[The prognostic value of morphological and functional parameters of cardiac magnetic resonance in patients with systemic light chain amyloidosis].

Objective: To investigate the features of morphological and functional parameters of cardiac magnetic resonance (CMR) in patients with systemic light chain (AL) amyloidosis, and the prognostic values of these related parameters. Methods: The data of 97 patients (including 56 males and 41 females, aged 36 to 71 years) with AL amyloidosis from April 2016 to August 2019 in the General Hospital of Eastern Theater Command were retrospectively analyzed. All patients underwent CMR examination. Those patients were divided into survival (n=76) and death groups (n=21) according to the clinical outcomes, and the differences in clinical baseline and CMR parameters between the two groups were analyzed and compared. A smooth curve fitting was used to analyze the association between morphological and functional parameters and extracellular volume (ECV), and Cox regression models were conducted to explore the association between related parameters and mortality. Results: The left ventricular global function index (LVGFI), myocardial contraction fraction (MCF) and stroke volume index (SVI) decreased with increasing ECV [ß (95%CI) was -0.566 (-0.685--0.446), -1.201 (-1.424--0.977), -0.149 (-0.293--0.004), respectively;all P<0.05]. Left ventricular mass index (LVMI), and diastolic left ventricular global peak wall thickness (LVGPWT) increased with increasing ECV [ß(95%CI) was 1.440 (1.142-1.739), 0.190 (0.147-0.233), respectively;both P<0.001]. While left ventricular ejection fraction (LVEF) began to decrease only at higher amyloid burden (ß=-0.460, 95%CI:-0.639--0.280, P<0.001). The median follow-up time was 39 months (range 2-64 months), and 21 patients died during the follow-up period. The estimated survival rates according to Kaplan-Meier curves at 1, 3, and 5 years were 92.8%, 78.7%, and 77.1%, respectively. MCF<39% (HR=10.266, 95%CI: 4.093-25.747) and LVGFI<26% (HR=9.267, 95%CI: 3.705-23.178) were independent risk factors for death in patients with AL amyloidosis after adjusting for other CMR parameters (P<0.001). Conclusion: Multiple morphologic and functional parameters of CMR vary with the increase of ECV. MCF<39% and LVGFI<26% were independent risk factors for death.

Sex steroid regulation of the inflammatory response: sympathoadrenal dependence in the female rat.

To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor alpha immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells.

Effects of bilirubin on cerebral arterial tone in vitro.

Hemoglobin and its metabolite, bilirubin, have been shown to be present in high concentrations in CSF following subarachnoid hemorrhage (SAH). Several reports have indicated that hemoglobin is a potent cerebral vasoconstrictor and therefore is considered to be an active principle in the genesis of cerebral vasospasm. The possible role of bilirubin on the genesis of cerebral vasospasm, however, has not been clarified. The effect of bilirubin on cerebral vessel tone was therefore examined using in vitro tissue bath techniques. Bilirubin (10(-5)-3 X 10(-5) M) induced strong constriction of cerebral arteries from the cat, dog, and pig. The vasoconstriction returned to baseline after bilirubin was washed by prewarmed Krebs solution. Vasomotor responses to various vasoactive substances were then examined after bilirubin was washed away (the bilirubin postwash effect). Norepinephrine (NE)-induced but not serotonin- or acetylcholine (ACh)-induced constrictions were significantly potentiated by bilirubin postwash effect. The potentiated NE-induced constriction was attenuated by yohimbine but not by prazosin. This enhanced vasoconstriction was mimicked by clonidine but not by phenylephrine, suggesting that the potentiation of NE-induced constriction by the bilirubin postwash effect was mediated by the alpha 2-adrenoceptor subtype. The bilirubin postwash effect also resulted in blockade of endothelium-dependent vasodilations induced by A-23147, ACh, and ATP without affecting relaxations induced by direct muscle relaxants such as beta-adrenoceptors, papaverine, and sodium nitroprusside. These results indicate that bilirubin induces direct vasoconstriction, potentiates alpha 2-adrenoceptor-mediated vasodilation. These actions of bilirubin may promote an enhanced overall vasoconstriction in vivo. Bilirubin, therefore, may be involved in the genesis of cerebral vasospasm following SAH.

Cholinergic and VIPergic innervation in cerebral arteries: a sequential double-labeling immunohistochemical study.

The possible co-localization of choline acetyltransferase (ChAT) and vasoactive intestinal polypeptide (VIP) in the nerve fibers of cat cerebral arteries was examined by a sequential double-labeling immunohistochemical method. Diaminobenzidine and tetramethylbenzidine were used as chromogens to distinguish ChAT (protein) and VIP (peptide) immunoreactivities. Since available fixatives often did not provide simultaneous preservation of optimal protein and peptide immunoreactivities, a new fixative, buffered periodate-paraformaldehyde-picric acid-formaldehyde-lysine (PPPFL), was formulated and tested. PPPFL fixative is more reliable for simultaneously preserving ChAT and VIP immunoreactivities than were periodate-lysine-paraformaldehyde (PLP) fixative, Zamboni's fixative, or 2% paraformaldehyde solution alone. Using PPPFL as fixative, both ChAT immunoreactive (ChAT-I) and VIP-immunoreactive (VIP-I) fibers in cerebral arteries appeared as bundle and fine fibers. Most ChAT-I and VIP-I fibers were separate. Portions of ChAT-I and VIP-I fibers often ran closely in parallel or across each other. Overlaying of VIP-I on ChAT-I fibers and relay connections between them were also observed. These morphological data suggest the potential functional interactions between cholinergic and VIPergic innervations. In less than 5% of the fibers examined did ChAT and VIP immunoreactivities appear to be co-localized. These data therefore do not support the hypothesis that acetylcholine and VIP are co-localized in most fibers innervating the cerebral arterial wall.

Inflammation modulates the contribution of receptor-subtypes to bradykinin-induced hyperalgesia in the rat.

While B2 receptors mediate pain and hyperalgesia induced by bradykinin, in normal rats, recent reports indicate that, in the setting of inflammation, B1 receptors also mediate pain and hyperalgesia. Since bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins released from the postganglionic sympathetic neurons, we have evaluated the contribution of the sympathetic nervous system to the hyperalgesia induced by bradykinin, a preferential B2-receptor agonist, and des-Arg9-bradykinin, a major metabolite of bradykinin and a selective B1-receptor agonist. Mechanical hyperalgesia was quantified by the Randall-Selitto paw-withdrawal method. Inflammation was induced by injecting Complete Freund's Adjuvant into the left hindpaw of the rat and testing mechanical nociceptive threshold in the right hindpaw after injecting B1 or B2 agonists and/or antagonists. Sympathectomy was achieved by surgically removing sympathetic ganglia L1-L4. Rats were used 48 h post-adjuvant injection. In the normal rat, intradermal injection of bradykinin but not des-Arg9-bradykinin, into the dorsal surface of the hindpaw, produced a dose-dependent decrease in mechanical nociceptive threshold. NPC 17731, a B2-receptor antagonist, but not des-Arg9-[Leu8]-bradykinin, a B1-receptor antagonist, almost completely inhibited the decrease in mechanical threshold, suggesting that bradykinin hyperalgesia in the normal rat hindpaw was mediated by B2 receptors. In rats whose left paws were treated, 48 h earlier, with adjuvant, intradermal injection of bradykinin or des-Arg9-bradykinin, into the right paw produced dose-dependent hyperalgesia. Bradykinin hyperalgesia was partially inhibited by NPC 17731, and the residual part by des-Arg9,[Leu8]-bradykinin. des-Arg9-bradykinin hyperalgesia was inhibited by des-Arg9,[Leu8]-bradykinin but not by NPC17731. These results suggest that in the setting of inflammation, bradykinin hyperalgesia was mediated by both B1 and B2 receptors, and that des-Arg9-bradykinin hyperalgesia was mediated by the B1 receptor. Forty-eight hours after injection of complete Freund's adjuvant, in sympathectomized rats, bradykinin or des-Arg9-bradykinin failed to produce hyperalgesia, suggesting that intact sympathetic postganglionic neurons are required for the hyperalgesia produced by these agents in this model. These results are consistent with the suggestions that B2 receptors mediate bradykinin-induced cutaneous hyperalgesia in the normal rat hindpaw. The hyperalgesia induced by bradykinin, 48 h post injection of complete Freund's adjuvant is mediated by both B1 and B2 receptors, that by des-Arg9-bradykinin is mediated by B1 receptors. The hyperalgesia induced by both agents is dependent on the presence of intact sympathetic postganglionic neurons.

Blockade of nociceptive inhibition of plasma extravasation by opioid stimulation of the periaqueductal gray and its interaction with vagus-induced inhibition in the rat.

We have previously shown that stimulation of cutaneous or visceral nociceptors suppresses inflammation measured as bradykinin-induced synovial plasma extravasation in the knee joint of the rat. This suppression occurs through the activation of a spinal as well as a supraspinal reflex pathway leading to activation of the adrenal medullae and probably the release of epinephrine. These nociceptive-neuroendocrine reflex pathways are tonically inhibited by activity in abdominal vagal afferents acting through an inhibitory descending pathway projecting through the dorsolateral funiculus (DLF) ipsilateral to the cutaneous afferent nociceptive input. Here we investigated whether the descending inhibitory pathway acted upon by vagal afferents is also modulated by the periaqueductal gray (PAG), similar to other bulbo-spinal pathways acting on spinal nociceptive transmission. Injection of morphine sulfate (10 nmol) in the ventrolateral PAG significantly inhibited the nociceptive-neuroendocrine reflex pathways, an effect that was significantly less after removal of vagal afferents (i.e. after release from tonic inhibition maintained by vagal afferents). Interruption of the DLF ipsilateral to the nociceptive input removed the inhibitory effect of vagal afferents and partly reduced the inhibition produced by morphine injected in the PAG. From these investigations we conclude that PAG-induced inhibition of the nociceptive-neuroendocrine reflex pathways is mediated through the DLF ipsilateral to the nociceptive input, involving the same descending inhibitory pathway that relays afferent vagal inhibition, and through other spinal and possibly supraspinal pathways.

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, (3aR,7aR)-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 alpha-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.

Chronically administered nicotine attenuates bradykinin-induced plasma extravasation and aggravates arthritis-induced joint injury in the rat.

We recently showed that acute administration of nicotine in the rat decreases bradykinin-induced plasma extravasation and that adrenal medullary-derived epinephrine, acting at a beta 2-adrenergic receptor, mediates the nicotine effect. Since agents which decrease bradykinin-induced plasma extravasation have been associated with increased joint injury in a rat model of chronic inflammation (experimental arthritis induced by subcutaneous injection of Mycobacterium butyricum) we examined the effect of chronic nicotine on both plasma extravasation and the severity of joint injury. In normal rats, bradykinin-induced plasma extravasation was decreased after nicotine administered both by repeated injection (10(-2) mg/kg, s.c., once per h for 4 h) and by continuous long-term infusion (subcutaneous mini-osmotic pump; 1.5 x 10(-3) mg/kg per h for 30 days). Nicotine-induced inhibition of bradykinin-induced plasma extravasation did not show tachyphylaxis. In rats with arthritis, chronic administration of nicotine also produced a decrease in bradykinin-induced plasma extravasation. This effect of chronic nicotine in the arthritic rats was antagonized by co-administration of hexamethonium (a nicotinic receptor antagonist), by surgical removal of the adrenal medulla, or by co-administration of ICI-118,551 (a beta 2-adrenoceptor antagonist). Chronic administration of nicotine decreased the latency to the onset of arthritis and, in a dose-dependent manner, led to an increase in the radiographic joint injury score.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat.

1. In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. 2. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective beta 2-adrenoceptor blocker) (30 micrograms ml-1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg-1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 microgram kg-1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that beta 2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg-1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. 3. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg-1, s.c.), and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg-1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. 4. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg-1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. 5. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone.

The role of vagal visceral afferents in the control of nociception.

We have shown that activity in subdiaphragmatic vagal afferents modulates mechanical hyperalgesic behavior in the rat. Subdiaphragmatic vagotomy decreases paw-withdrawal threshold to mechanical stimulation (baseline and after intradermal injection of bradykinin), thus enhancing mechanical hyperalgesic behavior. Most of this decrease is generated by an endocrine signal released by the adrenal medullae because denervation or removal of the adrenal medullae prevents or reverses these changes. This novel mechanism may imply that: (a) the brain is able to regulate sensitivity of nociceptors all over the body by a neuroendocrine mechanisms, (b) sensitivity of nociceptors can be influenced by changes in parts of the body which are remote from the location of the sensitized nociceptors and (c) circulating catecholamines can influence nociceptors in a way which is different from those reported so far (see Jänig and McLachlan, 1994; Jänig, 1996a; Jänig et al., 1996).

Endocrine and vagal controls of sympathetically dependent neurogenic inflammation.

Recently the very significant role of the postganglionic sympathetic neuron (PGSN) terminal in the production of neurogenic inflammation has been appreciated. An important model of this sympathetically dependent inflammation is venular plasma extravasation (PE) and neutrophil attraction produced by local intra-articular injection of the potent inflammatory mediator bradykinin (BK). Sympathetic-dependent PE in the synovium has been proposed as a protective mechanism in arthritis. In a recent series of studies, a novel mechanism has been discovered by which activation of primary afferent nociceptors exerts a potent feedback inhibition of PGSN-dependent PE. Activation of nociceptive afferents was shown to be involved in this feedback system. Such a negative feedback control of the acute inflammatory response would have survival value; the inflammatory response, as initiated by a high degree of positive feedback, and the inflammatory process itself when persisting can result in significant tissue injury. If indeed HPA axis activity plays a significant physiological role in the modulation of neurogenic inflammation, then physiological processes that modulate the HPA axis would be expected to influence neurogenic inflammation. A dramatic effect of this kind has been demonstrated, in the rat, for vagal afferent activity. In the presence of subdiaphragmatic (or celiac branch) vagotomy, the potency of nociceptive afferent activity to inhibit sympathetically dependent, BK-induced PE was increased by four orders of magnitude compared to vagus-intact animal. Hypoactivity or hyperactivity of these vagally mediated mechanisms could contribute to diseases characterized by either an inadequate or an exaggerated inflammatory response.

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.

Gender and gonadal hormone effects on vagal modulation of tonic nociception.

We studied the influence of gender and gonadal hormones on modulation of tonic nociception exerted by vagal activity. In male rats, subdiaphragmatic vagotomy resulted in significantly reduced nociceptive behavior during phase 2 of the formalin test. Whereas gonadectomy alone had no effect, it completely eliminated the suppressive effect of subdiaphragmatic vagotomy; however, sex hormone replacement with either testosterone or dihydrotestosterone did not restore the ability of subdiaphragmatic vagotomy to suppress nociceptive behavior. These results suggest that, in males, a gonad-dependent but androgenic gonadal hormone-independent mechanism contributes to pronociceptive effects of vagal afferent activity. Although neither gonadectomy nor subdiaphragmatic vagotomy alone affected the response to formalin in females, gonadectomy plus vagotomy resulted in significantly reduced nociceptive behavior during phase 2. Reconstitution with 17 beta-estradiol implants in gonadectomized females not only prevented suppression of nociceptive behavior seen with gonadectomy plus vagotomy, but also led to increased nociceptive behavior in the interphase between phases 1 and 2. However, placement of 17 beta-estradiol implants in gonad-intact females had no effect on formalin-induced nociceptive behavior. The finding that estrogen produced an increase in nociceptive behavior in gonadectomized female rats after vagotomy but not in normal female rats (with intact gonads and subdiaphragmatic vagus) suggests that the interaction between estrogen and nociceptive afferent activity is suppressed by vagal function. In conclusion, a nonandrogenic action of testicular function in male rats and estrogen in females seems to influence the effect of vagal activity on formalin-induced nociceptive behavior.

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 percent, 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.

VIP-ergic and cholinergic innervations in internal carotid arteries of the cat and rat.

Using immunohistochemical methods, choline acetyltransferase and vasoactive intestinal polypeptide immunoreactive (ChAT-I and VIP-I) fine fibers with varicosity-like structures were observed in the rat and cat cerebral arteries. Acetylcholine (ACh) induced dual responses in endothelium-intact internal carotid arteries of the cat; it induced vasodilation at low concentrations and constrictions at high concentrations (greater than 10(-6) M). ACh induced contraction exclusively in endothelium-rubbed preparations. Atropine (10(-7) M) blocked ACh-induced constriction and dilatation. ACh-induced vasodilation was potentiated by M & B 22,948 (2 x 10(-5) M), a selective cyclic GMP phosphodiesterase inhibitor. Vasoconstriction induced by ACh was inhibited by neomycin (3 x 10(-3) M), an inositol phosphate synthesis inhibitor, which did not affect the neuropeptide Y-induced contraction. VIP-induced dilation of the cat internal carotid arteries was not affected by removing the endothelial layer, but was blocked by VIP receptor antagonist ([Ac-Tyr1, D-Phe2]-GRF 1-29 amide) and potentiated by cilostazol (2 x 10(-5) M), a selective cyclic AMP phosphodiesterase inhibitor. These results are consistent with previous findings that cerebral blood vessels receive cholinergic and VIP-ergic innervations, and that ACh-induced endothelium-dependent vasodilation is mediated by cyclic GMP synthesis, and that VIP-induced endothelium-independent vasodilation is mediated by cyclic AMP synthesis. The present study, however, demonstrates for the first time the presence of varicosity-like structure associated with ChAT-I fibers, suggesting the presence of cholinergic nerve terminals and that ACh-induced cerebral vasoconstriction is mediated by phosphatidyl-inositide turnover.

Regional variation in acute vascular homologous tachyphylaxis.

The development of tachyphylaxis or desensitization in a tissue upon repeated application of an agonist is a well-established phenomenon. To investigate the possible basis of vascular homologous tachyphylaxis, vasomotor responses in isolated cerebral and peripheral blood vessels from the cat, dog and rabbit upon repeated application of several agonists were examined using in vitro tissue bath techniques. Tachyphylaxis to vasodilator responses developed to repeated application of vasoactive intestinal polypeptide (VIP) but not to beta adrenergic agonist, forskolin, 8-bromo-cyclic AMP, sodium nitroprusside or 8-bromo-cyclic GMP in feline cerebral arteries. The tachyphylaxis to VIP-induced responses varied among regions and was greatest in the internal carotid artery (ICA), followed by the middle cerebral artery and least in the basilar artery (BA). Cerebral arteries also developed significant tachyphylaxis to constriction induced by repeated applications of neuropeptide Y (NPY), alpha-1 adrenergic agonist, but not to alpha-2 adrenergic agonist, acetylcholine (ACh) or KCl. The tachyphylaxis to constrictions induced by repeated application of neuropeptide Y (NPY) also varied among regions, but was different from that induced by VIP; it was greatest in the BA, followed by the middle cerebral artery and least in the ICA. Similar results were obtained in arteries without endothelial cells. The density of regional innervation of NPY-immunoreactive fibers, which is densest in ICA and sparsest in BA, parallels that of VIP-immunoreactive fibers in these three regions. There is no positive correlation between density of catecholamine fluorescence fibers and degree of tachyphylaxis to noradrenaline-induced constriction in cat ICA, dog saphenous arteries and rabbit ear arteries either.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural and endocrine mechanisms mediating noxious stimulus-induced inhibition of bradykinin plasma extravasation in the rat.

We studied the mechanisms by which activation of primary afferent nociceptors inhibits bradykinin-induced plasma extravasation in the rat. First, capsaicin, administered into the plantar surface of the hindpaw, dose-dependently inhibited bradykinin-induced plasma extravasation in the knee joint, a site distant from the noxious stimulus. The inhibitory effect of capsaicin was markedly attenuated after T(12)/L(1) spinal transection combined with lumbar preganglionic sympathectomy, which interrupts ascending spinal tracts to rostral sites and to spinal sympathetic and sympathoadrenal outflow. Second, interruption of the sympathetics (cutting the L(1-3) white rami) or surgical adrenal denervation significantly attenuated capsaicin-induced inhibition of bradykinin-induced plasma extravasation. Interruption of the sympathoadrenal pathway produced the largest attenuation. Lesioning of the hypothalamic-pituitary-adrenal axis did not affect the inhibitory action of capsaicin. Third, intra-articular perfusion with phentolamine (10(-5) M, an alpha-adrenoceptor antagonist), propranolol (10(-5) M, a beta-adrenoceptor antagonist), and naloxone (10(-5) M, an opioidergic receptor antagonist) each attenuated the inhibitory action of capsaicin. Propranolol and naloxone produced the largest attenuation. Blocking glucocorticoid receptors (RU-38, 486, 30 mg/kg s.c.) did not affect the inhibitory action of intraplantar capsaicin. Fourth, the magnitude of the attenuation of capsaicin-induced inhibition of bradykinin-induced plasma extravasation after a combined treatment of surgical lumbar sympathetic decentralization with intra-articular phentolamine or surgical adrenal denervation with intra-articular propranolol or naloxone was similar to each of the surgical or pharmacological treatments of the same axis alone. These results support the suggestion that two neural/endocrine circuits, sympathoadrenal and sympathetic, account for most, if not all, of nociceptor activity-induced inhibition of bradykinin-induced plasma extravasation produced by capsaicin.

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.