Study of mechanisms mediating contraction to leukotriene C4, D4 and other bronchoconstrictors on guinea pig trachea

Contractions of guinea pig trachea in the absence and presence of indomethacin to LTD₄ > LTC₄ > K⁺ > histamine > acetylcholine were reduced following a 45 minute exposure of the tissues to calcium-free Krebs' solution (Ca²⁺-free Krebs' solution), were further reduced by a transient exposure to EGTA (1.25 mM) in Ca²⁺-free Krebs' solution and were virtually abolished when tested in the presence of EGTA (0.125 mM) in Ca²⁺-free Krebs' solution. In normal Krebs' solution (2.5 mM Ca²⁺) the Ca²⁺ entry blockers nifedipine (N) ? D-600 > verapamil (V) > diltiazem (D) almost completely abolished the contractions to K⁺ but blocked only a component of the maximum response to the other agonists. After exposure to Ca²⁺-free Krebs' solution for 45 minutes, any residual contractions to LTC₄ & LTD₄, were reversed by low concentrations of N (0.3 μM) or D-600 (2.1 μM). Leukotrienes appear to mobilize a superficial and a bound store of Ca²⁺ which gains entry through at least two types of Ca²⁺ channels (or mechanisms), one of which is blocked by N and D600. K⁺-induced contractions appear to be dependent on superficial and tightly bound Ca²⁺ but entry is solely through channels which are blocked by the Ca²⁺ entry blockers studied. Contraction to histamine and acetylcholine persisted following exposure of the tissues to Ca²⁺ free Krebs' solution but contractile activity was virtually abolished in Ca²⁺ free Krebs' solution containing EGTA. Residual contractions to histamine and part of the residual contractions to acetylcholine in Ca²⁺-free Krebs' solution were blocked by low dose N (0.3μM) or D600 (2.1 μM). These findings suggest a major role for extracellular Ca²⁺ during spasmogen-induced contraction in this tissue.