title: Effects of atorvastatin, amlodipine, and their combination on vascular dysfunction in insulin-resistant rats.
abstract: Deficiency of tetrahydrobiopterin (BH4) in the vascular tissue contributes to endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O2(-)) generation in the insulin-resistant state. We investigated the effects of atorvastatin, a 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor; amlodipine, a calcium antagonist; and their combination on blood pressure, arterial relaxation and contraction, and vascular oxidative stress in aortas of high fructose-fed rats. Oral administration of atorvastatin for 8 weeks did not significantly lower blood pressure, but normalized angiotensin II-induced vasoconstriction and endothelial function in the fructose-fed rats. Atorvastatin treatment of fructose-fed rats increased vascular BH4 content, which was associated with an increase in endothelial NO synthase activity as well as a reduction in endothelial O2(-) production. On the other hand, administration of amlodipine did not affect the angiotensin II-induced vasoconstriction and endothelial function, but normalized the elevated blood pressure in the fructose-fed rats. The combined treatment did not show synergistic but additive beneficial effects. The present study suggests that combined therapy of HMG-CoA reductase inhibitors and calcium antagonists prevents functional vascular disorders in the insulin-resistant state, possibly resulting in the protection against or delay of development of hypertension, vascular dysfunction in diabetes, and thereafter atherosclerosis.
authors.affiliation: Department of Pharmacology, Shiga University of Medical Science, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Okamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Tawa
authors.forename: Ayman
authors.initials: A
authors.lastname: Geddawy
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimosato
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Haruo
authors.initials: H
authors.lastname: Shintaku
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Masada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinozaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000069059:Atorvastatin; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013481:Superoxides; D017311:Amlodipine; D001708:Biopterins; D005632:Fructose; D009569:Nitric Oxide; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin