title: Erythropoietin Reverses Sepsis-Induced Vasoplegia to Norepinephrine Through Preservation of α1D-Adrenoceptor mRNA Expression and Inhibition of GRK2-Mediated Desensitization in Mouse Aorta.
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.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Kannan
authors.initials: K
authors.lastname: Kandasamy
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Soumen
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Vishakha
authors.initials: V
authors.lastname: Singh
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: M Pule
authors.initials: MP
authors.lastname: Addison
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Sazad Ahmad
authors.initials: SA
authors.lastname: Darzi
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Jaya Kiran
authors.initials: JK
authors.lastname: Kasa
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Thangamalai
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Jeevan Ranjan
authors.initials: JR
authors.lastname: Dash
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Faheem
authors.initials: F
authors.lastname: Sultan
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India tusingh80@gmail.com.
authors.forename: Thakur Uttam
authors.initials: TU
authors.lastname: Singh
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Subhashree
authors.initials: S
authors.lastname: Parida
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D002432:Cecum / Q000382:microbiology / Q000601:surgery; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008026:Ligation; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011677:Punctures; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000382:microbiology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D056987:Vasoplegia / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: C547720:Adra1d protein, mouse; D000316:Adrenergic alpha-Agonists; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D004921:Erythropoietin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D009638:Norepinephrine
keywords: CLP; GRK2; desensitization; erythropoietin; sepsis; α
  1D
   adrenoceptor