Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis.

OBJECTIVES: Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis. MATERIALS AND METHODS: Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients. INTERPRETATION: Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

Limited expression of heparan sulphate proteoglycans associated with Aß deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease.

AIMS: Alzheimer's disease (AD) is characterized by deposition of the amyloid beta (Aß) peptide in brain parenchyma and vasculature. Several proteins co-deposit with Aß, including heparan sulphate proteoglycans (HSPG). HSPG have been suggested to contribute to Aß aggregation and deposition, and may influence plaque formation and persistence by stimulating Aß fibrillization and by protecting Aß against degradation. Mouse models for AD, expressing the human amyloid precursor protein (APP), produce Aß deposits similar to humans. These models may be used to study disease pathology and to develop new therapeutic interventions. We aimed to investigate whether co-deposition of HSPG in AD brains can be replicated in the APPswe/PS1dE9 mouse model for AD and if a temporal association of HSPG with Aß exists. METHODS: We studied the co-deposition of several HSPG and of the glycosaminoglycan side chains of HSPG in the APPswe/PS1dE9 model at different ages by immunohistochemistry. RESULTS: We found that, although APPswe/PS1dE9 mice did develop severe Aß pathology with age, co-deposition of HS glycosaminoglycan chains and the various HSPG (agrin, perlecan and glypican-1) was scarce (<10-30% of the Aß deposits were stained). CONCLUSIONS: Our data suggest that the molecular composition of Aß deposits in the APPswe/PS1dE9 mouse, with respect to the several HSPG investigated in this study, does not accurately reflect the human situation. The near absence of HSPG in Aß deposits in this transgenic mouse model may, in turn, hinder the translation of preclinical intervention studies from mice to men.

Activation of normal and inflamed fine articular afferent units by serotonin.

In cats anesthetized with alpha-chloralose, extracellular recordings were made from fine afferent units belonging to the medial articular nerve (MAN) of the knee joint. The excitatory and sensitizing effects on articular afferents of serotonin (5-HT) applied intra-arterially close to the joint were examined. The joints were either normal or an experimental arthritis had been induced some hours before the recording session. Bolus injections of 1.35-135 micrograms 5-HT excited about 43% of group III (CV: 2.5-20 m/sec) and 73% of group IV units (CV: less than 2.5 m/sec) from normal joints. The latency was usually between 10 and 30 sec, and the duration and size of the responses were dose-dependent. Fast group III units (CV: greater than 16 m/sec) and group II units (CV: greater than 20 m/sec) were never excited by 5-HT. Repetitive administration led to pronounced tachyphylaxis of the 5-HT response. Inflammation induced an enhanced sensitivity of group III articular afferent units to close intra-arterial application of 5-HT. In particular the total duration of each response was considerably prolonged (4-10 min against 1-2 min under normal conditions). At the same time the tachyphylaxis seen under normal conditions was greatly reduced. In contrast, group IV articular afferent units did not become sensitized to 5-HT in the course of inflammation. In normal joints 5-HT did not sensitize fine afferent units for movement-induced responses. However, after inflammation, a distinct sensitization to such movements by 5-HT application could be observed both in group III and group IV fiber ranges. The sensitization had a short time course not exceeding 7 min. The tonic component of the movement-induced response was more enhanced than the phasic one. The bolus application of 5-HT led to temporary vasoconstriction of the knee joint vessels. This vasoconstriction was especially pronounced in inflamed joints and impeded the access of subsequently applied substances to the terminal regions of the afferent units under observation. It is concluded that the present results support the notion that 5-HT may participate in the mediation of pain from inflamed tissue such as an arthritic joint by exciting and sensitizing fine afferent units. During inflammation group III units are particularly sensitive to 5-HT and, thus, may carry the bulk of the 5-HT-induced nociceptive messages.

Interleukin-1 beta enhances capsaicin-induced neurogenic vasodilatation in the rat skin.

1. This study examined the effect of interleukin-1 beta (IL-1 beta) on the capsaicin-induced increase in cutaneous blood flow of anaesthetized rats as measured by laser Doppler flowmetry. 2. The substances were administered by intraplantar subcutaneous injection of 10 microliters-volumes, saline being injected into one hindpaw and IL-1 beta into the other. 3. IL-1 beta (0.5-500 pg) was without effect on blood flow on its own but dose-dependently enhanced the hyperaemic response to intraplantar capsaicin (0.3 microgram) up to 180% (P < 0.05) of the response seen in saline-treated paws. 4. Il-1 beta-(163-171), a fragment devoid of proinflammatory activity, failed to enhance capsaicin-induced hyperaemia when given at a dose of 50 pg. 5. Indomethacin (10 mg kg-1, i.p.) did not alter the capsaicin-induced vasodilatation but prevented IL-1 beta (50 pg) from augmenting the hyperaemic response to capsaicin. 6. The hyperaemia evoked by intraplantar calcitonin gene-related peptide (0.038-3.8 ng) was not altered by IL-1 beta (50 pg). 7. These data indicate that IL-1 beta enhances the cutaneous hyperaemic response to afferent nerve stimulation with capsaicin in a prostaglandin-dependent manner. This proinflammatory action of the cytokine appears to arise from sensitization of afferent nerve endings.

Tumor necrosis factor-alpha prevents interleukin-1 beta from augmenting capsaicin-induced vasodilatation in the rat skin.

The effect of tumor necrosis factor-alpha (TNF alpha) and tumor necrosis factor-beta (TNF beta) on the capsaicin-induced increase in cutaneous blood flow was investigated in anaesthetized rats. Skin blood flow was measured by laser-Doppler flowmetry. Intraplantar subcutaneous injections of 5-500 pg TNF alpha and 50-5000 pg TNF beta had no effect on local blood flow, whereas 5000 pg TNF alpha induced a transient hyperaemia. However, neither the pretreatment with TNF alpha (5-5000 pg) nor that with TNF beta (50-5000 pg) enhanced the vasodilatator response to intraplantar capsaicin (0.03 micrograms; 0.1 microgram), whereas 50 pg interleukin-1 beta augmented the capsaicin-induced hyperaemia (P < 0.05). This enhancement of the cutaneous hyperaemic response to capsaicin was absent when interleukin-1 beta (50 pg) was co-injected with TNF alpha (500 pg or 5000 pg). The vasodilatation caused by calcitonin gene-related peptide or bradykinin was not altered by 500 pg or 5000 pg TNF alpha. These data indicate that TNFs, in contrast to interleukin-1 beta, do not amplify the hyperaemic response to afferent nerve stimulation with capsaicin but reverse the augmentation mediated by interleukin-1 beta.

Nitric oxide mediates the amplification by interleukin-1 beta of neurogenic vasodilatation in the rat skin.

Blood flow in the plantar hindpaw skin of anaesthetized rats was measured by laser Doppler flowmetry. Intraplantar injection of interleukin-1 beta (50 pg) significantly enhanced the hyperaemic response to intraplantar capsaicin (0.3 microgram). Pretreatment with a neurotoxic dose of capsaicin reduced the capsaicin-evoked hyperaemia and prevented the facilitatory effect of interleukin-1 beta. Blockade of nitric oxide formation by NG-nitro-L-arginine methyl ester failed to affect the capsaicin-evoked vasodilatation but abolished its amplification by interleukin-1 beta. These data indicate that the enhancement by interleukin-1 beta of the capsaicin-induced hyperaemia involves thin afferent nerve fibres and depends on nitric oxide as essential intermediate.

Histamine excites groups III and IV afferents from the cat knee joint depending on their resting activity.

The effect of histamine on the sensory activity of primary afferents was studied in normal and acutely inflamed cat knee joints. A subpopulation of groups III and IV articular afferents could be activated by close-arterial bolus injections of histamine: units with a high resting activity (about 100/min) were particular sensitive to histamine and were excited even by 3.3 fg histamine. The lower the resting discharges of groups III and IV units both from normal and acutely inflamed joints, the higher the dose of histamine (up to 3.3 or 33 microg) necessary to excite the nerve fibres. Thirty-seven of 39 units without any resting activity were completely insensitive to histamine. In contrast to its clear excitatory effect, histamine caused only minor changes in the responses to joint movements. Movement-evoked activity remained unchanged in 22 of 28 units, 1 unit was sensitized and 5 units showed reduced activity after histamine (3.3 microg). The present results support the notion that histamine may participate in the mediation of pain from injured or inflamed tissue. It is remarkable that histamine has a profound excitatory action on a proportion of both groups III and IV articular afferents without changing their sensitivity to joint movements.

Concomitant treatment with urodilatin (ularitide) does not improve renal function in patients with acute renal failure after major abdominal surgery--a randomized controlled trial.

Acute renal failure after major abdominal surgery is a severe complication in critically ill patients in intensive care units (ICU). The aim of the study was to investigate the effect of urodilatin on the peak value and course of serum creatinine in patients with acute renal insufficiency after major abdominal surgery and the necessity of apparatus-based renal replacement treatment. Furthermore, the incidence and nature of adverse events under urodilatin was documented. In a prospective randomized double-blind placebo-controlled study, 12 critically ill patients after major abdominal surgery with acute renal failure in an intensive care unit (ICU) received 20 ng/kg b.w./min urodilatin (ularitide, INN) or placebo in addition to the standard diuretic therapy or low-dose dopamine (2.5 micrograms/kg b.w./min) and furosemide (1000 mg/24 hr) for a minimum of 96 hours. All patients received mechanical ventilation. Both groups had similar serum creatinine values on the day before the onset of urodilatin/placebo infusion (2.80 +/- 0.24 mg/dl, 2.93 +/- 0.48 mg/dl). Peak serum creatinine was lower in the urodilatin group (4.65 +/- 0.57 mg/dl) compared to vehicle treatment (5.78 +/- 1.58 mg/dl), although the difference did not reach statistical significance (P = 0.148). The total number of hemodialyses due to oligo-/anuria and/or hyperkalemia was the same in both groups during the study. In 4 patients of the placebo group, diuresis was reduced to anuria, whereas only 1 of the patients treated with urodilatin became anuric. No hemodynamic side effects or adverse events due to urodilatin were observed. This clinical study under double blind conditions revealed that the addition of urodilatin to the standard diuretic therapy of low-dose dopamine and furosemide failed to improve renal function in patients with established acute renal failure and that urodilatin did not eliminate the need for apparatus-based renal replacement treatment.

[Innovative treatment of acute migraine pain with CGRP receptor antagonists]. / Eine Innovation in der akuten Migränetherapie: CGRP-Rezeptorantagonisten.

Neurogenic inflammation caused by the release of vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) from nociceptive perivascular nerve fibres has been implicated in the development of acute migraine pain. It has recently been demonstrated that the CGRP receptor antagonist BIBN 4096 BS significantly reduces acute pain in migraine. This therapeutic efficacy provides further evidence for a critical role of CGRP in the pathophysiology of migraine. Given the apparent absence of vasoconstrictor activity both in meningeal and extracranial vessels, BIBN 4096 BS may provide an alternative for the treatment of migraine in those patients where triptans and ergotamine derivatives are contraindicated due to their side effects.

[Neurogenic inflammation. I. Basic mechanisms, physiology and pharmacology]. / Die neurogene Entzündung - I. Grundlegende Mechanismen, Physiologie und Pharmakologie -

Activation of sensory unmyelinated neurons by noxious stimuli evokes the release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. These neuropeptides and subsequently released mediators cause a local oedema, hyperaemia and an erythema which extends beyond the site of stimulation (so-called flare response). Since these inflammatory signs depend on the function and integrity of peripheral sensory nervous systems, the response has been termed neurogenic inflammation. Due to the fact that nearly all tissues in mammals including humans are innervated by afferent sensory neurons, this neurogenic inflammation can occur ubiquitously throughout the body. Albeit first evidence showing that sensory neurons contribute to the inflammatory signs, described as antidromic vasodilatation, axon reflex, triple response, neurogenic inflammation, elicited at the level of tissue that they innervate was first obtained more than one hundred years ago, it was in the last two decades that inflammation caused by the release of neuropeptides from afferent nerve endings was recognised as a physiologically and pathologically relevant process. A large number of exogenous and endogenous substances and autacoids may stimulate or sensitise sensory nerve endings, thus simultaneously producing pain and nociceptive responses, as well as neurogenic inflammation. On the basis of recent research a variety of pharmacological substances and antagonists of putative mediators have been identified to modulate or suppress neurogenic inflammation, thus providing a rationale for therapeutical strategies for various diseases in which neurogenic inflammation is suggested to be involved. Among them, capsaicin and other newly developed agonists and antagonists at the vanilloid receptor have attracted particular attention, since they were found to be capable of desensitizing nociceptive nerve structures and thus of preventing development of neurogenic inflammation or even of abolishing an ongoing inflammatory process.

[Neurogenic inflammation. II. pathophysiology and clinical implications]. / Die neurogene Entzündung. II. Pathophysiologie und klinische Implikationen.

Neurogenic inflammation is elicited by activation of unmyelinated sensory neurons through noxious stimuli and subsequent release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. The nerve-mediated inflammatory responses in the tissue consist of hyperaemia and oedema which under some circumstances may be accompanied by pain. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases with uncertain etiology. Signs of inflammation and hyperalgesia associated with chronic pain syndromes such as migraine, arthritis and complex regional pain syndrome resemble the characteristics of neurogenic inflammation. By extrapolation of convincing evidence obtained in rodent models, neurogenic inflammation is assumed to contribute to diseases of the respiratory system, gastrointestinal tract, urogenital tract, and skin in humans. Since, however, highly selective substance P receptor antagonists, found to be effective against inflammation in rodents, failed to inhibit inflammatory processes in clinical trials, the hypothesis of an involvement of neurogenic inflammation in human diseases is discussed critically in this review. Beyond its primarily inflammatory character neurogenic inflammation can be regarded as a mechanism that activates protective responses, thus bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair.

[Why are substance P(NK1)-receptor antagonists ineffective in pain treatment?]. / Warum versagen Substanz P (NK1)-Rezeptorantagonisten in der Schmerztherapie?

The undecapeptide substance P is expressed by primary afferent neurons where it is considered to be a cotransmitter of other peptides and glutamate. Since it is predominantly found in sensory neurons with unmyelinated fibres (C-fibres), substance P has long been thought to be a "pain transmitter". Following stimulation of nociceptive afferents, substance P is released in the spinal cord and substance P-mediated transmission is primarily brought about by tachykinin NK1 receptors. To inhibit this process, a considerable number of non-peptide, highly potent, highly selective and brain penetrant NK1 receptor antagonists have been developed during the past decade. Experimental studies have proved that NK1 receptor antagonists are indeed able to blunt pain in sensitized states and thus to reverse hyperalgesia, whereas acute pain is left fairly unchanged. The hyperalgesic role of substance P has been corroborated by the sensory deficits seen in substance P and NK1 receptor knockout mice. However, the concept that NK1 receptor antagonists would represent a novel class of analgesic drugs, as suggested by the preclinical studies, has not been borne out by the clinical trials that have been reported thus far. This article offers an overview of those hyperalgesic conditions in which NK1 receptor antagonists may be of therapeutic value and discusses possible reasons for the discrepancies between preclinical and clinical trials with NK1 receptor antagonists.

Sensitisation of group III articular afferents to mechanical stimuli by substance P.

OBJECTIVE: To examine the excitatory and sensitising effects of substance P (SP) on articular afferents in normal and acutely inflamed cat knee joints. MATERIALS AND METHODS: In anesthetised cats recordings were made from 15 group III (conduction velocity 2.5-20 m/s) and 25 group IV afferent units (conduction velocity < 2.5 m/s) of the medial articular nerve of normal and acutely inflamed knee joints. SP (10 and 100 microg) was administered close-arterially. RESULTS: SP at doses of 10 microg and 100 microg activated less than 50% of both group III and group IV units. The proportion of SP-positive units was significantly higher in inflamed (10 of 21) than in normal joints (2 of 18). SP induced activity in initially silent units or increased ongoing activity after latencies varying from 2 s to 5 min. The SP-evoked activity had an irregular pattern, a variable duration, and was not related to the dose injected. Bolus injections of SP (100 microg) sensitised group III articular afferents but not group IV units to noxious movements of the joint, regardless whether the units were from normal or acutely inflamed joints. The responses to innocuous movements were not influenced by SP. Group III units, initially not activated by any movement, displayed vigorous discharges to noxious movements after close-arterial SP. In 3 group III units tested, the SP-induced augmentation of responses to noxious movements was not mimicked by close-arterial injection of histamine (3.3 microg). CONCLUSIONS: It is concluded that SP contributes to the sensitisation of a subpopulation of high-threshold articular afferents. Thus this neuronal mediator released peripherally in response to an injury or acute inflammation causes considerable changes in the mechanosensitivity of this subpopulation of nociceptive joint afferents.

Interleukin 1 beta, but not tumor necrosis factor, enhances neurogenic vasodilatation in the rat skin: involvement of nitric oxide.

In phenobarbitone-anesthetized rats the effects of interleukin 1 beta (IL-1 beta) and tumor necrosis factors (TNFs) were examined on the capsaicin-induced increase of plantar cutaneous blood flow in the rat hind paw as measured by laser Doppler flowmetry. IL-1 beta (0.5-500 pg) or TNF alpha or TNF beta (50-500 pg) was injected subcutaneously into the left paws, while the right paws received vehicle (10 microL) only. IL-1 beta was without effect on blood flow by its own but dose dependently enhanced the hyperemia due to capsaicin (0.3 microgram). TNFs failed to enhance the capsaicin-induced vasodilatation although 5000 pg TNF alpha produced a transient increase of local blood flow. Indomethacin (10 mg/kg, i.p.) did not alter the capsaicin-induced vasodilatation but prevented IL-1 beta (50 pg) from augmenting the hyperemic response to capsaicin. Likewise, blockade of nitric oxide formation by NG-nitro-L-arginine methyl ester (L-NAME) failed to affect the capsaicin-evoked vasodilatation but abolished its amplification by IL-1 beta. Systemic pretreatment with a neurotoxic dose of capsaicin reduced the capsaicin-induced hyperemia and prevented the facilitatory effect of IL-1 beta. The hyperemia evoked by intraplantar calcitonin gene related peptide (0.038-3.8 ng) was not altered by IL-1 beta (50 pg). These data indicate that IL-1 beta but not TNF enhances the cutaneous hyperemic response to capsaicin. This proinflammatory action arises from sensitization of afferent nerve endings and depends on nitric oxide and cyclooxygenase products as essential intermediates.

[Chronic pain syndrome of the penis following cerebrovascular insult]. / Chronisches Schmerzsyndrom des Penis nach zerebrovaskulärem Insult.

Complex regional pain syndromes (formerly sympathetically maintained pain syndromes or reflex sympathetic dystrophy) encompass symptoms of pain, dysfunction and sympathetic disorder. They occur spontaneously or after peripheral or internal lesions (e.g. stroke or myocardial infarction) and predominantly affect the limbs, rarely the face or the trunk. This case report describes a 64-year old man who after a stroke suffered from heavy burning pain in the penis and perineum, which did not ameliorate after established conservative therapy. Sympathetic blockade, however, provided pain relief. The diagnosis of a complex regional pain syndrome, type I, was proposed according to the clinical symptoms in this patient, e.g. causalgia-like burning pain, allodynia, and the temporal association of an internal lesion to the onset of the pain. Other diagnoses such as neuropathic pain of unknown or diabetic etiology or a central post-stroke pain were considered.

Cyclooxygenase inhibitors acetylsalicylic acid and indomethacin do not affect capsaicin-induced neurogenic inflammation in human skin.

Neurogenic inflammation is evoked by neuropeptides released from primary afferent terminals and, presumably, by other secondarily released inflammatory mediators. This study examines whether prostaglandins might participate in the development of neurogenic inflammation in humans and whether cyclooxygenase inhibitors have any anti-inflammatory effect on this type of inflammation. In healthy volunteers, neurogenic inflammation was elicited by epicutaneously applied capsaicin (1%), after systemic pretreatment with acetylsalicylic acid, or topically applied indomethacin compared to pretreatment with saline or vehicle, respectively. The extent of neurogenic inflammation was quantified by planimetry of visible flare size and recording the increase of superficial cutaneous blood flow (SCBF) with a laser Doppler flowmeter. Capsaicin-induced flare sizes and outside SCBF (both representing neurogenically evoked inflammation) were unaffected by acetylsalicylic acid or indomethacin. Only the capsaicin-induced increase of inside SCBF was attenuated by local pretreatment with indomethacin, reflecting the participation of prostaglandins in the inflammatory response of those areas which were in direct contact with capsaicin.

Small reduction of capsaicin-induced neurogenic inflammation in human forearm skin by the glucocorticoid prednicarbate.

Capsaicin applied to human skin provokes a response known as neurogenic inflammation. Neuropeptides (substance P, CGRP), released from afferent C-fiber terminals and histamine, secondarily released from mast cells, are supposed to participate in this reaction. We investigated the contribution of arachidonic acid and metabolic products to neurogenic inflammation, using a potent topically applied glucocorticoid and the corresponding vehicle. Arachidonic acid is liberated from membrane phospholipids by phospholipase A2, an enzyme that can be blocked by glucocorticoids. In 12 healthy volunteers, neurogenic inflammation was induced by capsaicin 1% on both upper forearms after 16 h of topical pretreatment with either prednicarbate or vehicle. Neurogenic inflammation was assessed by laser Doppler flowmetry and by planimetry of flare sizes. Prednicarbate significantly reduced the laser Doppler flow values inside the flare responses, as well as the flare sizes themselves. These results show that to some extent glucocorticoids reduce capsaicin-induced neurogenic inflammation.

Sensory nerves, nitric oxide and NANC vasodilatation.

Primary afferent neurons, originating from the dorsal root ganglia, provide a perivascular network of fibres around the arterial system throughout the body. When stimulated, these fibres cause a nonadrenergic noncholinergic (NANC) vasodilatation by release of calcitonin gene-related peptide (CGRP). This peptide is a potent vasodilator and, in this action, cooperates with nitric oxide (NO) in a tissue-specific manner. The hyperaemic effect of intravascularly injected rat CGRP-alpha in the rat gastric mucosa is reduced by blockade of the NO synthesis, which indicates that CGRP dilates the gastric microvascular bed via NO-dependent and -independent mechanisms. This is also true for endogenous CGRP, as the gastric mucosal hyperaemia, which is caused by gastric acid challenge and involves CGRP, is likewise blocked by inhibition of the NO synthesis. The CGRP/NO-mediated vasodilatation is an important element of a neural emergency system that strengthens the resistance of the gastric mucosa in the face of pending acid injury. In the rat skin, CGRP participates in neurogenic inflammatory processes but the cutaneous vasodilator action of exogenous CGRP and the CGRP-mediated vasodilatation, evoked by antidromic stimulation of afferent nerve fibres, do not depend on the formation of NO. This L-arginine-derived autacoid, however, plays a role in the release of CGRP from afferent nerve fibres in the skin since it contributes to the CGRP-mediated vasodilator responses to chemical irritation or immunological challenge via interleukin-1 beta. These data indicate that the type of interaction between CGRP and NO in causing a NANC vasodilatation varies with the vascular bed under study. Depending on the tissue, NO may facilitate the release of CGRP from afferent nerve fibres or be a secondary vasorelaxant messenger of the peptide.

Diverse interactions of calcitonin gene related peptide and nitric oxide in the gastric and cutaneous microcirculation.

Calcitonin gene related peptide (CGRP) is the major mediator of afferent nerve mediated vasodilatation in the gastric mucosa and skin of the rat. Since receptors for CGRP occur on both the vascular endothelium and smooth muscle, it is conceivable that the vascular actions of CGRP involve multiple mechanisms. The vasodilator effect of rat CGRP-alpha in the rat gastric mucosa is indeed inhibited by blockage of nitric oxide (NO) synthesis, as is the gastric mucosal hyperemia in response to gastric acid challenge, which is mediated by CGRP release from afferent nerve fibres. In contrast, the vasodilator response to rat CGRP-alpha in the rat hind paw and the CGRP-mediated vasodilatation evoked by antidromic stimulation of afferent nerve fibres do not depend on the formation of NO. These data indicate that NO plays regionally different roles in the local vasodilator action of CGRP. NO is a secondary vasorelaxant messenger of CGRP in the gastric, but not in the cutaneous, microcirculation. However, this L-arginine-derived autacoid may have a role in the irritant-induced CGRP release from afferent vasodilator fibres in the skin.

[Thio- and oxybarbiturates inhibit peristalsis in the Guinea-pig ileum in vitro]. / Thio- und Oxybarbiturate hemmen die Dünndarmperistaltik. In vitro-Untersuchungen am Meerschweinchenileum.

INTRODUCTION: Inhibition of gastrointestinal motility by drugs used for anaesthesia or sedation in critically ill patients in the ICU is a major problem leading to various complications. Thus this study examines whether the thio- and oxybarbiturates thiopentone and pentobarbitone exert an inhibitory effect on intestinal peristalsis. METHODS: Peristalsis in isolated segments of the guinea-pig small intestine was elicited by distension of the gut wall through a rise of intraluminal pressure and recorded via the intraluminal pressure changes associated with the aborally moving peristaltic contractions. Thiopentone and pentobarbitone (0.1 - 300 microM)-induced inhibition of peristalsis was reflected by an increase of the peristaltic pressure threshold (PPT). RESULTS: Thiopentone (EC50 = 19,8 microM) and pentobarbitone (EC50 = 99.7 micro M) concentration-dependently increased the PPT. While the vehicle (saline) and 0.1 - 10 micro M thiopentone and pentobarbitone were without any effect on the PPT, 100 micro M caused a significant increase in PPT, and complete abolition of peristalsis occurred after 300 micro M thiopentone or pentobarbitone in all segments tested. Inhibition was reversed by changing the bath solution. CONCLUSIONS: Thio- and oxybarbiturates inhibit intestinal peristalsis in the guinea-pig ileum. It is assumed that thiopentone and pentobarbitone affect propulsive peristalsis also in the human small intestine.