El papel en la histamina en la respuesta inmune / The role of histamine in the immune response

Actualmente, se considera al sistema inmune dentro de un marco de interacciones celulares en las que participan tanto moléculas provenientes de linfocitos como de macrófagos/monocitos, que inducen tanto señales positivas como negativas que conllevan hacia una perfecta regulación de la respuesta. La producción por estas células de moléculas como las prostaglandinas, la histamina y los leucotrienos, así como la presencia de receptores para ellas, indican su papel como mediadores intercelulares que, junto con las linfocinas y las monocinas comúnmente conocidas, y de las que se diferencian por su estructura y por su amplia distribución en los tejidos, estarían participando dentro de esta intrincada red de interacciones celulares que, finalmente, conducirán hacia una respuesta adecuada. Fue así como se abrió una nueva área de investigación sobre el papel de estas moléculas, generalmente consideradas por su potencial de daño, como sustancias clave que están induciendo "señales finas" de regulación. A pesar de que la literatura sobre el tema es vasta, abundan los resultados contradictorios, que deben ser tomados en cuenta con sentido crítico. Con esta idea en mente, en esta revisión se trata de definir el papel de la histamina, las prostaglandinas y los leucotrienos en la respuesta inmune, haciendo siempre una breve consideración sobre la bioquímica de cada una de estas moléculas, lo que finalmente nos llevará a una mejor interpretación de los resultados

H1 and H2 blockade: a prophylactic principle in anesthesia and surgery against histamine-release responses of any degree of severity: Part 1.

In the perioperative period, histamine release was shown in numerous situations and pathological states. They include diseases or complications of diseases, preparation and premedication of patients, induction of anaesthesia, maintenance of anaesthesia and surgery, and administration of drugs and treatment in the immediate postoperative period. A premedication with histamine H1 and H2 receptor antagonists was developed which in five controlled clinical trials blocked histamine-release responses of all grades of severity. These included single spots of erythema or a wheal up to life-threatening reactions or even death of the patient or laboratory animal. The necessity for a new premedication was investigated by methods of medical decision-making considering the incidence of the reactions, classification of severity, efficiency of prophylaxis and treatment of anaphylactoid reactions, and side-effects. As a result, the premedication with dimethpyrindene (Forhistal, Fenistil) plus cimetidine (Tagamet) was recommended in a series of patients at risk: those with a history of hypersensitivity reactions to intravenous agents or atopy, patients with a second I.V. drug exposure within a few days, those undergoing surgery with a high risk of histamine release, patients of greater than 70 years age, and poor-risk patients with preoperative cardiac, respiratory or liver insufficiency and shock.

Local modulation of neurotransmitter release in bovine splenic vein.

Bovine splenic vein has an abundant sympathetic innervation. Isolated strips were used to examine whether autoinhibition of norepinephrine release from the noradrenergic nerve terminals could be demonstrated under various experimental conditions and whether additional local regulatory modulators of transmitter release could also be implicated. In particular, the possibility of a histamine interaction with presynaptic inhibitory receptors was examined because ultrastructural evidence disclosed a close spatial relationship between mast cells and noradrenergic nerve terminals in the vessel wall. To investigate the presence of presynaptic alpha-receptors the competitive blocking agent phentolamine was included in the superfusion medium at concentrations ranging from 1 to 50 microM during electrical field stimulation at frequencies between 1 and 10 Hz. Transmitter outflow was measured as fractional tritium release. Low frequency stimulation (1 Hz) with 1 microM phentolamine resulted in the typical increase in norepinephrine release characteristics for presynaptic alpha-receptor inhibition. In contrast, high frequency (10 Hz) stimulation in the presence of 50 microM phentolamine caused an unexpected decrease in norepinephrine outflow. This unusual result can be explained by additional pharmacological actions of phentolamine unrelated to alpha-receptor blockade, e.g. histamine release from the mast cells which subsequently can act on presynaptic inhibitory histamine receptors. This effect, manifested at higher phentolamine concentrations, would overcome the alpha-receptor blockade. The presence of histamine receptors was supported by the results from electrical stimulation in the presence of exogenous histamine. Histamine decreased norepinephrine outflow while increasing basal tension and the contractile response of the vein strip. Unexpectedly, these effects appeared to be mediated by histamine receptors of the H1-type because they were reduced after pyrilamine but unaffected by agonists and antagonists to receptors of the H2-type. It is speculated that interactions between mast cells and noradrenergic nerve terminals may serve to maintain homeostasis in the bovine splenic vein.

The use of H1 and H2 histamine antagonists with morphine anesthesia: a double-blind study.

High doses of morphine can produce significant cardiovascular effects generally attributed to histamine release. The authors examined the possibility that H1 and H2 histamine antagonists might prove beneficial in preventing these responses. In a randomized double-blind study, four groups of 10 patients each received 1 mg/kg morphine and either a placebo, diphenhydramine (H1), cimetidine (H2), or both of the histamine antagonists. The morphine-placebo group demonstrated a marked elevation in plasma histamine levels (880 +/- 163 to 7437 +/- 2684 pg/ml), a decrease in systemic vascular resistance (SVR) (15.5 to 9.0 l torr/(l . min-1) and diastolic BP (71 +/- 3 to 45 +/- 4 torr) and an increase in cardiac index (CI) (2.4 +/- 0.2 to 3.0 +/- 0.21 . min-1 . m-2). The administration of either cimetidine or diphenhydramine with morphine provided minimal protection. Those patients who received morphine and both antagonists demonstrated significant attenuation of these responses (CI 2.5 +/- 0.2 to 2.5 +/- 0.1 l . min-1 . m-2; SVR 17.4 to 14.6 torr/(l . min-1) although plasma histamine levels showed a comparable increase (1059 +/- 222 to 7653 +/- 4242 pg/ml). These data demonstrate directly that many of the hemodynamic effects of morphine can be attributed to histamine release. They further demonstrate that significant hemodynamic protection can be obtained by the use of histamine antagonists and the combination of H1 and H2 antagonists is superior to either given alone.

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients.

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.

Acupuncture and gastric acid studies.

The effects of therapeutic acupuncture on gastric acid secretion on pain relief in chronic duodenal ulcer patients were studied. Ten adult Nigerian patients with clinical, endoscopic as well as radiological evidence of duodenal ulcer constituted the "Ulcer Group." Four other patients who gave history of dyspepsia formed the "Dyspeptic Group." Pentagastrin stimulation test was performed on all subjects pre- and post-acupuncture therapy. The classical Chinese acupuncture loci were employed. The mean Basal Acid Output (BAO) in the duodenal ulcer group was markedly reduced from 4.04 +/- 1.01 mMols/hour to 1.05 +/- 2.5 mMols/hour. The mean Maximal Acid Output (MAO) was lowered from 34.72 +/- 13.81 mMols/hour to 15.34 +/- 4.01 mMols/hour. The difference was statistically significant (P less than 0.001). It is more probable, therefore, that the relief of pain is attributable to the therapeutic inhibition of gastric hyperacidity in our patients. Thus, though pain relief has been previously demonstrated in response to acupuncture, the results of this investigation have gone further to show that acupunture achieves symptomatic relief through therapeutic gastric depression in duodenal ulcer patients.