Histamine: Its novel role as an endogenous regulator of Con A – dependent T cell proliferation

Objective and design:The roles of histamine formed by the macrophage – T lymphocyte system were evaluated in the regulation of lymphocyte proliferation using mice lacking histamine receptors. Methods:Mice deficient in histamine type 1 (H1R), type 2 (H2R) or both receptors were employed to estimate possible intervention of the receptors in the histamine-dependent lymphocyte proliferation. Results:Histamine was produced de novo by spleen cells. Con A-dependent T cell proliferation decreased when histamine produced in the culture was degraded by the addition of histaminase. The H2R-deficient mice also showed a significant decrease in the Con A-dependent T cell proliferation, whereas it was not modulated in the H1R-deleted mice. Consistent with the reduction in T cell proliferation, there was a significant down-regulation of the production of IL-2, a T cell growth factor, in the H2R-deficient mice. Con A-dependent IL-2 synthesis was abrogated by the addition of histaminase. Conclusions:Con A-dependent T cell proliferation is (up)regulated by histamine produced de novo through the H2R, suggesting that histamine is a newly found regulator of T cell proliferation.Received 18 October 2003; returned for revision 17 December 2003; accepted by M. J. Parnham 6 February 2004     

Basophil histamine release and lymphocyte proliferation tests in latex contact urticaria

Basophil histamine release and lymphocyte proliferation tests were examined with latex allergen prepared from surgical gloves in 15 patients with latex contact urticaria. The basophil histamine release test (BHRT) yielded positive results in 13/14 (93%) patients, whereas commercial latex RAST was positive in only 9/15 (60%) patients. Lymphocyte proliferation test (LPT) was positive in 3/15 (20%) patients, suggesting that cell-mediated immune reactions may also occur in latex allergy. However, patch tests to latex were negative and neither were epidermal Langerhans cells able to present latex antigen to T lymphocytes in vitro.     

Involvement of opioid receptors in phencyclidine-induced enhancement of brain histamine turnover in mice

Summary When the histamine (HA) turnover in the brain of mice was estimated on the basis of the pargyline-induced accumulation of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, the enhancing effect of phencyclidine (PCP) on the HA turnover was antagonized by a large dose of naloxone. However, a dopamine receptor antagonist haloperidol, which is also a potent receptor antagonist, did not inhibit the effect of PCP on the HA turnover. [abetd-Ala², abetd-Leu⁵]enkephalin, a prototypic opioid agonist, markedly enhanced the HA turnover. The effect of this peptide was demonstrated not only when the HA turnover was determined by the pargyline-induced t-MH accumulation but when it was estimated by the HA depletion induced by -fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. A agonist, SKF-10047, and a agonist, ethylketazocine, had no PCP-like enhancing effect on the HA turnover. These results suggest that PCP enhances the brain HA turnover in mice by stimulating, probably indireclty, endogenous opioid systems. Send offprint requests to K. Saeki at the above address     

MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors

Summary The properties of MDL 72222 (1H,3,5H-tropan-3-yl-3,5-dichlorobenzoate), a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones, are described.On the rabbit isolated heart, MDL 72222 was a potent antagonist of responses mediated through the receptors for 5-HT present on the terminal sympathetic fibres. The threshold for antagonism was approximately 0.1 nM and the negative logarithm of the molar concentration of MDL 72222 which reduced the chronotropic response of the isolated rabbit heart to twice an ED₅₀ of 5-HT to that of the ED₅₀ was 9.27. MDL 72222 was also highly selective since responses to the nicotine receptor agonist, dimethylphenylpiperazinum iodine (DMPP), were inhibited only at concentrations more than 1000 times those necessary to inhibit 5-HT.In the anaesthetised rat, MDL 72222 produced marked blockade of the Bezold-Jarisch effect of 5-HT. Again, inhibition was selective since much higher doses of MDL 72222 failed to alter the response to electrical stimulation of the efferent vagus nerves. In contrast, MDL 72222 proved only a weak and essentially non-selective antagonist of responses mediated by the 5-HT M-receptor present on the cholinergic nerves of the guinea-pig ileum.MDL 72222 does not block smooth muscle contractile responses elicited by oxytocin or mediated through 5-HT D-receptors, muscarinic or nicotinic cholinoceptors or histamine H₁-receptors except at relatively high concentrations. Similarly, in a number of radioligand binding assays carried out using brain tissue membranes, the displacing effects of MDL 72222 were absent or weak at sites identifying compounds with activity at ₁, ₂ or -adrenoceptors, 5-HT₁ or 5-HT₂ receptors, benzodiazepine receptors or histamine H₁-receptors.MDL 72222 is the first reported selective and potent antagonist of responses mediated through the 5-HT receptors present on the terminal sympathetic neurones of the rabbit heart and on the neurones subserving the afferent limb of the Bezold-Jarisch reflex. The compound should provide a useful means by which responses mediated through such sites can be distinguished.     

Flexor Tenosynovectomy for Recurrent Carpal Tunnel Syndrome: A Retrospective Case Series of 108 Hands

Background: The etiology of recurrent carpal tunnel syndrome (CTS) is unclear, and outcomes following secondary surgery in this demographic have been poorer than primary surgery. Fibrosis and hypertrophy have been identified in the flexor tenosynovium in these patients. The authors use flexor tenosynovectomy (FTS) for recurrent CTS after primary carpal tunnel release and present a review of these patients. Methods: A retrospective chart review was performed of 108 cases of FTS for recurrent CTS from 1995 to 2015 by 4 attending surgeons at one institution. Demographic information, symptoms, and outcomes were among the data recorded. A phone survey was conducted on available patients where the shortened version of the Disabilities of the Arm, Shoulder and Hand Questionnaire (QuickDASH) and satisfaction were assessed. Results: Average office follow-up was 12 months. Average age was 57.5 years. A total of 104 (96%) reported symptom improvement and 48 (44%) reported complete symptom resolution. Forty patients were available for long-term follow-up at an average 6.75 years postoperatively via phone interview. Average QuickDASH score was 31.2 in these patients. Thirty-six (90%) of 40 patients were initially satisfied at last office visit, and 31 (78%) of 40 were satisfied at average 6.9 years, a maintenance of satisfaction of 86%. Satisfied patients were older (58 years) than unsatisfied patients (51 years). Conclusion: Both long-term satisfaction and QuickDASH scores in our cohort are consistent with or better than published results from nerve-shielding procedures. The authors believe a decrease in both carpal tunnel volume and potential adhesions of fibrotic or inflammatory synovium contributes to the benefits of this procedure. This remains our procedure of choice for recurrent CTS.     

Pentobarbital-induced drinking does not rely on a renal dipsogen

Injections of pentobarbital have been shown to produce drinking in both deprived and nondeprived rats and a number of other studies have shown that pentobarbital is a potent renin releasor. Since renin has been shown to be involved in thirst regulatory mechanisms and since the dipsogenic actions of other renin-releasing agents have been blocked by nephrectomy, we sought to determine whether or not pentobarbital-induced drinking relies on a renal dipsogen. Rats were either "sham" operated or nephrectomized under ether anesthesia. Five to six hours later, animals in each group were injected with either 9.5 mg/kg pentobarbital sodium or vehicle, and intakes were measured 60 minutes later. Statistical analysis of water intakes indicated that pentobarbital produced significant drinking in both control operated and in nephrectomized rats, and that the intakes in these two groups did not differ. These results indicate that pentobarbital-induced drinking is not secondary to increased plasma renin activity and may suggest the involvement of central mechanisms in the drinking response.     

Prejunctional inhibition of sympathetically evoked pupillary dilation in cats by activation of histamine H3 receptors

Summary Frequency-dependent pupillary dilations were evoked by electrical stimulation of the pre- or post-ganglionic cervical sympathetic nerve (sympatho-excitation) or the hypothalamus (parasympatho-inhibition) in sympathectomized anesthetized cats. Systemic administration of the selective histamine H₃ receptor agonist (R)--methylhistamine (RMeHA) produced a dose-dependent depression of mydriasis due to direct neural sympathetic activation but had no effect on responses elicited by parasympathetic withdrawal. The histamine H₂ receptor agonist, dimaprit, was inactive. RMeHA was much more effective in depressing sympathetic responses obtained at lower frequencies when compared to higher frequencies of stimulation.Responses evoked both pre- and postganglionically were inhibited by RMeHA. This peripheral sympathoinhibitory action of RMeHA was antagonized by the histamine H₃ receptor blocker thioperamide but not by intravenous pretreatment with the histamine H₁ receptor antagonist chlorpheniramine. Histamine H₂ receptor blockers cimetidine and ranitidine were also without effect. RMeHA did not depress pupillary responses elicited by i.v. (-)-adrenaline.The results demonstrate that histamine H₃ receptors modulate sympathetic activation of the iris at a site proximal to the iris dilator muscle. The predominant mechanism of action appears to the prejunctional inhibition of noradrenaline release from postganglionic sympathetic nerve endings. However, a concomitant ganglionic inhibitory action cannot be excluded. Correspondence to M. C. Koss at the above address     

Effects of 6-hydroxydopamine on pre- and post-junctional 5-HT1-like receptor-mediated responses in dog saphenous vein

Summary To investigate whether 5-HT₁-like receptor-mediated inhibition of adenosine 3 : 5-cyclic monophosphate (cyclic AMP) accumulation occurs in nerves or smooth muscle of saphenous vein, infusions of 6-hydroxydopamine (6-OHDA) were administered to dogs with the aim of inducing sympathetic nerve damage. The effects of 6-OHDA on other 5-HT₁-like receptor-mediated responses at the pre- and post-junctional level were investigated for comparison by studying 5-hydroxytryptamine (5-HT)-induced inhibition of ³H-noradrenaline release and contraction of smooth muscle respectively.Disruption of nerve function by 6-OHDA was revealed by the lack of catecholaminergic fluorescence and neurogenic contractile responses in saphenous veins from dogs treated with 6-OHDA. In addition, severe impairment of neuronal uptake mechanisms were apparent since basal efflux of ³H-noradrenaline, electrically-evoked release of ³H-noradrenaline and remaining ³H-noradrenaline content were considerably reduced. Some ³H-noradrenaline was taken up and released in 6-OHDA treated tissues which is consistent with the existence of nerve varicosities resistant to the present dosing regime of 6-OHDA, an observation substantiated by electron microscopy studies showing inconsistent lesions of nerve terminals.6-OHDA pre-treatment potentiated the smooth muscle contractile responses mediated by 5-HT₁-like receptors as well as potentiating 5-HT-evoked inhibition of prostaglandin E₂-stimulated cyclic AMP accumulation. It did not, however, affect 5-HT-induced inhibition of ³H-noradrenaline release. The present results suggest that inhibition of cyclic AMP accumulation by 5-HT occurs predominantly in smooth muscle. Correspondence to A. J. Kaumann at the above address     

Pharmacological characterization of mediators and vagal influence in the acute allergic bronchoconstriction in guinea pigs

Summary The allergic bronchoconstriction in guinea pigs has been attributed mainly to the release of mast cell mediators. Histamine has been involved in the first minutes of the anaphylactic reaction and new-formed compounds in the subsequent response. In this asthma model the vagal influence has been sparsely investigated. In the present work we evaluated the pharmacological modification of the acute allergic bronchoconstrictor response in guinea pigs sensitized to ovalbumin through aerosol exposure. Pyrilamine (20 g/kg), diethylcarbamazine (a lipoxygenase inhibitor, 10 mg/kg) and dexamethasone (4 mg/kg) each reduced the antigen-induced bronchoconstriction throughout the 30 min studied. Indomethacin (3.1 mg/kg) did not modify the response to the antigen. Atropine (2 mg/kg) plus bilateral vagotomy also diminished this response from 5 min onward. On the other hand, from 5 min ahead pyrilamine-resistant bronchoconstriction was partially inhibited by dexamethasone, and it was almost completely blocked during all of the response when atropine plus bilateral vagotomy were added to dexamethasone. Dipyridamole (an inhibitor of the adenosine uptake, 0.4 mg/kg) enhanced the bronchoconstriction, though this was significant only in the 2–5 min time-interval of the response. These results suggest that histamine and vagal influence play an important role in the whole response to antigen, that other mediators, probably leukotrienes, participate in this response from 5 min onward, and that adenosine could exert a potentiation effect on this response. Send offprint requests to L. M. Montaño at the Instituto Nacional de Enfermedades Respiratorias