9-bradykinin and other bradykinin fragments on the synthesis of prostacyclin and the binding of bradykinin by vascular cells in culture.

Bradykinin (BK) fragments, des arg1-BK, des arg1,pro2-BK, des phe8,arg9-BK and des pro7,phe8,arg9-BK were synthesized and along with des arginine9-BK (daBK), tested for their ability to induce prostacyclin synthesis in homogeneous cultures of cells from the calf pulmonary artery. Of the fragments daBK was the only peptide, in addition to bradykinin (BK), to activate the synthesis of prostacyclin (PGI2) and platelet activating factor (PAF) in endothelial cells and PGI2 in fibroblasts and smooth muscle cells. Half-maximal activation of PGI2 synthesis differed with the cell type. The other fragments tested did not directly affect PGI2 synthesis. These fragments also did not inhibit daBK or BK activation of PG synthesis. BK bound to endothelial cells with a dissociation constant (Kd) of 2.1 nM and a Bmax of 47.9 fmoles/10(6) cells. The Kd for the binding of BK to smooth muscle cells and fibroblasts was somewhat higher, 4.9 nM and 7.9 nM, respectively. None of the fragments tested, including daBK, altered the binding of BK. Des arg9[leu8]-BK, reported to be a competitive antagonist of the bradykinin B1 receptor, inhibited daBK induced PG of PAF synthesis in endothelial cells but had little effect of BK binding or BK induced PG synthesis. Finally, the BK antagonist [thi5,8, d-phe7]-BK blocked both BK binding and the ability of either BK or daBK to induce PG synthesis, thus substantiating that the binding of these kinins is a step in the activation of PG synthesis.

Bradykinin↗

PubMed1991

Effects of bradykinin and bradykinin analogs on the opossum lower esophageal sphincter: characterization of an inhibitory bradykinin receptor.

Bradykinin (BK) caused the circular muscle of opossum lower esophageal sphincter to relax and then contract in vitro. The effects of BK were not modified by indomethacin, tetrodotoxin, omega-conotoxin, atropine, propranolol, phentolamine, haloperidol, methysergide, pyrilamine or cimetidine. Apamin but not tetraethylammonium antagonized the inhibitory effect of BK and nifedipine antagonized its excitatory effect. Structure-activity relationships of 10 BK analogs known to be active on BK receptors were studied. Six analogs had distinct excitatory response profile and the rank order of potency of these agonists according to pD2 (shown in parentheses) was D-Arg-[Hyp3Thi5,8D-Phe7]-BK (6.49 +/- 0.19) greater than [Thi5,8D-Phe7]-BK (5.61 +/- 0.26) greater than Lys-Lys-[Hyp3-Thi5,8D-Phe7]-BK (5.45 +/- 0.14) greater than BK (5.16 +/- 0.20) greater than [des-Arg9]-BK (4.95 +/- 0.08) greater than [D-Phe7]-BK (4.73 +/- 0.10). However, only BK was fully efficacious (100%) and Emax values of all the analogs were less than that of BK. On the inhibitory response BK was the only agonist (pD2 = 5.48 +/- 0.08) and none of the BK analogs were agonist. All the BK analogs were also inactive as antagonists except Lys-Lys-[Hyp3-Thi5,8D-Phe7]-BK and Lys-Lys-[Hyp2,3-Thi5,8D-Phe7]-BK which competitively and selectively antagonized the BK inhibitory response. The pA2 value of Lys-Lys-[Hyp3-Thi5,8D-Phe7]-BK was 6.92 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Bradykinin receptor localization and cell signaling pathways used by bradykinin in the regulation of gonadotropin-releasing hormone secretion.

In a previous publication we provided evidence of a novel neuronal pathway for the control of GnRH secretion by bradykinin. The action of bradykinin appeared to be exerted through the bradykinin B2 receptor. In this study we demonstrated that the bradykinin B2 receptor is densely localized in the arcuate nucleus, median eminence, organum vasculosum of the lamina terminalis, and preoptic area, regions known to be critical for the control of GnRH secretion. To determine the mechanism of action of bradykinin in stimulating GnRH release, we used immortalized GnRH (GT1-7) cells in vitro. Bradykinin stimulation of GnRH secretion from GT1-7 cells appears to involve activation of the phospholipase C signaling pathway and mobilization of extracellular and intracellular calcium stores. Evidence to support this contention was derived from the observations that incubation of the phospholipase C inhibitor, U-73122 with bradykinin, blocked the ability of bradykinin to stimulate release from GT1-7 cells. This effect was specific, as a nitric oxide synthase inhibitor and a cyclooxygenase inhibitor were found to have no effect on bradykinin-induced GnRH secretion, suggesting that nitric oxide and PGs do not mediate bradykinin effects. Pertussis toxin also had no effect on bradykinin action. This suggests that the bradykinin B2 receptor may be coupled to a pertussis toxin-insensitive G protein in GT1-7 cells. With respect to calcium involvement in bradykinin action, fura-2 calcium indicator studies revealed that bradykinin can rapidly increase intracellular Ca2+ levels in GT1-7 cells. A role for intracellular Ca2+ in bradykinin action was further suggested by the finding that an intracellular calcium chelator, 1,2-bis(O-aminophenoxy)]ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, significantly attenuated the effects of bradykinin on GnRH release. The elevation of intracellular calcium by bradykinin appears to be due to mobilization of calcium from the endoplasmic reticulum, as incubation of the Ca2+-adenosine triphosphatase inhibitor thapsigarin, which depletes endoplasmic reticulum Ca2+ stores, significantly attenuated bradykinin action on GnRH release. Extracellular calcium may also be involved in bradykinin action, as the L-type Ca2+ channel blockers verapamil and nifedipine had no effect on bradykinin-induced GnRH release, whereas the nonselective Ca2+ channel blocker, nickel chloride, attenuated bradykinin-induced GnRH release. Taken as a whole, these studies demonstrate that the bradykinin B2 receptor is densely localized in key hypothalamic nuclei responsible for regulation of GnRH release, and that the mechanism of bradykinin stimulation of GnRH secretion involves activation of the phospholipase C signaling pathway, with a critical role implicated for calcium in bradykinin action in GT1-7 cells.

Animals↗

PubMed1984

Activation of protein formation and cell division by bradykinin and des-Arg9-bradykinin.

We employed des-Arg9-bradykinin to investigate the relation between bradykinin-induced prostaglandin (PG) synthesis and bradykinin-induced protein accumulation. In this feedback control system, bradykinin-induced PG synthesis limits bradykinin-induced protein production. At low concentration (5 X 10(-8) M), des-Arg9-bradykinin was significantly less active than bradykinin in stimulating the formation of prostaglandins by human fetal lung fibroblasts in culture. At high concentration (5 X 10(-6) M), bradykinin induced a 24% increase in protein formation, while des-Arg9-bradykinin induced a 61% increase in collagen formation and an 80% increase in total protein accumulation. In the presence of indomethacin, bradykinin-induced protein formation was increased further, whereas des-Arg9-bradykinin-induced protein formation was unchanged. The bradykinin derivative increased the production of types I and III procollagens without affecting the distribution of procollagen types. The incorporation of [3H]thymidine into DNA in lung fibroblast cultures was increased 3-fold by des-Arg9-bradykinin alone or by bradykinin in combination with indomethacin. Des-Arg9-[Leu8]bradykinin inhibited the des-Arg9-bradykinin-induced protein formation and cell division. These data indicate that both bradykinin and des-Arg9-bradykinin stimulate protein formation and cell division; des-Arg9-bradykinin alone stimulates protein formation and cell division without activating PG synthesis and PG feedback control.

Arachidonic Acid↗

PubMed1998

Biphasic response to bradykinin in isolated porcine iliac arteries is mediated by bradykinin B1 and B2 receptors.

Bradykinin-induced responses were studied in isolated porcine iliac arteries. Relaxation was endothelium dependent and seen at low concentrations (10(-10)-10(-8) M) of bradykinin. It was inhibited by the bradykinin B2-receptor antagonist icatibant (HOE-140) and by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. Bradykinin-induced relaxation was significantly potentiated by the kininase I carboxypeptidase inhibitor mergepta (10(-6) M). Bradykinin (>10(-7) M) elicited contraction of preparations with or without endothelium. The contraction was abolished by indomethacin but was not affected by the thromboxane A2/prostaglandin H2-receptor antagonist SQ 29,548. Icatibant and the bradykinin B1-receptor antagonist desArg9[Leu8]bradykinin significantly decreased bradykinin-induced contraction regardless of endothelial function. The contraction also was decreased by treatment with mergepta. The bradykinin B1-receptor agonist desArg9-bradykinin contracted endothelium-denuded arterial strips. This contraction was significantly decreased by desArg9[Leu8]bradykinin but not by icatibant. The desArg9-bradykinin-induced contraction also was inhibited by the protein-synthesis inhibitor cycloheximide. Neither bradykinin-induced relaxation nor contraction was affected by the ACE inhibitors enalaprilat or cilazaprilat. In conclusion, bradykinin-induced relaxation of isolated porcine iliac arteries was mediated by endothelial bradykinin B2 receptors and mainly nitric oxide. Bradykinin-induced contraction was endothelium independent, indomethacin sensitive, and probably mediated by bradykinin B1 (inducible) and B2 receptors located in the vascular smooth-muscle layer. Kininase I carboxypeptidase, and not ACE, is the main enzyme responsible for bradykinin degradation in these vessels.

3-Mercaptopropionic Acid↗

PubMed2006

Bradykinin and its metabolite bradykinin 1-5 inhibit thrombin-induced platelet aggregation in humans.

Bradykinin 1-5 is a major stable metabolite of bradykinin, formed by the proteolytic action of angiotensin-converting enzyme. In vitro and animal studies suggest that bradykinin 1-5 possesses biological activity. This study tests the hypothesis that bradykinin 1-5 affects vasodilation, fibrinolysis, or platelet aggregation in humans. Graded doses of bradykinin (47-377 pmol/min) and bradykinin 1-5 (47-18,850 pmol/min) were infused in the brachial artery in random order in 36 healthy subjects. Forearm blood flow (FBF) was measured, and simultaneously obtained venous and arterial plasma samples were analyzed for tissue plasminogen activator (t-PA) antigen. In seven subjects each, alpha- and gamma-thrombin-induced platelet aggregation was measured in platelet-rich plasma obtained from antecubital venous blood at baseline and during peptide infusions. Bradykinin caused dose-dependent increases in FBF and net t-PA release (P < 0.001 for both). Bradykinin 1-5 did not affect FBF (P = 0.13) or net t-PA release (P = 0.46) at concentrations >1500 times physiologic. In contrast, both bradykinin and bradykinin 1-5 inhibited alpha-and gamma-thrombin-induced platelet aggregation (P < 0.01 versus baseline). Bradykinin 1-5 inhibited gamma-thrombin-induced platelet aggregation 50% at a calculated dose of 183 +/- 3 pmol/min. Neither bradykinin nor bradykinin 1-5 affected thrombin receptor-activating peptide-induced platelet aggregation, consistent with the hypothesis that bradykinin and bradykinin 1-5 inhibit thrombin-induced platelet aggregation by preventing cleavage of the thrombin receptor and liberation of thrombin receptor-activating peptide. This study is the first to demonstrate biological activity of bradykinin 1-5 following in vivo administration to humans. By inhibiting thrombin-induced platelet aggregation without causing vasodilation, bradykinin 1-5 may provide a model for small molecule substrate-selective thrombin inhibitors.

Adult↗

PubMed1998

Bradykinin B2-receptor-mediated positive chronotropic effect of bradykinin in isolated rat atria.

The positive chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35+/-4 beats/min, approximately 25% of the 1 microM isoprenaline-induced maximal responses. In contrast, the active metabolite of bradykinin and selective bradykinin B1-receptor agonist, Des-Arg9-bradykinin, did not influence the spontaneous frequency of beating. Propranolol (1 microM) combined with prazosin (1 microM) did not affect the positive chronotropic effect of bradykinin. A selective bradykinin B2-receptor antagonist, Hoe 140, concentration-dependently shifted the response curves for bradykinin to the right, whereas the bradykinin B1-receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin had no effect. The tachycardic responses to bradykinin were potentiated by ramipril, an angiotensin-converting enzyme/kininase II inhibitor, but not affected by Nomega-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthesis inhibitor. Indomethacin and meclofenamate, two cyclooxygenase inhibitors, abolished the bradykinin-induced chronotropic effect. These results indicate that exogenous bradykinin induces a positive chronotropic effect that occurs independent of adrenoceptors. The bradykinin-induced chronotropic effect is mediated by bradykinin B2 receptors, whereas B1 receptors do not play a role in mediating this effect. Prostaglandins but not nitric oxide appear to be involved in bradykinin-induced positive chronotropic effect.

Animals↗

PubMed1992

Characterization of bradykinin B2 receptors on human IMR-90 lung fibroblasts: stimulation of 45Ca2+ efflux by D-Phe substituted bradykinin analogues.

[3H]Bradykinin binds to intact human IMR-90 fetal lung fibroblasts in a time and dose-dependent manner. Binding equilibrium was attained by 120 minutes at 4 degrees C. [3H]Bradykinin binding was saturable; Scatchard analysis of saturation binding data demonstrated a single binding site having a KD = 1.8 +/- 0.2 nM and a receptor concentration of 17.4 +/- 4.0 fmol/10(5) cells. The calculated value for KD(k-1/k1) from the association (k1 = 4.71 x 10(6) mol-1 min-1) and dissociation (k-1 = 1.13 x 10(-2) min-1) rate constants was 2.4 nM. The rank order of potency observed for bradykinin peptide agonists, bradykinin > Lys-bradykinin > Met,Lys-bradykinin > Ile,Ser-bradykinin >> des-Arg9-bradykinin, is consistent with that of a bradykinin B2 receptor. Bradykinin stimulated efflux of 45Ca2+ from IMR-90 cells dose dependently with an EC50 = 331 +/- 50 pM. 45Ca2+ efflux was also demonstrated with Lys-bradykinin and Met-Lys-bradykinin but not by des-Arg10-kallidin (100 nM) or NKA (1 microM). Hoe-140 inhibited bradykinin-induced 45Ca2+ efflux (IC50 = 3 +/- 2 nM). D-Phe7-substituted bradykinin analogues stimulated 45Ca2+ efflux dose dependently and this stimulation of 45Ca2+ efflux was inhibited by Hoe-140. These results suggest that D-Phe7 substituted bradykinin analogues are agonists at the bradykinin B2 receptor in IMR-90 cells.

Bradykinin↗

PubMed2006

Bradykinin modulates pacemaker currents through bradykinin B2 receptors in cultured interstitial cells of Cajal from the murine small intestine.

We studied the modulation of pacemaker activities by bradykinin in cultured interstitial cells of Cajal (ICC) from murine small intestine with the whole-cell patch-clamp technique. Externally applied bradykinin produced membrane depolarization in the current-clamp mode and increased tonic inward pacemaker currents in the voltage-clamp mode. Pretreatment with bradykinin B1 antagonist did not block the bradykinin-induced effects on pacemaker currents. However, pretreatment with bradykinin B2 antagonist selectively blocked the bradykinin-induced effects. Also, only externally applied selective bradykinin B2 receptor agonist produced tonic inward pacemaker currents and ICC revealed a colocalization of the bradykinin B2 receptor and c-kit immunoreactivities, but bradykinin B1 receptors did not localize in ICC. External Na(+)-free solution abolished the generation of pacemaker currents and inhibited the bradykinin-induced tonic inward current. However, a Cl(-) channel blocker (DIDS) did not block the bradykinin-induced tonic inward current. The pretreatment with Ca(2+)-free solution and thapsigargin, a Ca(2+)-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker currents and suppressed the bradykinin-induced action. Chelerythrine and calphostin C, protein kinase C inhibitors or naproxen, an inhibitor of cyclooxygenase, did not block the bradykinin-induced effects on pacemaker currents. These results suggest that bradykinin modulates the pacemaker activities through bradykinin B2 receptor activation in ICC by external Ca(2+) influx and internal Ca(2+) release via protein kinase C- or cyclooxygenase-independent mechanism. Therefore, the ICC are targets for bradykinin and their interaction can affect intestinal motility.

Animals↗

PubMed1977

The effects of bradykinin and the bradykinin potentiating peptide BPP5a on the electrical and mechanical responses of the guinea-pig taenia coli.

1 By means of the double sucrose-gap technique, the effects of bradykinin and the bradykinin potentiating peptide BPP(5a) were compared on the guinea-pig taenia coli under a number of experimental conditions.2 In normal Krebs solution the response to bradykinin was mostly a slight stimulation, characterized by a depolarization, an increase in spontaneous spike activity and a contraction. If BPP(5a) caused any effect at all, it was stimulation of the spike activity but without depolarization. Since the effect of bradykinin was little affected by an increase in dose, a potentiating effect of BPP(5a) could not be determined.3 Spontaneous spikes with a 5 to 7 s rhythm and prepotentials at their base were inhibited by bradykinin, whereas they were stimulated by BPP(5a).4 Oscillatory potentials (slow waves) induced by a calcium and magnesium-free medium were also suppressed by bradykinin and stimulated by BPP(5a). This effect of bradykinin was accompanied by a depolarization and a decrease in membrane resistance, phenomena not found after administration of BPP(5a).5 The amplitude of spontaneous spikes induced by potassium-depolarization was suppressed by bradykinin, even though the membrane resistance and potential had been decreased. BPP(5a) produced either no effect or a small stimulatory effect without influencing the membrane resistance.6 Reduction of the calcium concentration to 0.25 mM enhanced the stimulatory responses to both bradykinin and BPP(5a), especially the spike activity and depolarization. In this case the membrane resistance was increased by bradykinin as well as BPP(5a). These effects, especially those of BPP(5a), were inhibited by reduction of the sodium concentration to 15.5 mM. Reduction of the chloride concentration to 9.7 mM decreased rather than increased the stimulatory effects of both bradykinin and BPP(5a). Under these conditions bradykinin did not decrease the membrane resistance.7 Bradykinin can have both inhibitory and stimulatory effects on the taenia coli whereas BPP(5a) has only a stimulatory effect. Since under certain conditions both responses to bradykinin are accompanied by a sodium-dependent depolarization and decrease in membrane resistance, not influenced by lanthanum to any extent, it is suggested that bradykinin induces an increase in sodium conductance of the membrane. Under all the conditions investigated, except in low calcium, BPP(5a) did not affect the membrane potential and resistance. Thus, the underlying cause of its stimulatory effect is probably different from that of bradykinin.

Animals↗

PubMed1995

Bradykinin B2 receptor-mediated chronotropic effect of bradykinin in isolated guinea pig atria.

The present study was undertaken to characterize the direct chronotropic effect of bradykinin in isolated spontaneously beating atria of the guinea pig. Bradykinin caused concentration-dependent increases in the beating rate of atria. In contrast, the active metabolite of bradykinin and the typical bradykinin B1 receptor agonist, Des-Arg9-bradykinin, had no effect on the beating rate of atria. Inhibition of converting enzyme or neutral endopeptidase by captopril or SQ-28603, respectively, did not affect beating rate but potentiated bradykinin-induced increase in beating rate. The potent bradykinin B2 receptor antagonist, HOE 140, antagonized bradykinin-induced chronotropic effect. In contrast, the bradykinin B1 receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin, had no effect. The increase in beating rate caused by bradykinin was not affected by blockade of beta 1-adrenoceptors, cyclooxygenase, or nitric oxide synthesis using atenolol, indomethacin and N omega-nitro-L-arginine, respectively. Unlike bradykinin, angiotensin I and angiotensin II caused very small or no change in beating rate in the presence or absence of captopril and SQ-28603. These results indicate that bradykinin causes a direct positive chronotropic effect which is mediated by activation of bradykinin B2 receptors independently of prostaglandins and beta 1-adrenoceptors.

Adrenergic beta-Agonists↗

PubMed1994

Bradykinin inhibits adenylate cyclase activity in guinea pig ileum membranes via a separate high-affinity bradykinin B2 receptor.

In guinea pig ileum membranes, the pre-stimulated adenylate cyclase activity was dose-dependently inhibited by picomolar concentrations of bradykinin exhibiting an apparent IC50 value of approximately 30 pM. At nanomolar bradykinin concentrations (> 1 nM) this effect was attenuated. The inhibition of ileal adenylate cyclase was completely prevented by both the bradykinin B2 receptor antagonist Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) and pertussis toxin. The potency of bradykinin to inhibit ileal adenylate cyclase considerably correlates with a binding site with picomolar affinity for bradykinin. In addition, a second site was constantly found displaying nanomolar binding affinity for bradykinin. The occurrence of two independent bradykinin B2 receptors in guinea pig ileum membranes is further supported by three other lines of evidence: bradykinin stimulates [35S]GTP[S] (guanosine 5'-O-[3-thiotriphosphate]) binding to guinea pig ileum membranes in a biphasic manner with EC50 values which correspond to the affinities of both sites. In binding studies, the high-affinity site cannot be transformed into the low-affinity site in the presence of Gpp[NH]p (5'-guanylylimidodiphosphate). The specific binding of [3H]bradykinin to guinea pig ileum membranes was also biphasically inhibited by increasing concentrations of Gpp[NH]p. Thus, our results favour the existence of two separate bradykinin B2 receptors with different signal transduction pathways in guinea pig ileum membranes: one receptor with picomolar affinity for bradykinin which inhibits adenylate cyclase via a pertussis toxin-sensitive G protein of probably the Gi2 type and the other receptor with nanomolar affinity for bradykinin which might be responsible for bradykinin-induced stimulation of phosphoinositide hydrolysis.

Adenylate Cyclase Toxin↗

PubMed1994

Effects of the agents affecting cyclic nucleotide metabolism on the bradykinin- and des-Arg9-bradykinin-induced relaxations and contractions in isolated rat duodenum.

1. Bradykinin and related kinins possess two different types of action (consisting of relaxation and contraction) in the isolated rat duodenum via their specific receptors. However, the mechanisms of these actions have not been fully elucidated. The present study was undertaken to investigate the effects of the agents affecting cyclic nucleotide metabolism on bradykinin-induced relaxations and on bradykinin- and des-Arg9-bradykinin-induced contractions. 2. Des-Arg9-bradykinin, B1 receptor agonist, and high concentrations of bradykinin elicited dose-dependent contractile responses in the rat duodenum, while low concentrations of bradykinin caused a dose-dependent relaxation in this tissue. 3. Nicotinic acid, an inhibitor of adenylate cyclase, inhibited the relaxation of rat duodenum induced by bradykinin at low concentrations in a non-competitive manner. However, the inhibitory efficacy of nicotinic acid against bradykinin was limited by 39.9% and this inhibition was not further increased by higher concentrations of nicotinic acid up to 10(-3) M. 4. Imidazole, an activator of cyclic nucleotide phosphodiesterase, caused a slight inhibition of the relaxant responses to low concentrations of bradykinin and of the contractile responses to des-Arg9-bradykinin and high concentrations of bradykinin in isolated rat duodenum. These inhibitions were also limited in efficacies and not increased by higher concentrations of imidazole. 5. Methylene blue, an agent that inhibits soluble guanylate cyclase, suppressed the contractions of rat duodenum induced by des-Arg9-bradykinin and high concentrations of bradykinin in a non-competitive manner. Again, these inhibitions were limited and further increase in the inhibitory efficacy was not observed in spite of increasing the methylene blue concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Effects of bradykinin receptor antagonist on the release of beta-endorphin and bradykinin and on hemodynamic changes in a canine model of experimental acute pancreatitis.

Bradykinin and beta-endorphin increases during acute pancreatitis are thought to contribute to the development of hypotension and myocardial depression in acute pancreatitis. beta-Endorphin release is mediated by trypsin-like enzymes and bradykinin from the pituitary gland. This study was undertaken to investigate the effect of a long-acting bradykinin receptor antagonist on bradykinin and beta-endorphin release and on hemodynamic changes during acute pancreatitis. Pancreatitis was induced by the injection of autologous bile mixed with trypsin into the main pancreatic duct after ligation of the accessory duct. Serum bradykinin and plasma beta-endorphin levels and cardiovascular function were measured. Twelve dogs (control group) were given 10 ml/kg/h of lactate Ringer's solution intravenously beginning 1 h before the induction of pancreatitis and continuing throughout the experiments. Six dogs received an intravenous infusion of 0.6 mg/kg/h of a new bradykinin receptor antagonist, HOE 140, D-Arg-[Hyp3, Thi5, D-Tic, Oic8]-bradykinin, in lactate Ringer's solution soon after the induction of pancreatitis. Six of twelve dogs in the control group, and none of the six dogs in the bradykinin receptor antagonist group, died during the experiments. Serum bradykinin levels in both groups increased until 1 h after the induction of pancreatitis, but thereafter the levels in the bradykinin receptor antagonist group decreased gradually until 5 h after induction, and levels were significantly lower than those in the control group (p < 0.05). Plasma beta-endorphin levels in the control group increased significantly, to 291.8 pg/ml (+/- 6.6 SEM) 5 h after the induction of pancreatitis, from the mean levels of 47.8 pg/ml before the induction of pancreatitis, while the mean beta-endorphin level in the bradykinin receptor antagonist group did not increase after the induction of pancreatitis. Infusion of the bradykinin receptor antagonist improved survival rates, hypotension, myocardial depression, and plasma lactate, suggesting that the bradykinin receptor antagonist inhibited the release of bradykinin and beta-endorphin, which contributed to the clinical improvement.

Acute Disease↗

PubMed1987

Bradykinin receptor antagonists used to characterize the heterogeneity of bradykinin-induced responses in rat vas deferens.

The application of bradykinin to the isolated, transmurally stimulated rat vas deferens caused two effects: increase of the basal tension of the tissue and potentiation of the magnitude of electrically driven twitches. These bradykinin responses were not evenly distributed along the ductus. The direct contractile action of bradykinin was found to be stronger in the epididymal half of the tissue while the potentiation of the muscle twitches was more pronounced in the prostatic half of the rat ductus. Bradykinin is more potent to potentiate the electrically driven twitches than to act as a postjunctional agonist. Tyr-bradykinin, [Tyr5]bradykinin and [Tyr8]bradykinin exhibited significant differences in the potency ratio to produce each of these responses. [Thi5,8,D-Phe7]bradykinin is a weak postjunctional agonist but was a full agonist to potentiate the electrically induced twitches. Furthermore, this compound antagonized the bradykinin-induced contractions. [Hyp3,Thi5,8,D-Phe7]bradykinin was devoid of agonist activity at either pre- or postjunctional sites; it behaved as a pure antagonist and was more than potent its non-hydroxylated analog. The addition of a D-Arg residue at the amino terminal increased the antagonist potency significantly. The pA2 of D-Arg-[Hyp3,Thi5,8,D-Phe7]bradykinin to antagonize the postjunctional effect of bradykinin was 6.35, a value that differed significantly from the value of 6.93 required to block the prejunctional effect of the peptide. The bradykinin receptor antagonists did not modify significantly the magnitude of the contractile responses caused by angiotensin II, norepinephrine or 5-hydroxy-tryptamine.

Animals↗