AIMTo investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.

METHODSAnesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.

RESULTS(1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.

CONCLUSIONBrain histamine H3 receptors may be related to asthmatic respiratory responses.

Animals ; Asthma ; metabolism ; Brain ; metabolism ; Guinea Pigs ; Histamine Agonists ; pharmacology ; Histamine H3 Antagonists ; pharmacology ; Lateral Ventricles ; Male ; Methylhistamines ; pharmacology ; Muscle Contraction ; Piperidines ; pharmacology ; Receptors, Histamine H3 ; metabolism ; Substance P ; metabolism ; Trachea ; physiopathology

Interstitial cells of Cajal (ICCs) are the pacemaker cells in the gastrointestinal tract, and histamine is known to regulate neuronal activity, control vascular tone, alter endothelial permeability, and modulate gastric acid secretion. However, the action mechanisms of histamine in mouse small intestinal ICCs have not been previously investigated, and thus, in the present study, we investigated the effects of histamine on mouse small intestinal ICCs, and sought to identify the receptors involved. Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials (in current clamp mode) from cultured ICCs. Histamine was found to depolarize resting membrane potentials concentration dependently, and whereas 2-PEA (a selective H1 receptor agonist) induced membrane depolarizations, Dimaprit (a selective H2-agonist), R-alpha-methylhistamine (R-alpha-MeHa; a selective H3-agonist), and 4-methylhistamine (4-MH; a selective H4-agonist) did not. Pretreatment with Ca(2+)-free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished the generation of pacemaker potentials and suppressed histamine-induced membrane depolarization. Furthermore, treatments with U-73122 (a phospholipase C inhibitor) or 5-fluoro-2-indolyl des-chlorohalopemide (FIPI; a phospholipase D inhibitor) blocked histamine-induced membrane depolarizations in ICCs. On the other hand, KT5720 (a protein kinase A inhibitor) did not block histamine-induced membrane depolarization. These results suggest that histamine modulates pacemaker potentials through H1 receptor-mediated pathways via external Ca2+ influx and Ca2+ release from internal stores in a PLC and PLD dependent manner.
Animals ; Carbazoles ; Cyclic AMP-Dependent Protein Kinases ; Dimaprit ; Domperidone ; Estrenes ; Gastric Acid ; Gastrointestinal Tract ; Hand ; Histamine ; Indoles ; Interstitial Cells of Cajal ; Intestine, Small ; Membrane Potentials ; Membranes ; Methylhistamines ; Mice ; Neurons ; Permeability ; Phospholipase D ; Pyridoxal ; Pyrroles ; Pyrrolidinones ; Thapsigargin ; Type C Phospholipases