TACHYKININ-INDEPENDENT EFFECTS OF CAPSAICIN ON SMOOTH-MUSCLE IN HUMANISOLATED BRONCHI

Contractile and relaxant responses to capsaicin and resiniferatoxin we re examined in human isolated bronchus (5-12 mm o.d.). Bronchi isolate d from 10 of 16 lungs contracted in response to capsaicin. The contrac tions averaged 20% of maximal contraction at 1 mu M and averaged > 40% maximal contraction at 300 mu M (the highest concentration studied). The capsaicin-induced contractions were mimicked by resiniferatoxin (0 .1-10 mu M) and inhibited by the putative capsaicin receptor antagonis t, capsazepine (10 mu M). The contractile response to capsaicin was no t affected by the potent NK-2 selective antagonist SR 48968 (0.3 mu M) , whereas responses to concentrations of neurokinin A (10 nM), neuroki nin B (0.1 mu M), substance P (1 mu M), neuropeptide gamma (10 nM), an d neuropeptide K (10 nM) which produced similar-size contractions were almost abolished by 0.1 mu M SR 48968. The bronchi isolated from 8 of 16 lungs also exhibited relaxations in response to capsaicin. Capsaic in-induced relaxations were not inhibited by the nitric oxide synthase inhibitor L-nitro-n-arginine (10 mu M). In whole-cell patch-clamp exp eriments on human cultured airway smooth muscle cells, capsaicin was f ound to enhance outward currents due to the activation of charybdotoxi n-sensitive large conductance Ca2+-activated K+ channels. Neither the capsaicin-induced contractions nor the relaxations were mimicked by an giotensin II, bombesin, or calcitonin gene-related peptide at concentr ations up to 1 mu M. These results suggest that capsaicin and resinife ratoxin can alter smooth muscle tone, but this response does not appea r to involve substance P or related neurokinins. Relaxations to capsai cin may, however, involve the activation of large conductance Ca2+-act ivated K+ channels.