title: Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats.
abstract: Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048+/-22 versus 780+/-18 mg, P<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789+/-27, 825+/-20 mg, P<0.01, and 1118+/-29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Akiko
authors.initials: A
authors.lastname: Ogai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ogita
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Jiyoong
authors.initials: J
authors.lastname: Kim
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D017311:Amlodipine / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004095:Dihydropyridines / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology; D007700:Kinetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D011921:Rats, Inbred WKY; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D017311:Amlodipine; D009569:Nitric Oxide; C061004:benidipine; D019001:Nitric Oxide Synthase; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D019331:NG-Nitroarginine Methyl Ester