Histamine H2 receptor-mediated airway goblet cell secretion and its modulation by histamine-degrading enzymes.
BACKGROUND
Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.


METHODS
We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.


RESULTS
Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.


CONCLUSIONS
These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.
Tamaoki
J
J
First Department of Medicine, Tokyo Women's Medical College, Japan.
Nakata
J
J
Takeyama
K
K
Chiyotani
A
A
Konno
K
K
D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology*; D002927:Cimetidine / Q000494:pharmacology*; D017259:Dimaprit / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000032:analysis; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006637:Histamine N-Methyltransferase / Q000378:metabolism; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D009093:Mucus / Q000737:chemistry / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006023:Glycoproteins; D006146:Guanidines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D008761:Methylhistamines; D010880:Piperidines; D011994:Recombinant Proteins; C024535:SK&F 91488; C069357:alpha-methylhistamine; D002927:Cimetidine; D006632:Histamine; D006631:Amine Oxidase (Copper-Containing); D006637:Histamine N-Methyltransferase; C026259:2-methylhistamine; D011738:Pyrilamine; C052075:thioperamide; C004479:pimagedine; D017259:Dimaprit