Leukotriene D4 (
LTD4), a component of
slow reacting substance of anaphylaxis (SRS-A)1, produces marked
hypotension in laboratory animals2,3, implicating it as a potential mediator of
anaphylactic shock. It has been demonstrated that
naloxone reverses the
hypotension associated with endotoxaemia4-6, hypovolaemia7,8 and spinal injury9,10, presumably through blockade of endogenous
opioid systems11. More recently, it has also been shown that
thyrotropin releasing hormone (TRH) improves experimental shock12 and spinal injury13, and it has been postulated that TRH acts by 'physiological' antagonism of endogenous
opioid systems in these conditions. Here we report that TRH both blocked and reversed
leukotriene-
induced hypotension in the unanaesthetized guinea pig, whereas
naloxone had no effect.
LTD4 hypotension was also reversed by intracerebroventricular (i.c.v.) administration of TRH at a dose that had no effect when given systemically.
LTD4 administration was associated with sympatho-adrenomedullary activation, and TRH further augmented this response. Peripheral
cholinergic blockade with
methylatropine did not alter the
leukotriene hypotension. These data demonstrate the first dissociation of TRH and
naloxone in experimental
shock and suggest that the beneficial effects of TRH in this model result from central interactions which are not mediated by endogenous
opioids. The findings further provide a potential link between the physiological (that is, cardiovascular) effects of a
peptide (TRH) and those of a
leukotriene; this may have implications with regard to the pathophysiology and
therapy of
anaphylaxis.