Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons.

Abstract

The effect of sulfinpyrazone on endothelial injury induced by homocysteine has been studied both in vitro, using cultured human umbilical vein endothelial cells, and in vivo, using a primate model of homocysteine-induced arteriosclerosis. Oral sulfinpyrazone (250 mumol/kg body weight per day in three divided doses) in eight chronically homocystinemic baboons (0.14 +/- 0.04 mM plasma homocystine) decreased the extent of aortic endothelial injury as measured morphometrically by silver staining techniques, compared with six untreated comparably homocystinemic animals (denuded surface averaged 0.5% with range 0-2.1 vs 7.7 +/- 1.6%, respectively; P less than 0.001). Sulfinpyrazone therapy to homocystinemic baboons also normalized platelet survival and turnover measurements (5.1 +/- 0.4 days and 70,000 +/- 11,000 platelets/microliter per day vs. 2.8 +/- 0.6 days and 179,000 +/- 19,000 platelets/microliter per day in untreated homocystinemic controls; P less than 0.001). Sulfinpyrazone therapy also reduced the size and frequency of homocysteine-induced intimal lesion formation (P less than 0.001). Although sulfinpyrazone reduced the amount of specific 51Cr release from cultured human umbilical vein endothelial cells induced by 10 mM homocysteine after 24 hours of co-incubation, no effect was observed in assays of endothelial cell detachment when sulfinpyrazone (10(-5) M) or its thioether metabolite were pre- or co-incubated during 24 hours with homocysteine (2.5-10 mM). These data suggest that sulfinpyrazone may protect endothelial cells from injury in vivo by some apparently indirect mechanism.

Plasma homocysteine concentration and blood pressure in healthy Iranian adults: the Tehran Homocysteine Survey (2003–2004)

“…Hcy administration caused direct endothelial cell injury in vitro 12 and in animals. 13 In cell culture studies, Hcy induced oxidative stress to endothelium 14 and reduced available nitric oxide, a potent vasodilator. 15 Confirming these observations in humans, endothelium-dependent vasodilatation was impaired in temporary 16,17 or chronic 18,19 HHcy.…”

Micronutrient Vitamin Deficiencies and Cardiovascular Disease Risk: Advancing Current Understanding

“…The pathophysiologic mechanisms underlying hyperhomocysteinemia-induced CVD have been postulated to include induction of endothelial damage and dysfunction, enhanced oxidation of LDL-C, smooth muscle proliferation, endothelial-leukocyte interactions, innate autoimmune disorders, inflammation, and oxidative stress [73]. There is enhanced atherosclerosis, cerebrovascular and peripheral disease, and other CVD events, including alteration of platelet function and coagulation factors leading to enhanced thrombogenesis [73,74,75,76] (Figure 3C).…”

“…There is enhanced atherosclerosis, cerebrovascular and peripheral disease, and other CVD events, including alteration of platelet function and coagulation factors leading to enhanced thrombogenesis [73,74,75,76] (Figure 3C). …”

Hyperhomocysteinemia’s effect on antioxidant capacity in rats

“…Even though the mechanisms through which high levels of homocysteine generate thrombosis and cause cardiovascular events are not clear, the possible involvement of reactive species should be considered [16][17][18].…”