Induction of endogenous tumor necrosis factor-alpha: suppression of centrally stimulated gastric motility.
Gastric stasis is frequently seen in conjunction with critical infectious illness, chronic inflammatory disorders, radiation sickness, and carcinogenesis. These conditions are associated with elevated circulating levels of the cytokine tumor necrosis factor-alpha (TNF-alpha). The present studies examined the relationship between endogenously produced TNF-alpha and the central neural mechanisms that augment gastric motility. Systemic lipopolysaccharide (LPS) was employed to induce TNF-alpha production in thiobutabarbital-anesthetized rats. Sixty minutes after intravenous LPS injection, gastric motility could not be stimulated by a potent centrally acting gastrokinetic stimulant, thyrotropin-releasing hormone (TRH). This failure to elicit gastric motility via central mechanisms coincided with high circulating levels of TNF-alpha. However, intravenous injections of bethanecol, a peripherally acting cholinergic agonist with direct gastrokinetic effects, were still able to elicit normal increases in gastric motility in the presence of TNF-alpha and LPS. Therefore, the inability to stimulate gastric motility via central TRH could not be attributed to the direct inhibitory effects of either LPS or TNF-alpha on the stomach. If the production of endogenous TNF-alpha was suppressed via the use of urethan as the anesthetic agent, then intravenous injections of LPS were no longer effective in suppressing gastric motility. Thus these effects on gastric motility are not directly attributable to LPS nor are they due to direct effects on the gastric smooth muscle. Our previous study demonstrated that microinjection of femtomole quantities of TNF-alpha in the brain stem dorsal vagal complex (DVC) can modulate gastric motility. This central TNF-alpha effect on gastric motility was dose dependent and required an intact vagal efferent pathway. The results from these two studies suggest that systemically produced TNF-alpha may gain access to the DVC to modulate gastric function.
Hermann
G E
GE
Department of Physiology, College of Medicine, Ohio State University, Columbus, Ohio 43210, USA.
Tovar
C A
CA
Rogers
R C
RC
D000818:Animals; D018723:Bethanechol / Q000494:pharmacology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D007275:Injections, Intravenous; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology*
D018721:Muscarinic Agonists; D014409:Tumor Necrosis Factor-alpha; D018723:Bethanechol; D013973:Thyrotropin-Releasing Hormone