title: Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after balloon injury in porcine coronary arteries.
abstract: HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Eto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Kunio
authors.initials: K
authors.lastname: Morishige
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kunihiro
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kandabashi
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002404:Catheterization / Q000009:adverse effects / Q000379:methods; D017023:Coronary Angiography / Q000379:methods; D003331:Coronary Vessels / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012701:Serotonin / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020030:Nitric Oxide Donors; D011725:Pyridines; D014665:Vasodilator Agents; D009599:Nitroprusside; D012701:Serotonin; D000001:Calcimycin; C086276:cerivastatin; D052250:Nitric Oxide Synthase Type III; D009543:Nifedipine; D001920:Bradykinin