Expression and function of P2X purinoceptors in rat histaminergic neurons.
(1) The pharmacology of ATP responses and the expression pattern of seven known subunits of the P2X receptor were investigated in individual histaminergic neurons of the tuberomamillary nucleus (TM). (2) ATP (3-1000 micro M) evoked fast non-desensitizing inward currents in TM neurons. 2-methylthioATP (2MeSATP) displayed the same efficacy but a lower potency, EC(50)s 84 micro M versus 48 micro M, when compared with ATP. Adenosine-diphosphate (ADP), uridine-triphosphate (UTP) and alpha beta methylene-ATP (alphabeta-meATP) were inactive. (3) ATP-mediated whole cell currents were potentiated by acidification of the recording solution (pH 7.5 and 6.6 were compared). (4) Single-cell RT-PCR (scRT-PCR) analysis revealed that the P2X(2) receptor is expressed in all PCR-positive neurons. Each of the P2X(1), P2X(3), P2X(4), P2X(5) and P2X(6) mRNAs were detected in less than 35% of the cells. (5) Suramin antagonized ATP responses with an IC(50) of 4.2 micro M and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 1 micro M) reduced ATP responses to 43% of control, when antagonists were pre-applied 90s before the agonist. Cibacron blue (3 micro M) given together with ATP potentiated control responses by 67%, but inhibited it to 10% after pre-application. (6) 2',3'-O-(2,4,6-Trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP) antagonized ATP responses with an IC(50) of 7 micro M. (7) Pharmacological properties of ATP responses together with scRT-PCR data suggest that P2X(2) is the major purinoceptor on the soma of TM neurons, however the presence of heteromeric P2X(2/5) receptors in some neurons cannot be excluded. (+info
An inhibitory effect of acetycholine on the response of the guineapig ileum to histamine.
If small doses of histamine are alternated with small doses of acetylcholine on the isolated guinea-pig ileum in Tyrode solution, the response to histamine tends to diminish and may disappear. When the response to the small doses of histamine has disappeared, a contraction may be elicited by larger doses. The diminution is reversible, the response returning if the preparation is left unstimulated by drugs for varying periods of time. This phenomenon also occurs when the loops are suspended in Tyrode solution containing cocaine or atropine. (+info
Some effects of histamine in the normal and Haemophilus pertussis vaccinated rat.
The effects of histamine in the normal and H. pertussis vaccinated rat have been investigated. In the normal animal small doses of histamine (from 1 to 30 mg./kg., i.v.) produced significant, reversible alterations in the blood pressure, electrocardiogram and electroencephalogram. Doses of 100 mg./kg. or more caused bronchoconstriction and doses of 200 mg./kg. or more an effect on the muscular contractions after electrical stimulation of the nerve. Acute histamine intoxication resulted on rapid injection of 500 mg./kg. intravenously; death was probably due to cardiovascular collapse. In the vaccinated rat, a distinction could be made between the immediate and delayed effects of histamine. With a sublethal dose of histamine (5 mg./kg.) alterations in the blood pressure, electrocardiogram and electroencephalogram were noted. The neuromuscular system, which in the normal animal was the least reactive to histamine, showed the most marked increase in sensitivity in the vaccinated rat. The delayed effects of histamine observed after an interval of 5 to 30 min. were characteristic and irreversible, leading to death of the animal. The mechanism of death in the vaccinated rat after histamine appears to differ from that of the normal animal and has been discussed in the light of present knowledge. (+info
Perfusion of cerebral ventricles: effects of drugs on outflow from the cisterna and the aqueduct.
In cats under chloralose anaesthesia the cerebral ventricles were perfused with Locke solution at a rate of 0.1 ml./min. from an indwelling cannula in the lateral ventricle. The effluent was collected from a cannula either inserted into the cisterna magna or pushed into the aqueduct. When collection was from the cisterna the perfusion included relatively large areas of the subarachnoidal spaces since in cats the foramina of Luschka form the only outlet from the fourth ventricle. Tubocurarine, histamine, and adrenaline injected intravenously caused great variations in outflow from the cisterna, but these changes did not occur when the collection was from the aqueduct. The changes in outflow from the cisterna were similar whether the injection produced a fall of arterial blood pressure as after tubocurarine and histamine, or a rise, as after adrenaline. (+info
The mechanism of the inhibition by carbonic acid of the smooth muscle contraction produced by histamine and oxytocin.
Carbonic acid inhibited the stimulating action of histamine on guinea-pig intestine and of oxytocin on the uterus of many animal species. This effect was relatively specific. Under the same conditions the actions of acetylcholine, KCl, adrenaline (on rabbit uterus), and ergot alkaloids were not inhibited. The electrical excitability of smooth muscle was similarly not affected. The inhibitory action of carbonic acid is directly proportional to its concentration in the medium in which the isolated organ is maintained. The study of the activity of histamine and oxytocin at different pH in a medium free of NaHCO(3) and buffered with a mixture of sodium maleate and maleic acid suggested that the inhibitory action exerted by carbonic acid was specific and independent of the simultaneous modifications of the hydrogen ion concentration. The mechanism of these phenomena is discussed. (+info
Effect of histamine on ganglionic transmission.
Histamine has been shown to depress transmission through the perfused superior cervical ganglion of the cat when doses of 150 mug. or more were administered. The intensity of the ganglionic block was related to the dose of histamine employed. In one-third of the experiments, a slow contracture of the nictitating membrane occurred after histamine had been injected; the contracture lasted up to 10 min., and subsequent injections of histamine gave rise to progressively smaller responses. The blocking action of histamine was evident in all experiments and was the most prominent feature observed. Histamine in a sub-depressant dose enhanced the action of the competitive blocking agents tetraethylammonium and hexamethonium, and also the depolarizing blocking agents tetramethylammonium and nicotine. The possible physiological role of histamine in the autonomic nervous system is discussed. (+info
Effects of long-acting bronchodilators and placebo on histamine-induced asthma symptoms and mild bronchusobstruction.
STUDY OBJECTIVE: Accurate perception of airway caliber remains an important issue in asthma management. The way bronchodilation is perceived is partly related to the perception of the efficacy of bronchodilators in relieving complaints. In the present study, we compared the effects of salmeterol, formoterol and placebo on relief of histamine-induced asthma symptoms and mild bronchusobstruction. METHODS: In this randomized controlled, double blind study, 30 asthmatics were challenged with histamine until forced expiratory volume in 1s (FEV(1)) fell with > or =20%. Subjects received salmeterol, formoterol or placebo after the histamine provocation. Pulmonary function (FEV(1)) and asthma symptoms (Asthma Symptom Checklist, Borg Dyspnea Scale) were assessed 5 and 20 min later. RESULTS: FEV(1) improved significantly more in the salmeterol and formoterol group than in the placebo group (P<0.001, P<0.001 and P<0.05, respectively). Salmeterol and formoterol were not different with regard to the pulmonary function recovery. No significant differences were found between the effects of salmeterol, formoterol and placebo on any of the symptom responses at the different time points. CONCLUSIONS: We conclude that after a histamine-induced mild bronchusobstruction, a similar asthma symptom recovery occurred when inhaling salmeterol, formoterol or placebo, despite better recovery of pulmonary function in the active drug conditions. (+info
Histamine combined with melphalan in isolated limb perfusion for the treatment of locally advanced soft tissue sarcomas: preclinical studies in rats.
PURPOSE: To evaluate the potential benefit of histamine combined with melphalan in the isolated limb perfusion (ILP) as an alternative to TNF-alfa and melphalan combination, for the treatment of irresectable soft tissue sarcomas of the limbs in Brown Norway (BN) rats. METHODS: 20 BN rats had small fragments of syngeneic BN-175 fibrosarcoma inserted on the right hind limb. In 7-10 days the tumor reached a median diameter of 12-15 mm and they were randomly divided in four groups (sham, melphalan, histamine and escalating doses of histamine combined to melphalan) being submitted to experimental ILP for 30 minutes. Tumors were measured daily with a caliper and the volume was calculated. RESULTS: Response curves showed a significant effect of the combination of histamine 200 mg/mL with melphalan, with 66% overall response, including 33% complete responses (p< 0.01). There were no systemic collateral effects and locally only mild temporary edema was observed for some animals treated with histamine. CONCLUSION: Histamine combined with melphalan had a promising effect in the ILP warranting future studies to better explore the mechanism of action as well as its potential use in organ perfusion. (+info