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.
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
C A
CA
Maggi
R
R
Patacchini
F
F
Perretti
S
S
Meini
S
S
Manzini
P
P
Santicioli
E
E
Del Bianco
A
A
Meli
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