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Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions

Wayne H. Kaesemeyer, MD^*, Ruth B. Caldwell, PhD, Jianzhong Huang, MD^* and R. William Caldwell, PhD^*

^* Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA

View larger version (25K): [in a new window]   Figure 1 Diagram illustrating methods used to measure NO production. The upper left half of the figure illustrates the methemoglobin method for measuring NO production in endothelial cells. The bottom half of the figure illustrates the NO electrode method for measuring NO production in endothelial cells.

View larger version (20K): [in a new window]   Figure 2 Vasorelaxation response of preconstricted aortic rings to increasing concentrations of ACH, PRA and SIM. Responses to ACH and PRA were obliterated following removal of the endothelial cells. Responses to SIM were seen only with the open lactone ring form (OR) of the compound (responses to SIM in the closed lactone ring preparation (CR) were no different from those produced by the DMSO vehicle used to solubilize the compound). (*) Indicates difference from responses to all other agents or pretreatment. p < 0.05.

View larger version (40K): [in a new window]   Figure 3 (A) NO electrode assay of effects of ACH, PRA and SIM on NO release by cultured BAECs. Confluent cultures were prepared in 24-well plates and treated with 0.1 to 10 µmol/liter concentrations of ACH, PRA and SIM (open lactone ring preparation). Open bars indicate basal NO release. Shaded bars indicate responses to agents above basal production. (*) Indicates difference from basal release (control); () indicates difference from response at 0.1 µmol/liter, p < 0.05. (B) NO electrode assay of L-NAME effects on BAEC responses to 1 µmol/liter of ACH, PRA and SIM (open ring preparation only) as a percent of control responses to these agents (A). (*) Indicates difference from control responses for that agent and dose. p < 0.05.

View larger version (35K): [in a new window]   Figure 4 (A) Methemoglobin assay of ACH and PRA effects on NO release from cultured bovine aortic endothelial cells. BAECs (2 ml) grown on microcarrier beads were perfused with oxyhemoglobin (3 µmol/liter) buffer containing 50 µmol/liter L-arginine at 2 ml/min and then stimulated with acetylcholine and pravastatin (1 and 10 µmol/liter, 3 min, n = 7). Open bars indicate basal NO release. Shaded bars indicate responses to agents above basal production. (*) Indicates difference from basal release (control); () indicates difference from response at 0.1 µmol/liter p < 0.05. (B) Methemoglobin of BAEC responses to ACH and PRA in the presence of L-NAME and excess L-arginine as percent of control responses to these agents. Bars depict NO formation using the buffer above supplemented with L-NAME (1 µmol/liter, dark bar) or L-arginine (1 µmol/liter, light bar) stimulated with acetylcholine and pravastatin (1 and 10 µmol/liter, 3 min, n = 7). (*) indicates difference from control responses for that agent and dose; (#) indicates difference from responses with L-NAME and control response for that agent and dose. p < 0.05.