Modulation of capsaicin-sensitive nerve activation by low pH solutions in guinea-pig lung.
We have studied the stimulation of airways sensory nerves by low pH solutions and concomitantly induced bronchoconstriction. The effect of low pH buffer and lactic acid solutions at the same pH (5 and 6) were compared and the influence of low pH on the capsaicin effect was recorded. We have used the isolated guinea-pig perfused lung model taking the insufflation pressure as an indicator of bronchial smooth muscle tone while the calcitonin gene-related peptide-like immunoreactivity measured in the lung perfusate represented sensory nerves activation. Low pH buffer and lactic acid solution (3 and 4.1 mM) at the same pH of 5 and 6 induced pH-dependent bronchoconstriction and peptides release which were completely abolished after systemic pretreatment with capsaicin. Both responses were significantly inhibited after Ca2+-free infusion. Capsazepine (10(-6) M), a selective capsaicin antagonist, significantly reduced the calcitonin gene-related peptide-like immunoreactivity overflow evoked by all the solutions studied. Diclofenac (10(-5) M), a cyclooxygenase blocker, inhibited pH 5, pH 6 and lactic acid 3 mM (pH 6)-evoked peptide release, but not lactic acid 4.1 mM (pH 5). The functional response was not significantly modified after diclofenac while only the lactic acid 3 mM response was significantly reduced by capsazepine. There was a synergistic interaction between capsaicin and low pH buffer on calcitonin gene-related peptide-like immunoreactivity release and an additive effect on bronchoconstriction. It is concluded that in the isolated perfused guinea-pig lung, lactic acid and low pH buffer induced calcitonin gene-related peptide-like immunoreactivity release and bronchoconstriction by stimulation of capsaicin-sensitive C fibres via a pathway partly dependent of extracellular Ca2+. The mechanism of calcitonin gene-related peptide-like immunoreactivity release seems to be the same at pH 6, while differences are evident at pH 5 between low pH buffer and lactic acid. Our results also suggest that proton activity could exert a modulatory role on the capsaicin-sensitive sensory nerves by a mechanism which remains to be clarified.
Auberson
S
S
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden. Serge.Auberson@hcuge.ch
Lacroix
J S
JS
Lundberg
J M
JM
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D002021:Buffers; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000294:innervation*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology
D002021:Buffers; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D019344:Lactic Acid; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin