Effects of indomethacin on neural and myogenic components in equine airway smooth muscle
Gill, K.K.; Kroeger, E.A.
Journal of Pharmacology and Experimental Therapeutics 252(1): 358-364
1990
ISSN/ISBN: 0022-3565 PMID: 2105394 Document Number: 357854
Equine airway smooth muscle is innervated by vagal efferents and, in addition, displays spontaneous mechanical activity. The preparation thus appears to contain at least two discrete excitable components, the cholinergic neural elements and the smooth muscle membrane. Indomethacin (INDO), a cyclooxygenase (CO) inhibitor, exerts a considerable potentiation of function in this preparation. The latter may be effected indirectly, through loss of the inhibitory effect of endogenous prostaglandin E2 (PGE2) on neural acetylcholine release and through direct effects on smooth muscle of the generally antagonistic CO and lipoxygenase (LO) metabolites. The present studies were designed to assess the relative contributions of altered arachidonic acid metabolism on those respective elements. The utility of the model, in terms of distinguishing neural and myogenic components, was assessed by examining the effects of the muscarinic antagonist atropine (ATR) and the neurotoxin tetrodotoxin (TTX) on the stimulus-response (SR) relationship. The observations that TTX and ATR produced similar rightward (but not downward) shifts of the SR curve and that D-600 inhibited the TTX-insensitive responses are consistent with a selective activation of the muscle by the nerves at lower voltages and a direct stimulation of the muscle at higher voltages. INDO potentiated both the neural and myogenic components of the SR curve, effects which were sensitive to ATR 5,8,11,14-eicosatetraynoic acid, an inhibitor of LO, and reversed by PGE2. The finding that PGE2 at low doses (10-8 M) inhibited responses at lower voltages and that at higher concentration (10-7 M) it shifted the SR curve right and downward suggested that neurotransmitter release is more sensitive to PGE2 inhibition than is muscle response. These results suggest that INDO exerts its effects both indirectly, through regulation of cholinergic neurotransmitter release and/or via direct effects relating to decreased levels of CO products and increased LO metabolism.