Bradykinin-induced Plasma Extravasation Research Articles

Involvement of the TRPV1 receptor in plasma extravasation in airways of rats treated with an angiotensin-converting enzyme inhibitor

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in the treatment of hypertension, congestive heart failure and renal disease, and are considered relatively safe and generally well-tolerated drugs. However, adverse effects of ACEIs have been reported, including non-productive cough and angioedema, which can lead to poor adherence to therapy. The mechanisms by which ACEIs promote adverse effects are not fully elucidated, although increased bradykinin plasma levels following ACEI therapy seem to play an important role. Since bradykinin can sensitise the transient potential vanilloid receptor 1 (TRPV1), we investigated the role of TRPV1 in plasma extravasation in the trachea and bronchi of rats treated with the ACEI captopril. We observed that intravenous (i.v.) administration of captopril did not cause plasma extravasation in the trachea or bronchi of spontaneously breathing rats, but induced plasma extravasation in the trachea and bronchi of artificially ventilated rats. The intratracheal (i.t.) instillation of capsaicin or bradykinin also induced an increase in plasma extravasation in the trachea and bronchi of artificially ventilated rats. As expected, capsaicin-induced plasma extravasation was inhibited by i.t. pretreatment with the TRPV1 selective antagonist capsazepine (CPZ) while bradykinin-induced plasma extravasation was reduced by i.t. pretreatment with the selective B2 receptor antagonist Icatibant, originally known as HOE 140 (HOE). Interestingly, bradykinin-induced plasma extravasation was also inhibited by CPZ. The pretreatment with HOE and CPZ, singly or in combination and at doses which do not cause inhibitory effects per se, significantly inhibited the plasma extravasation induced by captopril treatment in artificially ventilated rats. In addition, treatment with a high dose of capsaicin in newborn rats, which induces degeneration of TRPV1-expressing sensory neurons, abolished both capsaicin and captopril-induced plasma extravasation in artificially ventilated rats. In conclusion, our study identified that captopril treatment promoted sensitisation of TRPV1, via B2 receptor activation, inducing plasma extravasation in the airways of mechanically ventilated rats. The present findings add a new view about the role of TRPV1 in the plasma extravasation induced by captopril and could to contribute to the elucidation of mechanisms by which ACEI induces adverse effects on airways.

Acute inflammation in the joint: Its control by the sympathetic nervous system and by neuroendocrine systems

Inflammation of tissues is under neural control involving neuroendocrine, sympathetic and central nervous systems. Here we used the acute experimental inflammatory model of bradykinin-induced plasma extravasation (BK-induced PE) of the rat knee joint to investigate the neural and neuroendocrine components controlling this inflammation. 1. BK-induced PE is largely dependent on the sympathetic innervation of the synovium, but not on activity in these neurons and not on release of norepinephrine. 2. BK-induced PE is under the control of the hypothalamo-pituitary-adrenal (HPA) system and the sympatho-adrenal (SA) system, activation of both leading to depression of BK-induced PE. The inhibitory effect of the HPA system is mediated by corticosterone and dependent on the sympathetic innervation of the synovium. The inhibitory effect of the SA system is mediated by epinephrine and β2-adrenoceptors. 3. BK-induced PE is inhibited during noxious stimulation of somatic or visceral tissues and is mediated by the neuroendocrine systems. The nociceptive-neuroendocrine reflex circuits are (for the SA system) spinal and spino-bulbo-spinal. 4. The nociceptive-neuroendocrine reflex circuits controlling BK-induced PE are under powerful inhibitory control of vagal afferent neurons innervating the defense line (connected to the gut-associated lymphoid tissue) of the gastrointestinal tract. This inhibitory link between the visceral defense line and the central mechanisms controlling inflammatory mechanisms in body tissues serves to co-ordinate protective defensive mechanisms of the body. 5. The circuits of the nociceptive-neuroendocrine reflexes are under control of the forebrain. In this way, the defensive mechanisms of inflammation in the body are co-ordinated, optimized, terminated as appropriate, and adapted to the behavior of the organism.

Receptor mediation and nociceptin inhibition of bradykinin-induced plasma extravasation in the knee joint of the rat

Objective and designThe aim was to investigate the signaling mechanisms and regulation of bradykinin (BK)-induced inflammation in rat knee joint.Materials and methodsKnee joints of anesthetized rats were perfused with BK (0.1–1.0 μM), and synovial plasma extravasation (PE) was evaluated by spectrophotometrical measurement of Evans Blue leakage. To examine the signaling pathway, B1 antagonist [des-Arg10]-HOE140 (0.1–1.0 μM) and B2 antagonist HOE140 (0.05–1.0 μM), calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 (0.5–1.0 μM), prostaglandin E2 antagonist AH-6809 (0.1–1.0 μM), and histamine H1 antagonist mepyramine (0.1–1.0 μM) were used. Nociceptin (0.0001–1.0 μM) and antagonist J-113397 were tested for modulation of BK-induced PE. The analyses were compared side-by-side with 5-hydroxytryptamine-induced PE.ResultsBK perfusion dose-dependently induced PE, which was blocked by HOE140, CGRP8-37, AH-6809, and mepyramine. It was also inhibited by nociceptin, which could be reversed by antagonist J-113397. In contrast, 5-hydroxytryptamine-induced PE was biphasically regulated by nociceptin and was not antagonized by CGRP8-37.ConclusionsBK-induced PE is mediated by B2 receptors and may involve CGRP, prostaglandin, and histamine pathways. BK-induced PE is inhibited by nociceptin through the activation of ORL1 receptors. There are differences between BK- and 5-hydroxytryptamine-induced inflammation in signaling and modulation.

Sexual dimorphism in the effect of nonhabituating stress on neurogenic plasma extravasation

The sympathoadrenal axis contributes to the sexual dimorphism of the inflammatory response. As stress both activates the sympathoadrenal axis and profoundly affects inflammation and inflammatory disease, we evaluated whether stress exerts a sexually dimorphic effect on a major component of the inflammatory response, plasma extravasation. We evaluated the effect of a nonhabituating stress, repeated intermittent sound (30 min/day for 4 days), on neurogenic synovial plasma extravasation, induced by bradykinin in the rat knee joint. Sound stress profoundly inhibited bradykinin-induced plasma extravasation in male rats, but profoundly enhanced it in female rats. These effects took 24 h to fully develop after the last exposure to stress. In gonadectomized males, bradykinin-induced plasma extravasation was lower than intact males, and sound stress now enhanced it, i.e. gonadectomized males were phenotypically like intact females. In gonadectomized females, bradykinin-induced plasma extravasation was greater than in intact adult females, and sound stress still enhanced it. Adrenal enucleation significantly attenuated the effect of sound stress on bradykinin-induced plasma extravasation in both male and female rats. We tested the hypothesis that these effects of sound stress were due to sustained enhanced plasma levels of stress hormones. Corticosterone and epinephrine, only when administered in combination, over five days, produced a qualitatively similar effect as sound stress, i.e. bradykinin-induced plasma extravasation was significantly decreased in males and increased in females. These findings suggest that a combined effect of the hypothalamic-pituitary adrenal and sympathoadrenal stress axes are responsible for the marked sexual dimorphism in the effect of stress on the inflammatory response.

Central terminals of nociceptors are targets for nicotine suppression of inflammation

Spinal intrathecal administration of nicotine inhibits bradykinin-induced plasma extravasation, a component of the inflammatory response, in the knee joint of the rat in a dose-related fashion. Nociceptors contain nicotinic receptors and activation of a nociceptor at its peripheral terminal, by capsaicin, also produces inhibition of inflammation. Therefore the aim of this study was to test the hypothesis that the spinal target for this effect of nicotine is the central terminal of the primary afferent nociceptor. Intrathecal administration of the neurokinin-1 receptor antagonist, (3a R,7a R)-7,7-diphenyl-2-(1-imino-2(2-methoxyphenyl)-ethyl) perhydroisoindol-4-1 hydrochloride or the N-methyl- d-aspartate receptor antagonist, dl-2-amino-5-phosphonovaleric acid, both antagonists of the action of primary afferent neurotransmitters, markedly attenuated the inhibition of bradykinin-induced plasma extravasation produced by both intrathecal nicotine and intraplantar capsaicin. Conversely, intrathecal administration of an α-adrenoceptor antagonist, phentolamine or an opioid receptor antagonist, naloxone, to block descending antinociceptive controls, which provide inhibitory input to primary afferent nociceptors, enhanced the action of both nicotine and capsaicin. These findings support the hypothesis that the central terminal of the primary afferent nociceptor is a CNS target at which nicotine acts to inhibit inflammation.

Pro-inflammatory Effect of Quercetin by Dual Blockade of Angiotensin Converting-enzyme and Neutral Endopeptidase In Vivo

The effect of the flavonoid quercetin on substance P- and bradykinin-induced plasma extravasation in rat tissues (duodenum, heart, pancreas, trachea and urinary bladder) was studied, and its modulation by endogenous peptidases. Plasma protein extravasation was assayed by extravasated Evans blue dye. Intravenous injection of substance P (1, 3 and 10 nmol/kg) increased the plasma extravasation in a dose-dependent manner in heart, pancreas, trachea and urinary bladder. Bradykinin (3 and 10 nmol/kg, i.v.) increased plasma extravasation in a dose-dependent manner in duodenum, pancreas, trachea and urinary bladder. Pre-treatment with a selected dose of quercetin potentiated the substance P-induced plasma extravasation in heart, pancreas and urinary bladder, and also the bradykinin-induced plasma extravasation in duodenum, heart, trachea and urinary bladder. The selective pharmacological inhibition of neutral endopeptidase and angiotensin-converting enzyme potentiated the substance P- and bradykinin-induced plasma extravasation, respectively; furthermore, treatment with receptor antagonists showed that the mediators involved in the potentiation of plasma extravasation by quercetin are substance P and bradykinin. Analysis of plasma angiotensin-converting enzyme activity demonstrated that quercetin inhibited this enzyme. These results suggest that quercetin potentiates plasma extravasation induced by substance P and bradykinin, and that this may result from inhibition of the degradative enzymes of these peptides.

Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine.

1. Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of sub-nanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla-derived delta-opioid receptor agonists. 2. While neurogenic plasma extravasation in the knee joint of the rat was not increased by intra-articular perfusion of nicotine (10(-8) M), perfusion of nicotine, at concentrations as low as 10(-10) M, combined with naloxone to block opioid receptors (or naltrindole to block delta-opioid receptors) was able to enhance bradykinin-induced plasma extravasation. This pro-inflammatory effect of intra-articular nicotine was mimicked by subcutaneous nicotine which was abolished by intra-articularly-administered hexamethonium, a nicotinic receptor antagonist. 3. Following denervation of the adrenal medulla, intra-articular nicotine, alone at 10(-8) M, enhanced plasma extravasation, which was no longer enhanced by naloxone. 4. Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin-1 receptor antagonist RP-87,580 abolished the pro-inflammatory effect of nicotine. 5. The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second-hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids.

Nociceptive neuroendocrine negative feedback control of neurogenic inflammation activated by capsaicin in the rat paw: role of the adrenal medulla.

Recently we have found that inhibition of bradykinin-induced synovial plasma extravasation by transcutaneous electrical stimulation at strengths which excite unmyelinated afferent axons is mediated by the hypothalamo-pituitary-adrenal axis. Here we tested whether stimulation of nociceptors in the rat paw by intradermally injected capsaicin inhibits bradykinin-induced synovial plasma extravasation and whether this inhibition is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. Furthermore, we tested whether inhibition of bradykinin-induced plasma extravasation generated by intraperitoneally injected capsaicin, which preferentially excites visceral afferents, is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. We used normal rats, subdiaphragmatically vagotomized rats, rats with denervated adrenal medullae and rats with acutely transected spinal cords at the segmental levels T1/T2 or T12/L1. Injection of capsaicin into the plantar or palmar surface of the paws produced a depression of bradykinin-induced plasma extravasation. The inhibition elicited from the forepaw was larger than that from the hindpaw. The inhibition of bradykinin-induced plasma extravasation elicited from both paws was potentiated by subdiaphragmatic vagotomy. Denervation of the adrenal medullae abolished the inhibitory effect of intradermal capsaicin in vagus-intact and in vagotomized animals. After spinalization at the segmental level T1/T2, capsaicin injected into the forepaw did not depress bradykinin-induced plasma extravasation either in vagus-intact or in vagotomized animals. Capsaicin injected into the hindpaw in these spinalized animals produced a small depression. After spinalization at the segmental level T12/L1 no depression was produced by capsaicin injected into the hindpaw. Depression of bradykinin-induced plasma extravasation generated by intraperitoneal injection of capsaicin in vagus-intact and in vagotomized animals was also abolished or attenuated after denervation of the adrenal medullae. This shows that this depression was also largely dependent on the activation of the sympatho-adrenal system. We conclude that depression of bradykinin-induced plasma extravasation during stimulation of nociceptors by capsaicin is mediated predominantly by the sympathoadrenal pathway. This finding differs from the inhibitory mechanism of depression of bradykinin-induced plasma extravasation generated by cutaneous electrical stimulation, which is mediated by the hypothalamo-pituitary-adrenal axis.

Bradykinin-induced neurogenic migration of neutrophils into the rat knee joint.

This study examined the dependence of neurogenic and non-neurogenic synovial plasma extravasation on neutrophils. Perfusion of bradykinin into the knee joint produced both a rapid increase in the magnitude of plasma extravasation and a significant increase in number of neutrophils in the synovium. Both bradykinin-induced plasma extravasation and neutrophil accumulation were dependent on sympathetic post-ganglionic neuron terminals, since both were blocked in sympathectomized rats. Platelet activating factor, which produces plasma extravasation independent of sympathetic neurons, did not increase the number of neutrophils in the synovium. These findings support the suggestion that bradykinin acts on sympathetic nerve terminals in the knee leading to attraction of neutrophils, which promotes plasma extravasation.

Corrigendum

CorrigendaCorrigendumPublished Online:01 Mar 1998https://doi.org/10.1152/jn.1998.79.3.1aOriginal articleMoreSectionsPDF (31 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Volume 78, September 1997 Pages 1285–1292: F. J.-P. Miao, W. Jänig, P. G. Green, and J. D. Levine, “Inhibition of Bradykinin-Induced Plasma Extravasation Produced by Noxious Cutaneous and Visceral Stimuli and Its Modulation by Vagal Activity.During the correction process Figure 1 was inadvertently replaced by Figure 4. Figure 1 as it should have appeared is shown here:Download figureDownload PowerPoint This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformationRelated articlesInhibition of Bradykinin-Induced Plasma Extravasation Produced by Noxious Cutaneous and Visceral Stimuli and Its Modulation by Vagal Activity 01 Sep 1997Journal of Neurophysiology More from this issue > Volume 79Issue 3March 1998Pages 1a-1a https://doi.org/10.1152/jn.1998.79.3.1aHistory Published online 1 March 1998 Published in print 1 March 1998 Metrics Downloaded 66 times

Modulation of bradykinin-induced mechanical hyperalgesia in the rat by activity in abdominal vagal afferents.

Bradykinin-induced plasma extravasation and mechanical hyperalgesia are sympathetic-dependent components of inflammation. Noxious stimulation has been found to inhibit bradykinin-induced plasma extravasation by activating the hypothalamo-pituitary-adrenal axis. The sensitivity of this nociceptive-neuroendocrine feedback control of inflammation is modulated by activity in subdiaphragmatic vagal afferents. In the present study, we tested the hypothesis that activity in the subdiaphragmatic vagus also modifies bradykinin-induced mechanical hyperalgesia in the rat, using the Randall-Selitto method. Following subdiaphragmatic vagotomy, the baseline paw-withdrawal threshold to mechanical stimulation decreased and bradykinin-induced mechanical hyperalgesia was enhanced. Mechanical hyperalgesia produced by prostaglandin E2, a direct-acting hyperalgesic agent, was not significantly affected by vagotomy. The effect of subdiaphragmatic vagotomy on bradykinin-induced hyperalgesia, but not on baseline paw-withdrawal threshold, was mimicked by coeliac branch vagotomy. Indomethacin blocked the hyperalgesia in normal rats, but not in vagotomized rats, suggesting that bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins, whose role was unexpectedly diminished after vagotomy. Bradykinin-induced hyperalgesia in normal rats was abolished by lumbar sympathectomy but not by sympathetic decentralization (cutting the preganglionic axons). In rats that were both vagotomized and sympathectomized, hyperalgesia induced by low-dose bradykinin was no longer present. These results demonstrate that vagotomy induces a decrease in baseline mechanical paw-withdrawal threshold and an enhancement of bradykinin-induced mechanical hyperalgesia and suggest that these phenomena are generated by actions in peripheral tissues.

Inhibition of bradykinin-induced plasma extravasation produced by noxious cutaneous and visceral stimuli and its modulation by vagal activity.

Intrathecally applied nicotine reduces bradykinin-induced plasma extravasation (BK-induced PE) in the rat knee joint. This depression is mediated by the hypothalamo-pituitary-adrenal (HPA) axis and is enhanced by interruption of impulse traffic in afferents of the abdominal vagus nerve. Like intrathecal nicotine, electrical stimulation of unmyelinated cutaneous fibers also depresses BK-induced PE, which is also dependent on an intact HPA axis. In this study, we investigated whether the inhibitory effect of intrathecal nicotine can be mimicked by noxious stimulation of skin and of viscera. Furthermore we determined whether this depression is potentiated after subdiaphragmatic vagotomy. Stimulation of visceral afferents in the peritoneum, by intraperitoneal capsaicin injection, dose-dependently decreased BK-induced PE. The capsaicin dose-response function was shifted by 1.5-2 orders of magnitude to the left after vagotomy. Stimulation of visceral afferents in the urinary bladder by capsaicin also dose-dependently reduced BK-induced PE, which similarly was potentiated after vagotomy. Transcutaneous stimulation of unmyelinated nociceptive afferents from the plantar skin of the paw depressed BK-induced PE. This depression had a threshold of approximately 0.25 Hz and was maximal at a stimulation frequency of approximately 1 Hz. After subdiaphragmatic vagotomy, the stimulus response function shifted to the left and the inhibition was significantly larger than in control, in the range of 0.125-1 Hz stimulation. These results show that noxious stimulation of skin and viscera depressed BK-induced PE and that such depression was potentiated after subdiaphragmatic vagotomy in a manner similar to that of intrathecally applied nicotine. Based on these observations, we hypothesize that intrathecal nicotine depresses BK-induced PE by exciting spinal nociceptive neurons or the central projections of nociceptive primary afferent neurons.

Vagal branches involved in inhibition of bradykinin-induced synovial plasma extravasation by intrathecal nicotine and noxious stimulation in the rat.

1. Stimulation of cutaneous and spinal visceral nociceptive afferents and intrathecal nicotine reduces bradykinin-induced plasma extravasation (BK-induced PE) in the knee joint of the rat. This depression is mediated by the hypothalamo-pituitary-adrenal (HPA) axis and is potentiated by subdiaphragmatic vagotomy. It is believed that activity in vagal afferents tonically inhibits ascending impulse transmission in the neuraxis projecting to the hypothalamus. Vagotomy, by removing such inhibition, allows greater depression of BK-induced PE. In this study we determined whether the vagal afferents which negatively regulate activities of the HPA axis are present in all branches of the abdominal vagus nerves or only in specific branches. 2. We measured the depression of BK-induced PE elicited by graded stimulation of spinal visceral afferents with intraperitoneal capsaicin and by intrathecal nicotine in vagus-intact rats and in rats in which specific vagal branches were selectively interrupted. (i) Interruption of the coeliac branches mimicked the effect of total subdiaphragmatic vagotomy in potentiating the depression of BK-induced PE generated by intrathecal nicotine and by stimulation of spinal visceral afferents. (ii) Interruption of the gastric and hepatic branches of the abdominal vagus nerves together or individually did not affect the depression of BK-induced PE generated by the two stimuli. 3. These results indicate that afferent activity in coeliac and accessory coeliac vagal branches is involved in the regulation of the nociceptive system-initiated depression of BK-induced PE. The afferent fibres in these vagal branches involved probably monitor physiological events in abdominal visceral organs.

Tachyphylaxis develops to bradykinin-induced plasma extravasation in the rat

Bradykinin, an inflammatory mediator produced from plasma kallikreins, has potent effects on vascular functions, including increasing plasma extravasation and vasodilation. Attenuation in the response (desensitization to maintained exposure or tachyphylaxis to repeated administration) to bradykinin actions on synovial vasculature, a critical variable with respect to the role of bradykinin in sustained or chronic synovial inflammation, has not been elucidated. In the present study, we determined if tachyphylaxis and desensitization for bradykinin-induced plasma extravasation in the knee joint occur. Bradykinin-induced plasma extravasation into the knee joint cavity was determined spectrophotometrically by measuring the concentration of Evans blue dye extravasation into the joint perfusate. To examine for the development of tachyphylaxis, perfusion of bradykinin (160 ng/ml) was repeated after a 40-min wash with normal saline. Continuous intra-articular perfusion of bradykinin produced an increase in plasma extravasation that remained relatively stable with only a small, approximately 15%, decrease over 170 min. On the other hand, the levels of plasma extravasation produced by intermittent perfusion of bradykinin were dramatically lower than that induced by the first exposure (i.e., tachyphylaxis). We conclude that bradykinin-induced plasma extravasation develops marked tachyphylaxis but only minimal desensitization.

Sympathetic-dependence in bradykinin-induced synovial plasma extravasation is dose-related

While previous studies have implicated a role for sympathetic postganglionic neuron-terminals in bradykinin-induced plasma extravasation, a recent report by Cambridge and Brain [Br. J. Pharmacol., 115 (1995) 641–647] has suggested that it is sympathetic-independent. However, the doses of bradykinin used in these two groups of studies were considerably different. Therefore, in the present study, we characterized the sympathetic-dependence of plasma extravasation at varying doses of bradykinin. By measuring the concentration of Evans blue dye extravasation into the joint perfusate following its intravenous injection, bradykinin-induced plasma extravasation in the knee joint cavity was determined spectrophotometrically. To examine the role of sympathetic postganglionic neuron terminals in mediating bradykinin-induced plasma extravasation, we used surgical ablation of the lumbar sympathetic chain. Intra-articular perfusion of BK dose-dependently increased synovial plasma extravasation. After surgical sympathectomy, the dose-response curve for bradykinin-induced plasma extravasation was significantly shifted to the right. We conclude that at concentrations observed in inflamed tissues (between 10 −8 and 10 −7 M), bradykinin-induced plasma extravasation is largely mediated by sympathetic postganglionic neuron terminals.

Halothane selectively inhibits bradykinin-induced synovial plasma extravasation.

In vitro studies demonstrate that halothane, but not isoflurane, inhibits bradykinin-induced calcium currents and prostacyclin release in cultured endothelial cells. Because bradykinin is an important endogenous mediator of inflammation, we assessed the effects of halothane, isoflurane, and pentobarbital on plasma extravasation, a component of tissue inflammation induced by bradykinin, in rats. We anesthetized 23 rats with halothane (0.8 or 1.3 minimum alveolar concentration [MAC]), isoflurane (1.3 MAC), or pentobarbital (total of 85 mg/kg intraperitoneally). Their tracheas were intubated and their lungs mechanically ventilated. After intravenous administration of Evans blue dye, we perfused normal saline followed by bradykinin or platelet-activating factor, another inflammatory mediator, intraarticularly via needles placed in the knee joint. We collected perfusate and estimated extravasation by measuring dye in the perfusate using spectrophotometry. Bradykinin increased plasma extravasation eight- to ninefold above baseline in both pentobarbital- and isoflurane-anesthetized rats. In contrast, bradykinin-induced plasma extravasation at 0.8 MAC and 1.3 MAC of halothane was approximately 40% (P < 0.01) and 15% (P < 0.001), respectively, of that in pentobarbital- and isoflurane-anesthetized rats. Baseline plasma extravasation was lower in rats anesthetized with either concentration of halothane compared with pentobarbital or isoflurane (all P < 0.001). Platelet-activating factor-induced plasma extravasation was similar for all anesthetics. Halothane, but not isoflurane or pentobarbital, inhibits both baseline and bradykinin-induced peripheral plasma extravasation, demonstrating that volatile anesthetics differentially modulate this important component of inflammation.

Neurogenic influences on contralateral responses during experimental rat monoarthritis.

Many inflammatory conditions show topographically precise symmetrical responses. In this study we assessed vascular and cellular responses of apparently normal knees following induction of monoarthritis on the opposite side. A strictly localised monoarthritis was induced in the right knee of experimental animals using intra-articular latex spheres. In both knee joints bradykinin-induced plasma extravasation was significantly enhanced increasing from 0.52 +/- 0.07 micrograms/ml Evans blue to 0.99 +/- 0.07 micrograms/ml and 0.88 +/- 0.1 micrograms/ml in the injected and uninjected, contralateral, knees respectively (P < 0.05). A bilateral increase in cellularity was also apparent with cell counts in the uninjected, and apparently normal, knee increasing from 512 +/- 42 cells/mm2 to a maximum of 812 +/- 125 cells/mm2 on day 10 (P < 0.05). Immunohistological analysis demonstrated that the infiltrating cells in both the ipsilateral and contralateral joints were predominantly macrophages. Cell counts were not increased in the other peripheral joints. Levels of the sensory neuropeptide substance P were significantly elevated in both the ipsilateral and contralateral dorsal root ganglia and prior inhibition of small unmyelinated nerve activity inhibited the cellular infiltrate on the contralateral side, suggesting that the effect was mediated, at least partially, by a specific neurogenic pathway. The data suggests the presence of a neurogenic mechanism able to induce a topographically precise response. This may serve to upregulate the cellular defences of at-risk tissues following a potentially damaging stimulus at another site.

Negative feedback neuroendocrine control of the inflammatory response in rats

We describe that an ongoing inflammatory response at one site (produced by complete Freund's adjuvant injection in the hindpaw) produces a negative feedback inhibition on plasma extravasation, produced by perfusion of the inflammatory mediator, bradykinin (160 nM), at a second site (the knee joint). This negative feedback process is abolished in rats that have been neonatally treated with capsaicin to deplete most of their unmyelinated primary afferent fibers, which suggests that this negative feedback process is mediated by activation of primary afferent fibers. Electrical stimulation of the hindpaw at intensities that excite C-fibers also inhibited bradykinin-induced plasma extravasation. Stimulation at intensities that only excite A-fibers had no effect on bradykinin-induced plasma extravasation. Platelet activating factor-induced plasma extravasation, which is not dependent on the innervation of the joint, was not inhibited by stimulation of C-fibers from the hindpaw. Acute surgical interruption of the lumbar sympathetic outflow to the hind limb (the paravertebral ganglia between L2 and L4) did not attenuate the depression of bradykinin-induced plasma extravasation produced by C-fiber stimulation. This indicates that the depression is not mediated by activity in the sympathetic outflow. Transection of the spinal cord, hypophysectomy, inhibition of corticosterone synthesis, and adrenalectomy (but not adrenal medullectomy) all prevented the inhibition of BK-induced plasma extravasation by electrical simulation, indicating that the negative feedback inhibition on plasma extravasation is dependent on an intact neuraxis and an intact hypothalamic-pituitary-adrenocortical axis. In summary, our data demonstrate a negative feedback inhibition of an inflammatory process, which is elicited by stimulation of C-fiber afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of bradykinin-induced plasma extravasation in the rat knee joint.

1. We have investigated the mechanism of bradykinin (BK)-induced plasma extravasation into the knee joint of the anaesthetized rat. Accumulation of [125I]-human serum albumin within the synovial cavity was used as a marker of increased vascular permeability. 2. Perfusion with BK (1 microM) produced significant plasma extravasation into the knee which was inhibited by co-perfusion of the selective bradykinin B2 receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140, 200 nM). 3. The bradykinin B1 receptor agonist, [des-Arg9]-BK (up to 100 mM), did not induce plasma extravasation into the knee joint, over this time period. 4. Chemical sympathectomy by chronically administered 6-hydroxydopamine (6-OHDA) did not inhibit bradykinin-induced plasma extravasation. Acute intra-articular perfusion with 6-OHDA (to stimulate transmitter release from sympathetic nerve terminals) at concentrations up to 50 mM did not induce significant plasma extravasation. Intra-articular perfusion of 100 mM 6-OHDA induced significant plasma extravasation but produced severe systemic toxicity. 5. The selective neurokinin1 (NK1) receptor antagonist, RP67580 (230 nmol kg-1), or receptor antagonists for the mast cell products histamine and 5-hydroxytryptamine did not significantly inhibit BK-induced plasma extravasation. 6. Co-perfusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (1 mM) did not significantly inhibit the response to BK. 133Xe clearance from L-NAME (1 mM)-injected joints was significantly (P < 0.05) reduced compared to D-NAME injected joints, suggesting a reduction in blood flow as a result of decreased basal NO production. Systemic administration of L-NAME at doses sufficient to produce significant and sustained elevation of blood pressure (5 or 30 mg kg-1, i.v. 15 min prior to BK perfusion) also failed to significantly inhibit the BK-induced response.7 We conclude that, in normal joints, BK induces plasma extravasation by acting on bradykinin B2 receptors and that this response is not dependent on secondary release of mediators from sympathetic nerve terminals, sensory nerves, mast cells or on generation of NO.

Involvement of tachykinins in plasma extravasation induced by bradykinin and low pH medium in the guinea-pig conjunctiva.

1. The effect of bradykinin, capsaicin, substance P and low pH medium on plasma extravasation in the guinea-pig conjunctiva has been studied. Evans blue dye was measured in the conjunctiva after local instillation of the agents into the conjunctival sac. 2. Bradykinin (2-50 nmol), capsaicin (20-50 nmol) and substance P (0.5-5 nmol) caused a dose-dependent increase in plasma extravasation with the following order of potency: substance P > bradykinin = capsaicin. The effect of capsaicin (50 nmol) and substance P (5 nmol) was abolished by the tachykinin NK1 receptor antagonist, CP-99,994 (8 mumol kg-1, i.v.) (P < 0.01), whereas CP-100,263 (8 mumol kg-1, i.v.) the inactive enantiomer of CP-99,994 was without effect. CP-99,994 inhibited by 70% (P < 0.01) the effect of bradykinin. 3. The kinin B2 receptor antagonist, Hoe 140 (icatibant, 10 nmol kg-1, i.v.) abolished the response to bradykinin (50 nmol) (P < 0.01), but did not affect the responses to capsaicin (50 nmol) or substance P (5 nmol). Plasma extravasation induced by low pH medium (pH 1) was abolished by CP-99,994 (P < 0.01) and by Hoe 140 (P < 0.01). 4. The present findings suggest that: endogenous or exogenous tachykinins increase plasma extravasation in the guinea-pig conjunctiva by activation of NK1 receptors; bradykinin-induced plasma extravasation is mediated by tachykinin release from sensory nerve endings; low pH media cause plasma extravasation via release of kinins that by activation of B2 receptors release tachykinins from sensory nerve endings.