Effects of HMG-CoA Reductase Inhibition by Simvastatin on Vascular Dysfunction Induced by Lipopolysaccharide in Rats

Abstract

Aims: 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. Conclusion: These results suggest that statins may reduce iNOS-mediated NO production in endothelial but not in vascular smooth-muscle cells.

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

“…They are widely prescribed cholesterol-lowering drugs and are the first-line treatment for the prevention of coronary artery disease and atherosclerosis [5]. Simvastatin have been shown to exhibit important immunomodulatory and anti-inflammatory effects independent of lipid lowering [6,7]. Statins have pleiotropic effects on endothelium, platelets, smooth muscle cells and inflammation.…”

Comparing the anti-inflammatory effects of Simvastatin and Rosuvastatin by measuring IL-1β, IL-6 and TNF-α levels using a murinic caecal ligation and puncture induced sepsis model / Compararea efectelor anti-inflamatoare ale Simvastatinei și Rosuvastatinei măsurând nivelele serice ale IL-1β, IL-6 si TNF-α folosind un model de sepsis la șobolan indus prin ligatură și puncție cecală

“…This class of drugs was first introduced in clinical practice for their cholesterol-lowering effect but the inhibition of HMG-CoA reductase and cholesterol biosynthetic pathway exhibits some less studied effects generally referred to as pleiotropic: the reduced expression of class II MHC (major histocompatibility complex), effects on cell signalling and consequent transcriptional level changes, inhibiting vascular smooth muscle growth, reducing vascular inflammation, the direct alteration of leukocyte-endothelial cell interaction, the induction of haem oxygenase, enhancing the stability of atherosclerotic plaques, beneficial effects on endothelial function and blood flow, decreasing LDL-C oxidation and modulating platelet aggregation (4,5). These anti-inflammatory, antithrombotic, immunomodulatory and antioxidant properties were documented in a number of observational studies (6)(7)(8)(9)(10)(11)(12)(13)(14) but also in six large trials (15)(16)(17)(18)(19)(20) with published results. In spite of the ongoing efforts of understanding these pleiotropic properties and establishing the role of statins in the management and treatment of the septic patient, there are only few authors that offer clear recommendations.…”

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

“…Numerous animal experiments and cell studies have shown that statins have a positive effect on vascular injury in sepsis by reducing inducible nitric oxide (NO) synthase‐mediated NO production and by inhibiting cytokines and their downstream signal transduction pathways . Other studies have reported that statins failed to affect the prognosis of sepsis and increased doses raised the risk of liver and kidney damage .…”

“…Numerous animal experiments and cell studies have shown that statins have a positive effect on vascular injury in sepsis by reducing inducible nitric oxide (NO) synthase-mediated NO production and by inhibiting cytokines and their downstream signal transduction pathways. [20][21][22][23] Other studies have reported that statins failed to affect the prognosis of sepsis 24,25 and increased doses raised the risk of liver and kidney damage. 26 However, a recent editorial noted that the cause of some heterogeneity among previous findings was unclear and that most reports were retrospective studies, which were not well randomized.…”