salicylates and Metabolic-Syndrome

Inflammation is fundamental to the development of atherosclerosis. We examined the effect of anti-inflammatory doses of salicylate on endothelium-dependent vasodilation, a biomarker of cardiovascular risk, in a broad range of subjects.. We performed a randomized, double-blind, placebo-controlled crossover trial evaluating the effects of 4 weeks of high-dose salsalate (disalicylate) therapy on endothelium-dependent flow-mediated and endothelium-independent vasodilation. Fifty-eight subjects, including 17 with metabolic syndrome, 13 with atherosclerosis, and 28 healthy controls, were studied. Among all subjects, endothelium-dependent flow-mediated vasodilation decreased after salsalate compared with placebo therapy (P=0.01), whereas nitroglycerin-mediated, endothelium-independent vasodilation was unchanged (P=0.97). Endothelium-dependent flow-mediated vasodilation after salsalate therapy was impaired compared with placebo therapy in subjects with therapeutic salicylate levels (n=31, P<0.02) but not in subjects with subtherapeutic levels (P>0.2).. Salsalate therapy, particularly when therapeutic salicylate levels are achieved, impairs endothelium-dependent vasodilation in a broad range of subjects. These data raise concern about the possible deleterious effects of anti-inflammatory doses of salsalate on cardiovascular risk.. www.clinicaltrials.gov. Unique Identifiers: NCT00760019 and NCT00762827.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Biomarkers; Boston; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Female; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Salicylates; Treatment Outcome; Vasodilation; Vasodilator Agents

Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

Topics: Adipose Tissue, Brown; Animals; Animals, Genetically Modified; C-Reactive Protein; Fatty Acids, Nonesterified; Humans; Hypertension; Inflammation; Insulin Resistance; Lipid Metabolism; Liver; Metabolic Syndrome; NLR Proteins; Oxidative Stress; PPAR alpha; Rats; Salicylates; Tumor Necrosis Factor-alpha

In the high proportion of vascular disorders associated with excessive oxidative stress and production of pro-inflammatory cytokines, activation of NF-kappaB plays a key pathogenic role. Thus, there is considerable evidence that NF-kappaB is a mediator of atherogenesis, plaque destabilization, ischemia-reperfusion damage, cardiac remodeling, atrial fibrillation, and aneurysm formation and rupture; some studies suggest that it may also play a role in the microvascular complications of diabetes. I kappaB kinase-beta (IKK beta) is the upstream kinase that appears to be primarily responsible for NF-kappaB activation in these disorders; moreover, chronic IKK beta activation plays a prominent role in induction of insulin resistance in the metabolic syndrome. Salicylate inhibits IKK beta in concentrations that are achievable with dose schedules traditionally used in treating rheumatoid arthritis (3-4.5 g daily); indeed, this is likely to be the mechanism responsible for salicylate's utility in this disorder. Salicylate, unlike aspirin, is only a very weak, reversible inhibitor of cyclooxygenase in clinical doses, and thus is not associated with the potentially dangerous side effects seen with NSAIDs; fully reversible ototoxicity, the dose-limiting side effect in salicylate therapy, can be avoided in most patients by dosage adjustment. Hence, it is proposed that salicylate may have practical utility in the prevention or management of a wide range of vascular disorders as well as of metabolic syndrome and diabetes; its efficacy in these regards would likely be complemented by effective antioxidant measures, which would lessen the stimulus to NF-kappaB activation while providing benefits independent of NF-kappaB activity. Salsalate, consisting of two salicylate molecules united by an ester bond, is a venerable drug that may be the best tolerated delivery vehicle for salicylate. Appropriate rodent studies should pave the way for clinical trials with salsalate in patients at vascular risk.

Topics: Dose-Response Relationship, Drug; Humans; I-kappa B Kinase; Metabolic Syndrome; NF-kappa B; Oxidative Stress; Salicylates; Vascular Diseases