NEURAL AND MYOGENIC EFFECTS OF LEUKOTRIENES C-4, D-4, AND E-4 ON CANINE BRONCHIAL SMOOTH-MUSCLE

The leukotrienes (LTs), referred to as the slow-reacting substance of anaphylaxis (SRS-A), are reported to have little or no activity in the canine airway. The objective of this study was to determine whether LTC(4), LTD(4), and LTE(4) (10(-10)-10(-7) M) play a role in neuromuscular control of third- to fifth-order canine bronchi. In the presence of 1 mu M indomethacin (Indo), canine bronchial smooth muscle contracted and was depolarized in a concentration-dependent manner by LTC(4) or LTD(4) but not by LTE(4). LTC(4) and LTD(4) concentration-response curves were not significantly affected when conducted in the presence of any of the following: 10(-7) M propranolol (beta-adrenoceptor antagonist), 10(-6) M chlorpheniramine (H-1-receptor antagonist), 10(-6) M ketanserin (nonselective Ei-hydroxytryptamine receptor antagonist), 10(-7) M atropine (muscarinic receptor antagonist), and 10(-6) M tetrodotoxin (sodium channel blocker). LTC(4) and LTD(4) also potentiated electrical field-stimulated (EFS) excitatory junction potentials (EJPs), suggesting a possible prejunctional enhancement of acetylcholine release. In the absence of Indo, no postjunctional responses to LTC(4) and LTD(4) occurred. Endogenous prostaglandin E(2) (PGE(2)) and 6-keto-PGF(1 alpha) (a stable metabolite of PGI(2)) levels from canine bronchi were significantly reduced by Indo. In the presence of Indo, addition of greater than or equal to 10(-8) M of PGE(2) suppressed contractions to LTC(4) and LTD(4). These data suggest that the decrease in PGE(2) and PGI(2) production by Indo is sufficient to unmask the excitatory postjunctional actions of LTC(4) and LTD(4) on bronchial smooth muscle. Serine berate (45 mM; an inhibitor of gamma-glutamyl transpeptidase, which prevents the conversion of LTC(4) to LTD(4)) increased selectively the contractile activity of LTC(4). L-Cysteine (3 mM; an inhibitor of an aminopeptidase, which prevents the conversion of LTD(4) to LTE(4)) enhanced the contractile responses to LTD(4). Serine berate increased the amplitude and duration of EFS contractions and potentiated the amplitude of EFS EJPs; the last effects were prevented by nordihydroguaiaretic acid. These and other studies suggest that LTs are synthesized by canine bronchi and have receptors on canine bronchial smooth muscle but that contractions to LTC(4) and LTD(4) in the canine airway are usually not observed because of the presence of inhibitory prostanoids (PGE(2) and PGI(2)). We suggest that decreases in PGE(2) and PGI(2) in models of airway disease in combination with increases in LTC(4), LTD(4), and thromboxane Az may contribute to airway hyperresponsiveness in vitro.