cyclo(gln-trp-phe-gly-leu-met) and Bronchial-Spasm

Epinastine is an antihistamine and antiallergic drug. The object of this work was to use a rat model of noncholinergic bronchospasm to identify novel nonantihistamine mechanisms that might contribute to the efficacy of this drug in asthma. Oral epinastine blocked bronchospasm (increase in RL) in BDE rats induced by the adenosine A3 receptor agonist N6-2-(4-aminophenyl)ethyladenosine with an ED50 of only 0.47 mg/kg. An intravenous dose of 10 microg/kg epinastine was also effective. In vitro, epinastine bound 5-HT2a, 5-HT7, and 5-HT3 receptors (Ki values, respectively, 21, 33, and 159 nM). In the in vivo rat model, 5-HT2a antagonist ketanserin, 5-HT7 agonist 5-carboxamidotryptamine, and (to a limited extent) 5-HT3 antagonist ondansetron could all, like epinastine, block bronchospasm, but the "classic" antihistamine chlorpheniramine was ineffective. Epinastine could not block bronchospasm in the presence of 1 mg/kg NK2 receptor antagonist L 659877 or 20 microg/kg potassium channel blocker iberiotoxin, suggesting the epinastine was acting on a neurokinin- and potassium channel-mediated mechanism. Epinastine has other modes of action apart from its antihistamine activity that may be relevant to its use in asthma.

Topics: Adenosine; Administration, Oral; Animals; Bronchi; Bronchial Spasm; Dibenzazepines; Histamine H1 Antagonists; Imidazoles; Injections, Intravenous; Peptides; Peptides, Cyclic; Potassium Channel Blockers; Purinergic P1 Receptor Agonists; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Activation of the adenosine A3 receptor subtype by the agonist N6-2-(4-aminophenyl)ethyladenosine is shown here to induce bronchospasm (increased pulmonary resistance and decreased pulmonary compliance) in BDE strain rats. The effect is substantially reduced by pretreating the rats with compound 48/80, disodium cromoglycate (30 micrograms/kg) or epinastine (10 micrograms/kg), which is compatible with involvement of mast cells. It is also substantially reduced by combined vagotomy and atropinization or by pretreatment with the NK2 receptor antagonist L-659,877, suggesting involvement of neuropeptide-mediated neural pathways. The mechanism by which activation of the adenosine A3 receptor induces bronchospasm is distinct from the mechanism by which activation of the adenosine A1 receptor induces bronchospasm. In particular, the A1 agonist 2-chloro-N6-cyclopentyladenosine can increase pulmonary resistance independently of mast cell activation. These results are in accord with the concept that a pathway exists in vivo by which activation of mast-like cells can activate axon reflexes, that adenosine acting through its A3 receptor can potentially up-regulate this pathway and that antiallergic substances such as disodium cromoglycate and epinastine may interfere with this pathway.

Topics: Adenosine; Animals; Atropine; Blood Pressure; Bronchial Spasm; Female; Injections, Intravenous; Lung; Male; Mast Cells; Neuropeptides; Peptides, Cyclic; Purinergic P1 Receptor Agonists; Rats; Receptors, Neurokinin-2; Receptors, Purinergic P1; Vagotomy; Xanthines

1. The aim of this study was to characterize the tachykinin NK2 receptor subtype mediating the spasmogenic response in the human isolated bronchus. The motor response to neurokinin A (NKA) and the selective NK2 agonist [beta Ala8]NKA(4-10), as well as the antagonistic effects of cyclic (L659,877) and linear (MEN 10376) peptide NK2 antagonists were assessed in the presence or absence of amastatin (an inhibitor of aminopeptidases A and M). 2. NKA was more potent than [beta Ala8]NKA(4-10) in eliciting bronchoconstriction (pD2 being 7,43 and 6,87 respectively). In the presence of amastatin (1 microM), the estimated affinity of [beta Ala8]NKA(4-10), but not that of NKA, was significantly increased to yield a pD2 of 7,44. 3. L659,877 and MEN 10376 inhibited [beta Ala8]NKA(4-10)-induced contraction with similar affinities; pA2 values were 5.7 +/- 0.22 and 6.3 +/- 0.32, respectively. Amastatin (1 microM) increased the potency of MEN 10376 to 7.28 +/- 0.46, whereas that of L659,877 was unaffected. 4. In the presence of amastatin the pseudopeptide MDL 28,564 behaved as a partial agonist. 5. We conclude that the NK2 receptor subtype present in the human bronchus has properties similar to those described for the circular muscle of the human colon and thus may be classified as a 'NK2A' subtype. We show that the apparent potency of peptides, bearing N-terminal acidic residues, is influenced by an amastatin-sensitive peptidase, possibly aminopeptidase A.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Bronchi; Bronchial Spasm; Female; Humans; In Vitro Techniques; Male; Molecular Sequence Data; Neurokinin A; Peptide Fragments; Peptides; Peptides, Cyclic; Receptors, Neurokinin-2; Tachykinins