Effects of HMG-CoA reductase inhibition by simvastatin on vascular dysfunction induced by lipopolysaccharide in rats.
OBJECTIVE
Statins have been identified as a potentially interesting treatment against sepsis. Here, we study the vascular reactivity of aortae from rats treated with lipopolysaccharide (LPS), 4 mg . kg(-1), following chronic administration of simvastatin (SV) 10 mg . kg(-1).


METHODS
The rats were treated with either vehicle or SV for 4 weeks before administration of LPS. After 18 h, the systolic blood pressure (SBP) was measured using a tail cuff and vascular and endothelial responses of aortic rings to several agonists were studied in an organ bath.


RESULTS
LPS injection decreased the SBP by 38 mm Hg and vascular response to phenylephrine (Phe) by 60%. Plasma nitrates and nitrites (NO(x)) were 3-fold higher after LPS. This attenuated response to Phe was prevented by incubation with either the inducible-nitric-oxide-synthase (iNOS)-selective inhibitor 1400W or the endothelial nitric oxide synthase (eNOS)/iNOS nonselective blocker L-NAME. The presence of endothelium did not alter these findings. Administering LPS to SV-treated rats also decreased the SBP and increased the NO(x) concentration. The impaired response to Phe was restored by blocking NO synthesis in endothelium-denuded but not in intact aortic rings. The response to acetylcholine demonstrated an enhanced reduction in arteries from the SV + LPS group compared with the LPS group. The inhibition of iNOS prevented acetylcholine-induced relaxation in rings from LPS-treated rats but not in those from the SV + LPS group.


CONCLUSIONS
These results suggest that statins may reduce iNOS-mediated NO production in endothelial but not in vascular smooth-muscle cells.
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain. aldesoto@us.es
Maria
M
Alvarez de Sotomayor
Silvia
S
Vega
Carmen
C
Mingorance
Elisa
E
Marhuenda
Maria Dolores
MD
Herrera
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy; D019821:Simvastatin / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II