Alteration of leukotriene D4 hypotension by thyrotropin releasing hormone

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.