A Novel Peptide Inhibits Induction of Nitric Oxide Synthase
Alpha-melanocyte stimulating hormone has been shown to prevent endotoxin shock. A heptapeptide analog (HPA) has recently been synthesized and shown to be an even more potent protective agent. Since the hypotensive and toxic actions of endotoxin lipopolysaccharide (LPS) appear to involve the induction of nitric oxide synthase, we have examined the actions of HPA on induction of iNOS using an endotoxemia model in conscious rats. In vascular smooth cells, we also determined whether the HPA could directly alter the actions of LPS, TNFα or I1-1β on NOS induction. Rats were instrumented for measurement of blood pressure and i.v. administration of agents prior to the day of experiment. In the conscious state, rats were given E. coli LPS (5 mg/kg, i.v.) and monitored for 6 hrs. One group of rats received HPA (30 μg/kg) 0.5 hr before LPS. Using L-NAME-sensitive cGMP production as an estimate of NOS activity, we determined that LPS increases iNOS and that HPA pretreatment markedly reduces this response. In isolated aortic cells, LPS and I1-1β, but not that of LPS. This former action was reversed by L-arginine. In conclusion, HPA can prevent the in vivo induction of NOS by LPS. It does not appear to directly prevent this action of LPS. Possibly, a metabolite of HPA or a secondary mediator is involved.