Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice.
We tested the hypothesis that endothelial nitric oxide (NO) synthase (eNOS)-derived NO modulates rho-kinase-mediated vascular contraction. Because 3-hydroxy-3-methylglutaryl (HMG)-CoA-reductase inhibition can both upregulate eNOS expression and inhibit rhoA/rho-kinase function, a second hypothesis tested was that statin treatment modulates rho-kinase-mediated contraction and that this can occur independently of eNOS. Contractile responses to the receptor-dependent agonists serotonin and phenylephrine but not to the receptor-independent agent KCl were greater in aortic rings from eNOS-null (eNOS(-/-)) vs. wild-type (eNOS(+/+)) mice. Similarly enhanced responses were seen in eNOS(+/+) rings after acute NOS inhibition. The rho-kinase inhibitor Y-27632 abolished or profoundly attenuated responses to receptor agonists in both eNOS(+/+) and eNOS(-/-) rings, but responses in eNOS(+/+) were more sensitive to Y-27632. Mevastatin treatment (20 mg/kg sc per day, 14 days) reduced responses to serotonin and phenylephrine in female mice of both strains. KCl-induced contractions were slightly smaller in eNOS(+/+)-derived aortic rings only. Levels of plasma cholesterol, and aortic expression of rhoA and rho-kinase, did not differ between groups. Thus eNOS-derived NO suppresses rhoA/rho-kinase-mediated vascular contraction. Moreover, a similar suppressive effect on rho-kinase-mediated vasoconstriction by statin therapy occurs independently of effects on eNOS or plasma cholesterol.
Budzyn
Klaudia
K
Department of Pharmacology, University of Melbourne, Parkville, Victoria 3010, Australia.
Marley
Philip D
PD
Sobey
Christopher G
CG
D000577:Amides / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases
D000577:Amides; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; C012258:mevastatin; D009569:Nitric Oxide; D002784:Cholesterol; D008148:Lovastatin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D019331:NG-Nitroarginine Methyl Ester