Porcine hepatic response to sepsis and its amplification by an adrenergic receptor alpha1 agonist and a beta2 antagonist.
1. We investigated the effect of adrenergic receptor stimulation or inhibition on the hepatic ultrastructural changes in a porcine faecal peritonitis model of multi-organ failure. We infused either the alpha1 adrenergic receptor agonist methoxamine or the beta2 adrenergic receptor antagonist ICI 118551 during 8 h of the study.2. Anaesthetized pigs (25-30 kg) were divided into four non-septic groups (control, non-septic, non-septic methoxamine and non-septic ICI 118551) and three septic groups (septic, septic methoxamine and septic ICI 118551).3. Changes in hepatic ultrastructure were measured by morphometric analysis. The septic group was significantly worse than all the non-septic groups. Septic methoxamine and septic ICI 118551 were significantly worse than the septic group.4. Septic methoxamine and septic ICI 118551 had a significantly increased perisinusoidal space; septic methoxamine had significant hepatocyte vacuolation.5. Hepatic ultrastructural changes were independent of hepatic blood flow.6. Septic methoxamine had significant myocardial depression.7. The alpha1 adrenergic receptor agonist methoxamine or the beta2 antagonist ICI 118551 both amplified the hepatic injury normally found during sepsis in our porcine model.8. These findings suggest that during sepsis a protective endogenous beta2 adrenergic receptor-mediated anti-inflammatory response is activated via cell membrane transduction to stimulate the trimeric G-protein complex Gs and activate the second cell messenger cAMP.9. In addition, it is likely that alpha1 adrenergic receptor agonists amplify the inflammatory response by stimulating the cell-surface receptor-linked trimeric G-protein complex to activate Gq and the second cell messenger phospholipase C.
Tighe
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Department of Physiological Medicine, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, U.K.
Moss
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Bennett
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D
D000316:Adrenergic alpha-Agonists / Q000009:adverse effects*; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects*; D000704:Analysis of Variance; D000818:Animals; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure*; D008729:Methoxamine / Q000009:adverse effects*; D009102:Multiple Organ Failure / Q000473:pathology; D011412:Propanolamines / Q000009:adverse effects*; D018805:Sepsis / Q000473:pathology*; D013552:Swine
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; C026777:ICI 118551; D008729:Methoxamine