Ghrelin Protects Against Experimental Sepsis; Relation to Sympathetic Excito-Toxicity and Role of Vagus

Background: Sepsis is a life-threatening complication of infections. Despite improvement in the management of septic patients, none of the current therapies are entirely effective. Ghrelin has been shown to possess anti-inflammatory properties together with prokinetic activity. The aim of this work was to study the effect of administration of ghrelin on outcome of sepsis induced by cecal ligation and puncture (CLP) in rats and to investigate the effect of vagotomy on ghrelin effect. Also, to test whether administration of exogenous ghrelin affects norepinephrine (NE) release, this may contribute to its anti-inflammatory and cardiac protective effects in sepsis. Methods: Fifty male rats (200–250g) were divided into 5 groups, 10 rats each. Group 1: Normal control rats, sham operated, Group 2: (CLP), rats underwent CLP, Group 3: (CLP+GR) group, rats underwent CLP and received ghrelin at dose of 10nmol/kg at the time of operation and 60nmol/kg BW 5hrs after surgery, Group 4: Rats underwent CLP and followed after 5 hours by vagotomy operation, Group 5: Rats underwent CLP, followed after 5hrs by vagotomy operation and received ghrelin at and 5hrs after the CLP. In all rats, TNFa , IL-6 and NE levels were measured. Systolic blood pressure and the cardiac contractile functions were assessed by measuring the left ventricular developed pressure (LVDP) and The maximum rate of pressure rise (dp/dt). Results: CLP induced a significant increase in serum levels of TNF-a , IL-6 and NE level in vehicle-treated animals as compared with sham-operated animals (p<0.05). Administration of ghrelin significantly attenuated serum levels of TNF-a , IL-6 and NE. Vagotomy performed 5 hours after CLP had an insignificant effect on TNF-a , IL-6 or NE as compared to CLP group values (p>0.05). Vagotomy partially abolished the inhibitory effects of ghrelin on serum levels of TNFa , IL-6 and NE to become significantly higher than values recorded in ghrelin treated group ( p<0.05). SBP, LVDP and dp/dt of rats in ghrelin-treated group was significantly increased compared with CLP group (p<0.05). Vagotomy partially blocked the beneficial effect of ghrelin on hemodynamic parameters in CLP+GR+VagX group compared to CLP+GR group. Conclusion: Ghrelin represents a feasible therapeutic agent for sepsis and other inflammatory disorders. Ghrelin` s Correspondence to: Dr. Samah Elattar, The Department of Physiology, Faculty of Medicine, Cairo University anti-inflammatory action may be mediated partially by its direct action on the immune cells, and partialy by acting as a modulator that restores the dysregulated balance of sympathetic/parasympathetic nervous system during sepsis. Ghrelin improves cardiac functions and restores blood pressure in septic rats.