Statin-stimulated nitric oxide release from endothelium.
BACKGROUND
There is increasing evidence that loss of endothelium-derived NO is a major factor in cardiovascular complication events, and that NO might exert antiatherosclerotic actions. The beneficial effects of HMG CoA reductase inhibitors (statins) therapy in atherosclerosis outweigh those expected from simply lowering low-density lipoprotein (LDL) cholesterol, and may be related to the direct action in the endothelium. Based on these concepts, in the studies described here, the effect of new statin derivatives on nitric oxide (NO) and superoxide (O2-) release in bovine endothelial cells was tested.


METHODS
Highly sensitive electrochemical NO and O2--microsensors were placed near the surface of endothelial cells, and the concurrent kinetics of NO and O2-- release were measured in situ.


RESULTS
All tested statins stimulated NO release. The peak concentration of NO after stimulation with 1 Kmol/l Lovastatin, 1 Kmol/l Atorvastatin, 1 Kmol/l Pravastatin, or 1 Kmol/l Simvastatin was about 77%, 73%, 72%, and 44% lower, respectively, as compared with the NO peak concentration after stimulation with 1 Kmol/l calcium ionophore A23187 (receptor-independent agonist). The tested statins stimulated NO release in a modest way, which resulted in diminishing O2- generation during activation of nitric oxide synthase. Moreover, the kinetics of O2- release after administration of the statins suggested that these compounds may also scavenge O2-. The NO/O2- peak concentration ratio after the NOS agonists administration was as follows: 7.51 for CaI, 6.56 for Lovastatin, 6.00 for Atorvastatin, 4.17 for Pravastatin and 6.25 for Simvastatin.


CONCLUSIONS
The tested statins, i.e. Lovastatin, Atorvastatin, Pravastatin and Simvastatin demonstrate variable potency to enhance the NO/O2- concentration ratio after stimulation of NOS, resulting in an increase of NO bioavailability in endothelial cells.
Dobrucki
L W
LW
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
Kalinowski
L
L
Dobrucki
I T
IT
Malinski
T
T
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D013481:Superoxides; D009569:Nitric Oxide; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin