Adrenocorticotropin reverses vascular dysfunction and protects against splanchnic artery occlusion shock

Tumour necrosis factor (TNF‐α) is involved in the pathogenesis of splanchnic artery occlusion (SAO) shock. On the other hand, inhibition of TNF‐α 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) (adrenocorticotropin fragment 1–24) on the vascular failure induced by SAO shock. 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‐α 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 n M –10 μ M ) (E max and ED 50 in shocked rats=7.16 mN mg −1 tissue and 120 n M , respectively; E max and ED 50 in sham‐shocked rats=16.31 mN mg −1 tissue and 100 n M , respectively), reduced responsiveness to acetylcholine (ACh, 10 n M ‐10 μ M ) (E max and ED 50 in shocked rats=30% relaxation and 520 n M , respectively; E max and ED 50 in sham‐shocked rats=82% relaxation and 510 n M , respectively) and increased staining for intercellular adhesion molecule‐1 (ICAM‐1). ACTH‐(1–24) [160 μg 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‐α (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. 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. 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‐α. Furthermore, they demonstrate, for the first time, that this inhibition is responsible for the adrenocorticotropin‐induced reversal of vascular failure and leukocyte accumulation.British Journal of Pharmacology (1999) 128 , 816–822; doi: 10.1038/sj.bjp.0702848