Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin.
BACKGROUND
Although statins preserve endothelial function by reducing serum cholesterol levels, it has been suggested they may also stimulate nitric oxide (NO) synthase in endothelium with concurrent increase in superoxide (O2-) generation, leading to impairment of NO activity. Therefore, measurements of biologically active NO and O2- in endothelium after exposure to the HMG-CoA reductase inhibitor cerivastatin were undertaken to evaluate its potential effect on NO biological activity.


RESULTS
Highly sensitive electrochemical NO and O2- microsensors were placed near the surface of a single human umbilical vein endothelial cell, and the kinetics of NO and O2- release were recorded in vitro. Cerivastatin demonstrated a time-dependent effect on NO release in endothelial cells. The initial release (approximately the first 3 minutes) was concentration-dependent (0.01 to 10 micromol/L) and was similar to that observed for typical NO synthase agonists calcium ionophore or acetylcholine. Cerivastatin stimulated NO release at a favorable rate and scavenged O2-, which led to the preservation of the active concentration of NO. The sustained effect (after approximately 6 hours) of cerivastatin on endothelium was associated with an approximately 35% increase in NO release as compared with the initial effect. In contrast to the initial effect, the sustained effect of cerivastatin was shown at concentrations approximately 100-fold lower and was dependent on inhibition of endothelial HMG-CoA reductase.


CONCLUSIONS
These data provide direct evidence to prove that in the presence of cerivastatin, the NOS system in endothelium operates with high efficiency toward increasing NO activity by activation of NO release and by concurrent inactivation of O2-.
Kalinowski
Leszek
L
Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, USA.
Dobrucki
Lawrence W
LW
Brovkovych
Viktor
V
Malinski
Tadeusz
T
D001682:Biological Availability; D015374:Biosensing Techniques; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D008845:Microinjections; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D011725:Pyridines / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D009566:Nitrates; D011725:Pyridines; D013481:Superoxides; D009569:Nitric Oxide; C086276:cerivastatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D008798:Mevalonic Acid