Involvement of different Ca2+ sources in changes of responsiveness of guinea-pig trachea to repeated administration of histamine and acetylcholine.

The role of Ca(i) and Ca(o) in changes of responsiveness of guinea pig tracheal smooth muscle strips to repeated applications of histamine and acetylcholine was investigated. Homologous desensitization to histamine developed when the airways were exposed to concentrations higher than 10(-5) mol/l, while sensitization to acetylcholine was recorded even when its highest concentration did not exceed 10(-5) mol/l. The maximum of the concentration response curves (CRC) was reduced upon repeated histamine, and enhanced upon repeated acetylcholine administration. There was, however, no significant difference in EC50 values for repeated CRCs of the stimulants. In Ca2+ free, EGTA (10(-4) mol/l) containing solution the second contraction elicited by single (10(-3) mol/l) or cumulative (10(-9)-10(-3) mol/l) histamine application was significantly smaller, while that elicited by acetylcholine did not differ significantly from the first one. In Ca(2+)-free, caffeine (10(-2) mol/l) and EGTA containing solution the contractile responses to repeated additions of Ca2+ (2.7 mmol/l) in histamine and acetylcholine (10(-3) mol/l) treated tracheae was decreased and unchanged, respectively. Addition of nifedipine (10(-6) mol/l) to this solution fully prevented Ca2+ in inducing contraction in histamine treated tracheae, while Ca2+ still induced contraction in acetylcholine treated tracheae. TMB-8 (10(-5) mol/l) was ineffective in blocking the remaining acetylcholine induced contractions. The present data suggest that contractions of the guinea pig trachea elicited by histamine and acetylcholine are due to release of intracellular Ca2+ from a caffeine sensitive store and to influx of Ca2+ from the extracellular space via voltage operated channels (VOC). Moreover, acetylcholine activated Ca2+ entry into guinea pig tracheal smooth muscle cells via the nifedipine insensitive mechanism, probably receptor operated channels (ROC). It is concluded that desensitization to histamine in the guinea pig trachea is most probably due to alterations in intracellular Ca2+ mobilization and Ca2+ influx via VOC. In contrast, sensitization to acetylcholine involved primarily enhanced Ca2+ influx via VOC and Ca2+ induced Ca2+ release.