title: Tachykinin receptors mediating non-cholinergic contraction of the guinea-pig isolated main bronchus in response to field stimulation.
abstract: 1. The primary aim of the present study was to classify the receptors activated by tachykinins released by field stimulation of intramural nerve terminals of the guinea-pig isolated main bronchus by using the novel non-peptide NK1 and NK2 receptor-selective antagonists SR 140333 and SR 48968, respectively. 2. Log concentration-response curves to substance P (SP), the NK1 receptor-selective agonist [Sar9, Met(O2)11]-SP and the NK2 receptor-selective agonist [Nle10]-neurokinin (NK) A(4-10) were constructed in the presence of indomethacin (2 mumol/L) and phosphoramidon (5 mumol/L). Substance P was the least potent of these agonists. 3. In left and right main bronchi, SR 140333 (100 nmol/L) antagonized concentration-related contractions evoked by SP yielding pKB values of 8.02 and 7.68, respectively. SR 140333 (10 nmol/L) antagonized the effects of [Sar9, Met(O2)11]-SP on the left bronchus with a pKB value of 8.04. 4. SR 48968 (100 nmol/L) antagonized the effects of SP yielding pKB estimates of 7.88 (left bronchus) and 7.31 (right bronchus). 5. [Nle10]-NKA(4-10) was more potent in the left than in the right main bronchus. SR 48968 (0.1-10 nmol/L) antagonized the effects of [Nle10]-NKA(4-10) on the left bronchus with pKB estimates of 8.26-10.25. 6. In the presence of indomethacin (2 mumol/L), phosphoramidon (5 mumol/L) and atropine (1 mumol/L), electrical field stimulation (EFS; 30 V, 1 ms, 15 s at 1, 3, 10 and 30 Hz) produced prolonged contractions. SR 48968 (0.1 mumol/L) markedly reduced responses to stimulation, whereas SR 140333 (0.3 mumol/L) caused a small but significant rightward displacement of the log frequency-response curve. In combination, these concentrations of SR 48968 and SR 140333 produced complete inhibition to field stimulation at 10 Hz. 7. These results indicate that: (i) both NK1 and NK2 receptor subtypes are present in the guinea-pig main bronchi with the left bronchus being more sensitive to an NK2 receptor agonist; and (ii) EFS of the main bronchus leads to frequency dependent contractions due to the release of tachykinin(s) that predominantly activate an NK2 receptor.
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Heavey
authors.forename: W A
authors.initials: WA
authors.lastname: Lan
authors.forename: J N
authors.initials: JN
authors.lastname: Pennefather
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors; D018039:Receptors, Tachykinin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D001549:Benzamides; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018039:Receptors, Tachykinin; C085215:SR 140333; C073839:SR 48968; D001285:Atropine; D002217:Carbachol