Combined Inhibition of Histamine H1 Receptors and Leukotrienes Reduces Compound 48/80-Induced Contraction of the Human Bronchus in vitro.

BACKGROUND/AIMS: Bronchial asthma continues to be a big challenge to therapy. Mast cells play an important role in allergic asthma. Histamine and leukotrienes are established mast cell mediators, but antihistamines currently play no role in asthma therapy. METHODS: Human bronchial strips were exposed to the mast cell activator compound 48/80 (200 µg/ml) in isolated organ experiments. RESULTS: The contractile response was not inhibited by the H1 receptor antagonist antihistamine chloropyramine (0.3 µmol/l), the leukotriene cys-LT1 receptor antagonist MK 571 (3 µmol/l), the 5-lipoxygenase inhibitor MK 886 (5 µmol/l), the cyclo-oxygenase inhibitor indomethacin (5 µmol/l), tetrodotoxin, or atropine. Chloropyramine, combined with either MK 571 or MK 886 significantly reduced the response. CONCLUSION: A supra-additive effect is proposed for the antihistamine and the anti-leukotrienes, which might have relevance to human asthma therapy as well; such a combination deserves a large-scale clinical study. These data also indicate that substances like compound 48/80 should be denoted as mast cell activators rather than 'histamine liberators'.

Evidence that adrenergic and cholinergic but not capsaicin-sensitive nerves are involved in the nerve-mediated contraction of the guinea pig seminal vesicle.

BACKGROUND/AIMS: The neurotransmitters participating in the nerve-mediated contraction of the guinea pig seminal vesicle (GPSV) have not been firmly established. There is debate as to the mediating role of norepinephrine and acetylcholine. METHODS: We have used longitudinally and circularly oriented strips of GPSV and activated their intramural nerves by electrical field stimulation (5 and 10 Hz for 30 s). RESULTS: Contractile responses to stimulation were enhanced by a cholinesterase inhibitor and reduced by the adrenergic α-receptor antagonist phentolamine (2.5 µmol/l). Atropine (1 µmol/l) significantly reduced responses in longitudinal preparations; a less consistent inhibition was found in circular preparations. The sensory neuron stimulant and blocker capsaicin was without effect. CONCLUSIONS: It is concluded that adrenergic nerves and also acetylcholine mediate the contractile response of the GPSV.

Purinoceptor-mediated, capsaicin-resistant excitatory effect of allyl isothiocyanate on neurons of the guinea-pig small intestine.

Allyl isothiocyanate (AITC; 200 µM) caused atropine- and tetrodotoxin-sensitive longitudinal muscle contraction on the guinea-pig small intestine. The response was not influenced by hexamethonium, a functional blockade of capsaicin-sensitive neurons or by antagonists acting at TRPV1 or TRPA1, but was abolished by the P2 purinoceptor antagonist PPADS (50 µM). It is concluded that cholinergic motoneurons are activated by a purinergic mechanism in the course of the AITC response, independently of capsaicin-sensitive processes or even TRPA1.

The contractile effect of anandamide in the guinea-pig small intestine is mediated by prostanoids but not TRPV1 receptors or capsaicin-sensitive nerves.

Although exogenous and endogenous cannabinoid receptor agonists have well-documented inhibitory effects on gastrointestinal motility, a TRPV1 receptor-mediated excitatory action of anandamide (arachidonoyl ethanolamide, AEA) in the guinea-pig ileum strip has also been described. We used in vitro capsaicin desensitization for assessing the possible participation of sensory neurons in the contractile effect of anandamide on the guinea-pig whole ileum, as well as autonomic drugs and a cyclooxygenase inhibitor for characterizing this response. Isolated organ experiments were used with isotonic recording. Contractions induced by anandamide (1 or 10 µM) were strongly inhibited by tetrodotoxin, indomethacin or atropine plus a tachykinin NK(1) receptor antagonist, but weakly to moderately reduced by atropine alone and partly diminished by the fatty acid amide hydrolase inhibitor URB 597. Neither capsaicin pre-treatment nor the TRPV1 receptor antagonist BCTC, the ganglionic blocking drug hexamethonium or cannabinoid (CB1 or CB2 ) receptor antagonists, influenced the effect of anandamide. It is concluded that the capsaicin-insensitive, neuronal excitatory effect of anandamide in the intestine is most probably mediated by cyclooxygenase products. Such a mechanism may also play a role at other sites in the mammalian body.