Effects of inflammatory mediators on canine airway neuromuscular function.
Inflammatory mediators can both enhance or inhibit canine airway reactivity. PGE2 and PGI2 in general are inhibitory, interfering with release of acetylcholine and with responses to bronchoconstrictors. These prostaglandins may be more effective against agonists that open voltage-dependent Ca2+ channels to induce Ca2+ influx and contraction compared with those agonists that release internal Ca2+. Other mediators are excitatory: histamine, PGD2, thromboxane A2 (TxA2), and leukotrienes (LT) C4, D4, and E4. In canine airway only histamine and TxA2 have effects in the absence of indomethacin, i.e., in the presence of the large amounts of PGE2 and PGI2 produced in vitro LTs are ineffective. Effects of TxA2 and histamine may be potentiated if the synthesis of these inhibitory PGs is inhibited. Whether histamine or TxA2 normally promote synthesis and release of PGE2 and PGI2 in a kind of homeostasis remains to be explored. It is also unclear whether pre- as well as post-junctional TxA2 receptors exist and have different pharmacological sensitivities to antagonists. LTC4 and LTD4 also constrict canine bronchi but only when PGE2 and PGI2 synthesis is blocked and, again, whether this is a result of LT-induced release of inhibitory mediators is unknown. The concept that airway responsiveness can be caused by turning off PGE2 and PGI2 production and turning on TxA2 or LT production (or unmasking their actions) needs further exploration. Our recent data suggest that such a mechanism may explain ozone-induced responsiveness in dogs.
Daniel
E E
EE
Department of Biomedical Sciences, Faculty of Medicine, McMaster University, Hamilton, Ont., Canada.
Abela
A P
AP
Janssen
L J
LJ
O'Byrne
P M
PM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004285:Dogs; D004594:Electrophysiology; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D015289:Leukotrienes / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects* / Q000294:innervation
D016085:Bronchoconstrictor Agents; D015289:Leukotrienes; D010277:Parasympathomimetics; D010972:Platelet Activating Factor; D006632:Histamine; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine