Tachykinin receptors mediating non-cholinergic contraction of the guinea-pig isolated main bronchus in response to field stimulation.
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.
Heavey
M L
ML
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Lan
W A
WA
Pennefather
J N
JN
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*
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