Celiprolol, a vasodilatory beta-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice.
BACKGROUND
The blockade of beta-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective beta(1)-blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway.


RESULTS
In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N(G)-nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70+/-0.42 in TAC, 6.61+/-0.44 with celiprolol 100 mg x kg(-1) x d(-1) PO, P<0.01) and the ratio of lung weight to body weight (mg/g) (10.27+/-1.08 in TAC, 7.11+/-0.70 with celiprolol 100 mg x kg(-1) x d(-1) PO, P<0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice.


CONCLUSIONS
These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective beta1-adrenergic receptor blockade and NO-dependent pathway.
Liao
Yulin
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Asakura
Masanori
M
Takashima
Seiji
S
Ogai
Akiko
A
Asano
Yoshihiro
Y
Shintani
Yasunori
Y
Minamino
Tetsuo
T
Asanuma
Hiroshi
H
Sanada
Shoji
S
Kim
Jiyoong
J
Kitamura
Soichiro
S
Tomoike
Hitonobu
H
Hori
Masatsugu
M
Kitakaze
Masafumi
M
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control*; D017272:Celiprolol / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006984:Hypertrophy; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010656:Phenylephrine / Q000494:pharmacology; D011312:Pressure / Q000009:adverse effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D012333:RNA, Messenger; D014665:Vasodilator Agents; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain; D010656:Phenylephrine; D009569:Nitric Oxide; D017272:Celiprolol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester