ABSTRACT
We investigated the effect of erythropoietin (EPO) posttreatment on survival time and vascular functions in a mouse model of sepsis. Sepsis was induced by cecal ligation and puncture. After 20 ± 2 hours of sepsis, thoracic aorta was isolated for assessing its reactivity to norepinephrine (NE) and acetylcholine (ACh). We also measured the tissue nitric oxide (NO) level, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), G protein-coupled receptor kinase 2 (GRK2), and α1D adrenoceptor messenger RNA (mRNA)/protein expression. In septic mice, EPO moderately improved the survival time from 19.68 ± 0.75 to 34.7 ± 3.2 hours. Sepsis significantly decreased the aortic contractile response to NE along with reduced α1D mRNA and protein expression. Erythropoietin significantly preserved the α1D receptor expression and restored NE-induced contractions to control levels in septic mice. Further, it attenuated the aortic α1D receptor desensitization in sepsis which was evident from reduced GRK2 mRNA expression. Accordingly, a selective GRK2 inhibitor markedly restored the contractile responses to NE in sepsis. Erythropoietin treatment attenuated iNOS mRNA expression and iNOS-induced overproduction of NO, but improved endothelium-dependent relaxation to ACh associated with increased eNOS mRNA expression. In conclusion, EPO seems to reverse sepsis-induced vasoplegia to NE through the preservation of α1D adrenoceptor mRNA/protein expression, inhibition of GRK2-mediated desensitization, and attenuation of NO overproduction in the mouse aorta.
Subject(s)
Adrenergic alpha-Agonists/pharmacology , Aorta, Thoracic/drug effects , Erythropoietin/pharmacology , G-Protein-Coupled Receptor Kinase 2/metabolism , Norepinephrine/pharmacology , RNA, Messenger/metabolism , Receptors, Adrenergic, alpha-1/drug effects , Sepsis/drug therapy , Vasoconstrictor Agents/pharmacology , Vasoplegia/prevention & control , Animals , Aorta, Thoracic/enzymology , Aorta, Thoracic/physiopathology , Cecum/microbiology , Cecum/surgery , Disease Models, Animal , Dose-Response Relationship, Drug , G-Protein-Coupled Receptor Kinase 2/antagonists & inhibitors , G-Protein-Coupled Receptor Kinase 2/genetics , Ligation , Male , Mice , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Protein Kinase Inhibitors/pharmacology , Punctures , RNA, Messenger/genetics , Receptors, Adrenergic, alpha-1/genetics , Receptors, Adrenergic, alpha-1/metabolism , Sepsis/complications , Sepsis/enzymology , Sepsis/microbiology , Sepsis/physiopathology , Signal Transduction/drug effects , Time Factors , Vasoconstriction/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Vasoplegia/enzymology , Vasoplegia/etiology , Vasoplegia/genetics , Vasoplegia/physiopathologyABSTRACT
The inflammatory response induced by cardiopulmonary bypass decreases vascular tone, which in turn can lead to vasoplegic syndrome. Indeed the hypotension consequent to on-pump cardiac surgery often necessitates vasopressor and intravenous fluid support. Methylene blue counteracts vasoplegic syndrome by inhibiting the formation of nitric oxide. We report the use of methylene blue in a 75-year-old man who developed vasoplegic syndrome after cardiac surgery. After the administration of methylene blue, his hypotension improved to the extent that he could be weaned from vasopressors. The use of methylene blue should be considered in patients who develop hypotension refractory to standard treatment after cardiac surgery.
