The effect of thiorphan and epithelium removal on contractions and tachykinin release produced by activation of capsaicin-sensitive afferents in the guinea-pig isolated bronchus.
(1) We have studied the effect of epithelium removal (rubbing) and the endopeptidase 24.11 inhibitor, thiorphan, on the contractile response of the guinea-pig isolated bronchi (atropine and indomethacin in the bath) produced by electrical field stimulation, capsaicin or exogenously administered tachykinins (substance P and neurokinin A). (2) The response to field stimulation, thought to involve release of endogenous tachykinins, was potentiated by thiorphan in both epithelium-free and intact bronchi. However, at low frequencies (1-5 Hz), the effect of thiorphan was more evident in intact preparations. (3) The response to capsaicin was enhanced by both epithelium removal and thiorphan administration. (4) The response to exogenous substance P or neurokinin A was potentiated by thiorphan both in epithelium-free and intact bronchi. (5) Capsaicin (1 microM) evoked a consistent release of substance P-like immunoreactivity (determined by radioimmunoassay) and tachykinin-like immunoreactivity (determined by a novel immunoenzyme assay), which was enhanced by thiorphan in both epithelium-free and intact bronchi. (6) These findings suggest that a thiorphan-sensitive mechanism, presumably 'enkephalinase' (endopeptidase 24.11), plays a major role in inactivating endogenous tachykinins released from sensory nerves and that this enzymatic activity is still present after removal of the bronchial epithelium.
Maggi
C A
CA
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Patacchini
R
R
Perretti
F
F
Meini
S
S
Manzini
S
S
Santicioli
P
P
Del Bianco
E
E
Meli
A
A
D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000294:innervation; D002211:Capsaicin / Q000494:pharmacology*; D004558:Electric Stimulation; D004848:Epithelium / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors; D015288:Neurokinin A / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011863:Radioimmunoassay; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000378:metabolism*; D015244:Thiorphan / Q000494:pharmacology*
D015320:Tachykinins; D013373:Substance P; D011189:Potassium Chloride; D015288:Neurokinin A; D015244:Thiorphan; D015260:Neprilysin; D002211:Capsaicin