Hemodynamic effects of early versus late glucocorticosteroid administration in experimental septic shock.
Recent findings in human septic shock suggest that glucocorticosteroids can limit and even reverse hemodynamic disturbances and dependence on catecholamines. In a rodent model of hypotensive and hypokinetic septic shock, we investigated the effects of early or late dexamethasone administration on hemodynamics, response to catecholamines, and cardiac beta-adrenergic signalling. As compared with sham-operated rats, the untreated septic rats displayed significant arterial hypotension and reduced aortic blood flow. However, in vivo pressor response to epinephrine and phenylephrine was not different among sham and septic animals. Conversely, the chronotropic response to isoproterenol was significantly attenuated in septic animals. Steroid-treated septic animals displayed complete reversal of hypotension, improvement in aortic blood flow, and reduced plasma lactate and nitrite/nitrate concentrations as compared with untreated septic animals. The number of myocardial beta-adrenergic receptors and in vivo isoproterenol-stimulated myocardial cAMP content were similar in sham and septic animals. Glucocorticosteroids, although not changing these patterns, significantly decreased the receptors affinity when administered late, but not early. In this model of septic shock, hemodynamic abnormalities may not be related to adrenergic receptor desensitization. That steroids can improve them suggests that they could act mainly distal to adrenergic receptors, for instance, on myocardial and vascular smooth fiber contraction properties through mechanisms probably including inducible nitric oxide synthase inhibition.
Mansart
Arnaud
A
Laboratoire de Néphrologie UPRES-JE, Faculté de Médecine, 54100 Vandoeuvre les Nancy, France.
Bollaert
Pierre Edouard
PE
Seguin
Carole
C
Levy
Bruno
B
Longrois
Dan
D
Mallié
Jean Pierre
JP
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000097:blood / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D017983:Receptors, Catecholamine / Q000378:metabolism; D018805:Sepsis; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D000316:Adrenergic alpha-Agonists; D002395:Catecholamines; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D009566:Nitrates; D009573:Nitrites; D011943:Receptors, Adrenergic, beta; D017983:Receptors, Catecholamine; D010656:Phenylephrine; D019344:Lactic Acid; D003907:Dexamethasone; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine