Impaired Ca(2+) Homeostasis and Decreased Orai1 Expression Modulates Arterial Hyporeactivity to Vasoconstrictors During Endotoxemia.
We hypothesized that SIRS/endotoxemia-associated hyporesponsiveness to vasoconstrictors is mediated by smaller increases in intracellular Ca(2+) levels due to reduced signaling via the STIM/Orai. Male Wistar rats were injected either with saline or bacterial LPS (i.p.; 10 mg/kg), and experiments were performed 24 h later. LPS-injected rats exhibited decreased systolic blood pressure, increased heart rate, neutrophils' migration into the peritoneal cavity, and elevated alanine aminotransferase levels. Additionally, second-order mesenteric arteries from endotoxemic rats displayed hyporeactivity to contractile agents such as phenylephrine and potassium chloride; decreased contractile responses to Ca(2+); reduced contraction during Ca(2+) loading; and smaller intracellular Ca(2+) stores. Decreased Orai1, but not STIM1, expression was found in resistance mesenteric arteries from LPS-treated rats. Additionally, cultured vascular smooth muscle cell (VSMC) treated with LPS resulted in increased TLR-4 expression, but Myd-88 and STIM-1 expression were not changed. Our data suggest that in endotoxemia, Ca(2+) homeostasis is disrupted in VSMC, with decreased Ca(2+) influx, smaller concentrations of Ca(2+) in the sarcoplasmic reticulum, and decreased activation of Orai1. Abnormal Ca(2+) handling contributes to LPS-associated vascular hyporeactivity.
Institute of Biological and Health Sciences, Federal University of Mato Grosso, Av. Valdon Varjao, 6930, 78600-000, Barra do Garças, Mato Grosso, Brazil.
Arthur Oliveira
AO
Nonato
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Vania C
VC
Olivon
Institute of Biological and Health Sciences, Federal University of Mato Grosso, Av. Valdon Varjao, 6930, 78600-000, Barra do Garças, Mato Grosso, Brazil.
Vanessa
V
Dela Justina
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Camila Z
CZ
Zanotto
Department of Physiology, Augusta University, Augusta, GA, USA.
R Clinton
RC
Webb
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Rita C
RC
Tostes
Institute of Biological and Health Sciences, Federal University of Mato Grosso, Av. Valdon Varjao, 6930, 78600-000, Barra do Garças, Mato Grosso, Brazil.
Victor V
VV
Lima
Institute of Biological and Health Sciences, Federal University of Mato Grosso, Av. Valdon Varjao, 6930, 78600-000, Barra do Garças, Mato Grosso, Brazil. fernandagiachini@hotmail.com.
Fernanda R
FR
Giachini
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology*; D006706:Homeostasis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D000071740:ORAI1 Protein / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000071737:Stromal Interaction Molecule 1 / Q000032:analysis / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D008070:Lipopolysaccharides; D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D014662:Vasoconstrictor Agents; D002118:Calcium
calcium homeostasis; hypotension; vascular reactivity; vascular smooth muscle cell