Adrenocorticotropin reverses vascular dysfunction and protects against splanchnic artery occlusion shock

1 Tumour necrosis factor (TNF-alpha) is involved in the pathogenesis of splanchnic artery occlusion (SAO) shock. On the other hand, inhibition of TNF-alpha is an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock. We therefore investigated the effects of the melanocortin peptide ACTH-(1-24) (adrenacorticotropin fragment 1-24) on the vascular failure induced by SAO shack. 2 SAO-shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham-shocked rats survived for more than 4 h), enhanced serum TNF-alpha concentrations (755 +/- 81 U ml(-1), decreased mean arterial blood pressure, leukopenia, and increased ileal leukocyte accumulation, as revealed by means of myeloperoxidase activity (MPO = 9.4 +/- 1 U g(-1) tissue). Moreover, aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM-10 mu M) (E-max and ED50 in shocked rats = 7.16 mN mg(-1) tissue and 120 nM, respectively; E-max and ED50 in sham-shocked rats = 16.31 mN mg(-1) tissue and 100 nM, respectively), reduced responsiveness to acetylcholine (ACh, 10 nM-10 mu M) (E-max and ED50 in shocked rats = 30% relaxation and 520 nM, respectively; E-max and ED50 in sham-shocked rats = 82% relaxation and 510 nM, respectively) and increased staining for intercellular adhesion molecule-1 (ICAM-1). 3 ACTH-(1-24) [160 mu g kg(-1) intravenously (i.v.), 5 min after SAO] increased survival rate [SAO + ACTH-(1-24) = 80% at 4 h of reperfusion], reversed hypotension, reduced serum TNF-alpha (55 +/- 13 U ml(-1)), ameliorated leukopenia, reduced ileal MPO (1.2 +/- 0.2 U g(-1) tissue), restored the reactivity to PE, improved the responsiveness to ACh and blunted the enhanced immunostaining for ICAM-1 in the aorta. 4 Adrenalectomy only in part - but not significantly -reduced the ACTH-induced shock reversal, the survival rate of SAO + ACTH-(1-24) adrenalectomized rats being 60% at 4 h of reperfusion; and methylprednisolone (80 mg(-1) i.v., 5 min after SAO) had a non-significant effect (10% survival) at 4 h of reperfusion. 5 The present data show that melanocortins are effective also in SAO shock, their effect being, at least in part, mediated by reduced production of TNF-alpha. Furthermore, they demonstrate, for the first time, that this inhibition is responsible for the adrenocorticotropin-induced reversal of vascular failure and leukocyte accumulation.