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(Circulation. 2004;110:692-699.)
© 2004 American Heart Association, Inc.

Original Articles

Celiprolol, A Vasodilatory ß-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

Yulin Liao, MD; Masanori Asakura, MD, PhD; Seiji Takashima, MD, PhD; Akiko Ogai, BS; Yoshihiro Asano, MD, PhD; Yasunori Shintani, MD; Tetsuo Minamino, MD, PhD; Hiroshi Asanuma, MD, PhD; Shoji Sanada, MD, PhD; Jiyoong Kim, MD; Soichiro Kitamura, MD, PhD; Hitonobu Tomoike, MD, PhD; Masatsugu Hori, MD, PhD; Masafumi Kitakaze, MD, PhD

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan (Y.L., M.A., S.T., Y.A., Y.S., T.M., H.A., S.S., M.H.); and the Cardiovascular Division of Medicine, National Cardiovascular Center, Suita, Osaka, Japan (J.K., A.O., S.K., H.T., M.K.).

Correspondence to Masafumi Kitakaze, Cardiovascular Division of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan. E-mail kitakaze{at}zf6.so-net.ne.jp

Received September 4, 2003; de novo received March 21, 2004; revision received May 6, 2004; accepted May 11, 2004.

	Abstract

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Background— The blockade of ß-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective ß₁-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.

Methods and 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 · kg^–1 · 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 · kg^–1 · 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 ß₁-adrenergic receptor blockade and NO-dependent pathway.

Key Words: receptors, adrenergic, beta • heart failure • hypertrophy • nitric oxide

	Introduction

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Accumulated evidence shows that stimulation of ß-adrenergic receptors (ARs) can induce cardiac myocyte hypertrophy. Indeed, a nonselective ß-AR agonist, isoproterenol, is frequently used as a pharmacological inducer of cardiac hypertrophy.¹ Animal studies and clinical trials have shown that ß-blockers can attenuate ventricular hypertrophy.^2,3 However, the mechanism is not completely understood.

In recent years, nitric oxide (NO) has been demonstrated to be effective in antihypertrophy and inhibiting cardiac remodeling.^4,5 Augmented endothelial NO synthase (eNOS) signaling by some drugs, such as ACE inhibitors,⁶ statins,^7,8 and estrogens,⁹ has been reported by our and other laboratories to be associated with improvement of cardiac remodeling. Intriguingly, ß-blockers with vasodilating properties, such as nebivolol and carvedilol, have also been reported to augment NO release from endothelial cells.¹⁰ Recent studies in our laboratory demonstrated that celiprolol, a selective ß₁-blocker with vasodilating properties, increased NO production in canine myocardial ischemia,¹¹ and we also reported that inhibition of eNOS can induce myocardial hypertrophy in rats.¹² However, very few studies were designed to explore the relation between eNOS signaling pathway and the inhibitory effect of ß-blockers on cardiac remodeling. Thus, we hypothesized that celiprolol may inhibit cardiac remodeling via the NO signal pathway. To test this idea, we evaluated the effects of long-term treatment with celiprolol on cardiac hypertrophy and heart function in a murine model of ventricular pressure overload induced by transverse aortic constriction (TAC). We examined plasma NO levels, myocardial eNOS protein levels, and its phosphorylation. We also tried to confirm whether celiprolol-induced attenuation of cardiac hypertrophy is blunted by N^G-nitro-L-arginine methyl ester (L-NAME). Moreover, to delineate the role of NO in cardiac hypertrophy and failure, we measured cardiac hypertrophy, pulmonary congestion and plasma NO levels in a time course and analyzed the correlation among them.

	Methods

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Cell Culture
Rat neonatal ventricular myocytes were isolated and cultured as we described previously.¹³ Cardiomyocytes were exposed to either phenylephrine (PE) (10^–4 mol/L), or isoproterenol (10^–6 mol/L or other concentrations) for 24 hours in the presence or absence of celiprolol (Nippon Shinyaku Co Ltd), and the extent of increase in [³H]leucine uptake was examined. To test whether the inhibitory effect of celiprolol on protein synthesis induced by PE was mediated via release of NO, we used L-NAME in an attempt to suppress this effect.

TAC Model and Protocols
All procedures were in accordance with institutional guidelines for animal research. Mice (C57BL/6, male, 8 to 9 weeks old, weighing 19 to 23 g) were anesthetized with a mixture of xylazine (5 mg/kg) and ketamine (25 mg/kg, intraperitoneal injection). The TAC model was created as we described previously.^14,15

We treated the mice with saline (TAC group) or celiprolol at 100 mg · kg^–1 · d^–1 (PO, Celi low group) and 200 mg · kg^–1 · d^–1 (PO, Celi high group). L-NAME at 100 mg · kg^–1 · d^–1 in drinking water and L-NAME plus celiprolol 100 mg · kg^–1 · d^–1 PO were also used. No difference was found among all the experimental groups in age and body weight before surgery. Two to 3 mice in each group were used to measure the transstenosis pressure gradient. Tail-cuff blood pressure and heart rate were measured (BP-98A, Softron). Mice were euthanized at different time points after TAC, and morphometric analysis was performed. Cell surface area and myocardial and perivascular fibrosis measurements were performed using 3 hearts in each group as described previously.^15,16

Echocardiographic Assessment
Transthoracic echocardiography was performed with a Sonos 4500 and a 15-6 L MHz transducer (Philips). Mice were lightly anesthetized with 2.5% Avertin (0.06 mL/10 g) and fixed. When they had recovered consciousness (10 minutes), good 2D short-axis views of the left ventricle (LV) were obtained for guided M-mode measurements of the LV posterior wall thickness, LV end-diastolic diameter, and LV end-systolic diameter.

NO Measurement
The plasma levels of nitrite and nitrate (NO_x) were measured as previously described.¹⁷ Cardiac myocardial protein level of eNOS, inducible NOS (iNOS), neuronal NOS (nNOS), and eNOS phosphorylated activity were checked by use of Western blot analysis.^16,18 Expression of these proteins was detected by use of the diaminobenzidine method and quantified by densitometry.

RNA Analysis
Assessment of the cardiac gene expression for natriuretic peptide precursor type B (BNP), protein inhibitor of NOS (PIN), and sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2) was performed by real-time polymerase chain reaction (RT-PCR).¹⁹ The Quantitect SYBR Green RT-PCR kit (Qiagen) was used to perform amplifications with the One-step protocol as described by the manufacturer.

Statistical Analysis
For all statistical tests, multiple comparisons were performed by 1-way ANOVA with the Tukey-Kramer exact probability test. The least-squares method was used for linear correlation between selected variables. Data were reported as the mean±SEM. A value of P<0.05 was considered statistically significant.

	Results

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Celiprolol Inhibits Myocyte Protein Synthesis Induced by Either Isoproterenol or PE
Isoproterenol, a nonselective ß-AR agonist, increased myocyte protein synthesis. The selective ß₁-AR antagonist celiprolol suppressed the enhancement by 70% (Figure 1A), suggesting that it is predominantly ß₁-ARs that mediate the isoproterenol-induced increase in protein content. As shown in Figure 1B, celiprolol also reduced the increase in protein synthesis stimulated by PE, indicative of an antihypertrophic effect independent of ß₁-AR blockade. PE increased cell size, whereas celiprolol significantly suppressed the increase (Figure 1, C and D). The inhibition of eNOS by L-NAME partially abolished the antihypertrophic effect of celiprolol on the PE-induced increase in protein synthesis (Figure 1, B–D).

View larger version (34K): [in this window] [in a new window]   Figure 1. Results of cardiac myocyte culture. A, Protein synthesis was inhibited by celiprolol (celi) at concentrations ranging from 10–4 to 10–7 mol/L in a dose-independent manner, and this concentration range did not affect normal myocytes. *P<0.01 vs Control. B, Celiprolol (10–6 mol/L) inhibited protein synthesis stimulated by PE (10–4 mol/L), and this effect was partially abolished by cotreatment with L-NAME (10–6 mol/L). *P<0.01 vs PE, $P<0.05 vs PE+Celi. C, Cell size was calculated from 200 cells in every treatment group. Increase in cell size caused by PE was reduced by treatment with celiprolol (10–6 mol/L), and L-NAME diminished effect of celiprolol. *P<0.01 vs PE, $P<0.05 vs PE+Celi. D, Representative images of cardiac myocytes stained with rhodamine phalloidin and 4',6-diamidino-2-phenylindole dihydrochloride (DAPI). Concentrations for all agents are same as in B.

Celiprolol Attenuates Pathological Cardiac Hypertrophy
Consistent with the results in vitro, low-dose celiprolol markedly attenuated cardiac hypertrophy 4 weeks after TAC (Figure 2, A and B). Histological examination also revealed that the extent of myocyte hypertrophy (Figure 3 A–C) was reduced and both myocardial and perivascular fibrosis were ameliorated in celiprolol-treated mice (Figure 2, C and D and Figure 3, D and E). The same results were achieved at a higher dose of celiprolol.

View larger version (35K): [in this window] [in a new window]   Figure 2. Celiprolol improves heart remodeling. HW/BW ratio (A) and myocyte cross-sectional area (B) were decreased significantly in TAC mice treated with celiprolol 100 mg · kg–1 · d–1 (Celi low) or 200 mg · kg–1 · d–1 (Celi high) in comparison with untreated TAC mice. L-NAME (100 mg · kg–1 · d–1) alone did not increase degree of myocyte hypertrophy under conditions of pressure overload. However, it partially abolished antihypertrophic effect of celiprolol (100 mg · kg–1 · d–1). Similar results on myocardial fibrosis (C) and perivascular fibrosis (D) were also noted. Numbers of mice in Sham, TAC, TAC+Celi low, TAC+L-NAME, and TAC+Celi+L-NAME groups are 10, 19, 11, 6, and 5, respectively.

View larger version (96K): [in this window] [in a new window]   Figure 3. Representative pictures of cardiac histology. Row A, representative images of whole-heart cross section obtained by microscopic analysis (hematoxylin-eosin stain). LV wall thickness was markedly decreased in celiprolol (100 mg · kg–1 · d–1)–treated compared with TAC mice. Row B, cardiac myocyte cross surface (hematoxylin-eosin stain; magnification x400; scar=20 µm). Row C, long-axis view of cardiac myocyte (hematoxylin-eosin stain, x200). Myocardial fibrosis (row D) and perivascular fibrosis (row E) were stained with azan-Mallory stain (x100).

The results of hemodynamics and echocardiography measured just before the animals were killed are shown in the Table. Celiprolol reduced heart rate significantly but did not affect tail-cuff systolic blood pressure. The LV wall became thinner in celiprolol-treated mice than in TAC mice. Between the 2 celiprolol groups, no significant differences were noted in hemodynamic and echocardiographic findings, although there was a tendency for the LV cavity to be smaller, the LV wall to be thicker, and LV fractional shortening to be higher in mice treated with the higher dose (data not shown).

View this table: [in this window] [in a new window]   Hemodynamic and Echocardiographic Results

We recorded echocardiographs and hemodynamics for all mice before surgery and found no differences among the 6 groups (data not shown). The transstenosis pressure gradient measured in 2 to 3 mice in each group showed no significant difference (Table).

L-NAME Partially Abolishes the Antihypertrophic Effect of Celiprolol
Treating TAC mice with celiprolol plus L-NAME decreased but did not completely abolish the antihypertrophic effect of celiprolol, whereas L-NAME alone did not further increase cardiac hypertrophy in the TAC mice (Figure 2, A–D).

Celiprolol Prevents Transition to Heart Failure
TAC induced congestive heart failure, manifested by increases in lung weight and reductions in fractional shortening. Compared with values in sham-operated mice, the ratio of lung weight to body weight (LW/BW) increased by 84% in TAC mice but only by 27% in low-dose celiprolol–treated mice (Figure 4, A and B), respectively. LV fractional shortening was also significantly higher in celiprolol-treated mice than TAC mice (Figure 4C). The same results on heart function were achieved at the higher dose of celiprolol. Furthermore, L-NAME markedly counteracted these beneficial effects produced by celiprolol.

View larger version (39K): [in this window] [in a new window]   Figure 4. Celiprolol prevents heart failure induced by TAC. A, Representative images of echocardiography and macroscopic view of lungs in different groups. B, LW/BW ratio was decreased significantly in TAC mice treated with celiprolol 100 mg · kg–1 · d–1 in comparison with untreated TAC mice. L-NAME (100 mg · kg–1 · d–1) alone did not affect heart function under conditions of LV pressure overload. However, it partially abolished antihypertrophic effect of celiprolol (100 mg · kg–1 · d–1). C, LV fractional shorting was increased in response to celiprolol treatment. Number of mice in each group is same as described in Figure 3.

NO Production Is Associated With Cardiac Hypertrophy and Heart Failure
To further clarify the role of NO in cardiac hypertrophy and heart failure, we evaluated the time course of cardiac hypertrophy, heart failure, and the plasma levels of NO_x. Heart weight–to–body weight ratio (HW/BW) and LW/BW were increased time-dependently from 1 to 4 weeks (Figure 5, A and B), whereas plasma levels of NO_x were decreased time-dependently (Figure 5C). Significant negative linear correlations were found between HW/BW and plasma NO_x (Figure 5D) and between LW/BW and plasma NO_x (Figure 5E). We also noted that celiprolol treatment partially prevented the decrease of NO production in TAC mice (Figure 5C).

View larger version (20K): [in this window] [in a new window]   Figure 5. Time course of cardiac hypertrophy, pulmonary congestion, and NO production. HW/BW ratio (A) and LW/BW ratio (B) increased, plasma of NO production (C) decreased time-dependently, and celiprolol (100 mg · kg–1 · d–1) treatment increased NO production. Significant negative linear correlations were noted between HW/BW and plasma NO level (D) and LW/BW and plasma NO level (E). Numbers of mice in Sham, TAC 1 week (1w), TAC 2w, TAC 4w, and TAC+Celi groups are 6, 5, 5, 7, and 6, respectively. *P<0.01, P<0.05 vs sham; P<0.01 vs TAC 4w.

Celiprolol Increases eNOS Protein and Its Activity
Myocardial protein levels of eNOS and its phosphorylation were decreased in TAC mice; celiprolol treatment increased eNOS and its phosphorylation significantly (Figure 6, A and B). We also tried to check the protein levels of iNOS and nNOS in myocardium with Western blot analysis and found that they were hardly detectable (data not shown), which is similar to previous reports.^16,20

View larger version (23K): [in this window] [in a new window]   Figure 6. Effect of celiprolol (100 mg · kg–1 · d–1) treatment on cardiac myocardial eNOS protein (A) and its phosphorylated activity (P-eNOS) (B). *P<0.05 vs sham. n=4 to 6 per group. Lanes 1 and 2 refer to Sham; Lanes 3 and 4, TAC; Lanes 5 and 6, TAC+Celiprolol 100 mg · kg–1 · d–1 in both A and B.

Celiprolol Induces Altered Transcriptional Expression
As shown in Figure 7, quantitative real-time PCR demonstrated that celiprolol treatment decreased levels of the hypertrophic molecular marker BNP, downregulated expression of PIN, and upregulated expression of SERCA. These changes further support our findings in vitro and in vivo that celiprolol attenuates cardiac hypertrophy and improves heart function partially by increasing the release of NO.

View larger version (12K): [in this window] [in a new window]   Figure 7. Results of real-time PCR. GAPDH was used as an endogenous control reference. Fold change was displayed as relative to sham. *P<0.05 vs TAC. Dose of celiprolol is 100 mg · kg–1 · d–1; n=4 in each group.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study demonstrated 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 ß₁-AR blockade and NO-dependent pathway.

In this study, we found a negative correlation between plasma NO_x and cardiac remodeling, indicating that NO production diminished time-dependently in the process of cardiac remodeling, which is in agreement with previous reports.^21–24 Celiprolol inhibits cardiac remodeling via attenuating myocardial hypertrophy, decreasing cardiac fibrosis, and ameliorating pulmonary edema; this process is mediated, at least in part, by augmented eNOS signaling, because L-NAME partially abrogated this effect. Previous studies also demonstrated that celiprolol inhibited cardiac fibrosis,²⁵ and overexpression of eNOS improved both cardiac and pulmonary function.²⁶ Although no significant difference was noted in tail-cuff pressure between the TAC mice treated with L-NAME+celiprolol and celiprolol alone, a vascular disparity really existed. Our echocardiographic data demonstrated an increase of LV chamber and myocardial hypertrophy and a decrease of LV ejection fraction in L-NAME+celiprolol–treated mice, indicating an increase of LV resistance.

The main finding in this study is that celiprolol inhibits the myocyte hypertrophy via activation of the NO signaling pathway. Experimental²⁷ and clinical²⁸ studies have also shown that activation of the NO-dependent pathway attenuates the effect of submaximal concentrations of catecholamines in the heart. These findings serve to support the results of the present study that PE-induced myocyte hypertrophy can be inhibited by celiprolol via the NO signaling pathway. Because stimulation of the adrenergic system is also involved in the pathogenesis of LV hypertrophy induced by pressure overload,²⁹ activation of the NO-dependent pathway by celiprolol should make some contribution to the attenuation of hypertrophy shown in our in vivo study.

Furthermore, ours is the first evidence that celiprolol can downregulate PIN, one of the potential mechanisms for the antihypertrophic effect of celiprolol. PIN has attracted significant attention for its potential importance as a regulator of nNOS,³⁰ and it also inhibits another 2 types of NOS isoenzymes (eNOS and iNOS).³¹ The mechanisms for the linkage of ß₁-blockade to eNOS upregulation have been clarified by other investigators. Kalinowski et al¹⁰ demonstrated that some ß-blockers augment NO production via activation of ATP efflux, with consequent stimulation of P₂Y purinoceptor. Celiprolol was also reported to activate eNOS through the PI3K-Akt signaling pathway.¹⁸ Conversely, the impact on PIN may be a specific effect of ß₁-blockers. It was reported that an association exists between nNOS decrease in the hypothalamus and enhanced sympathetic tone in rats with heart failure.³² Because ß₁-blockers are known to reduce sympathetic tone, it seems plausible that upregulation of nNOS via inhibiting PIN may make some contribution to the sympathetic inhibition of ß₁-blockers.

We showed in this study that celiprolol completely inhibited the decrease in myocardial eNOS protein levels, whereas its inhibition was partial in plasma NO_x levels. This discrepancy might be likely. In the chronic heart failure state, in addition to the reduced myocardial eNOS expression, platelet-derived NO production³³ and nNOS expression in neural tissue was also reported to be decreased.^34,35 However, there seems to be no evidence to show that celiprolol can completely inhibit the decrease in platelet-derived NO production or nNOS expression in neural tissue, which may be one reason that celiprolol only partially prevented the plasma NO_x decrease in TAC mice.

Considering its excellent level of safety,³⁶ the favorable effect on serum lipid metabolism and insulin sensitivity in chronic heart failure,³⁷ the benefit from the blockade of ß₁-ARs confirmed in large-scale clinical trials,³⁸ and its ability to activate the eNOS signaling pathway, a further large-scale and long-term clinical trial is needed to provide conclusive evidence for the effect of celiprolol in patients with chronic heart failure, especially those with hypertension, cardiac hypertrophy, diabetes mellitus, or hyperlipidemia.

	Acknowledgments

 
This work was supported by Grants-in-Aid for Human Genome, Tissue Engineering, and Food Biotechnology (H13-Genome-011), Health and Labor Sciences Research Grants, and Comprehensive Research on Aging and Health (H13-21seiki [seikatsu]-23), Health and Labor Sciences Research Grants from Ministry of Health, Labor, and Welfare, Japan.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Friddle CJ, Koga T, Rubin EM, et al. Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc Natl Acad Sci U S A. 2000; 97: 6745–6750.[Abstract/Free Full Text]

2. Morisco C, Zebrowski DC, Vatner DE, et al. Beta-adrenergic cardiac hypertrophy is mediated primarily by the beta(1)-subtype in the rat heart. J Mol Cell Cardiol. 2001; 33: 561–573.[CrossRef][Medline] [Order article via Infotrieve]

3. Gottdiener JS, Reda DJ, Massie BM, et al. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation. 1997; 95: 2007–2014.[Abstract/Free Full Text]

4. Calderone A, Thaik CM, Takahashi N, et al. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest. 1998; 101: 812–818.[Medline] [Order article via Infotrieve]

5. Scherrer-Crosbie M, Ullrich R, Bloch KD, et al. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation. 2001; 104: 1286–1291.[Abstract/Free Full Text]

6. Linz W, Wohlfart P, Scholkens BA, et al. Interactions among ACE, kinins and NO. Cardiovasc Res. 1999; 43: 549–561.[Free Full Text]

7. Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest. 2001; 108: 1429–1437.[CrossRef][Medline] [Order article via Infotrieve]

8. Hayashidani S, Tsutsui H, Shiomi T, et al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002; 105: 868–873.[Abstract/Free Full Text]

9. Ogita H, Node K, Liao Y, et al. Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice. Hypertension. 2004; 43: 237–242.[Abstract/Free Full Text]

10. Kalinowski L, Dobrucki LW, Szczepanska-Konkel M, et al. Third-generation ß-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003; 107: 2747–2752.[Abstract/Free Full Text]

11. Asanuma H, Node K, Minamino T, et al. Celiprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release. J Cardiovasc Pharmacol. 2003; 41: 499–505.[CrossRef][Medline] [Order article via Infotrieve]

12. Sanada S, Node K, Minamino T, et al. Long-acting Ca²⁺ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats. Hypertension. 2003; 41: 963–967.[Abstract/Free Full Text]

13. Asakura M, Kitakaze M, Takashima S, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med. 2002; 8: 35–40.[CrossRef][Medline] [Order article via Infotrieve]

14. Liao Y, Ishikura F, Beppu S, et al. Echocardiographic assessment of LV hypertrophy and function in aortic-banded mice: necropsy validation. Am J Physiol. 2002; 282: H1703–H1708.

15. Liao Y, Takashima S, Asano Y, et al. Activation of adenosine A₁ receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. Circ Res. 2003; 93: 759–766.[Abstract/Free Full Text]

16. Kurisu S, Ozono R, Oshima T, et al. Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension. 2003; 41: 99–107.[Abstract/Free Full Text]

17. Kitakaze M, Node K, Minamino T, et al. Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs. J Am Coll Cardiol. 1996; 27: 1804–1812.[Abstract]

18. Kobayashi N, Mita S, Yoshida K, et al. Celiprolol activates eNOS through the PI3K-Akt pathway and inhibits VCAM-1 via NF-B induced by oxidative stress. Hypertension. 2003; 42: 1004–1013.[Abstract/Free Full Text]

19. Asano Y, Takashima S, Asakura M, et al. Lamr1 functional retroposon causes right ventricular dysplasia in mice. Nat Genet. 2004; 36: 123–130.[CrossRef][Medline] [Order article via Infotrieve]

20. Silvagno F, Xia H, Bredt DS. Neuronal nitric-oxide synthase-mu, an alternatively spliced isoform expressed in differentiated skeletal muscle. J Biol Chem. 1996; 271: 11204–11208.[Abstract/Free Full Text]

21. Yu CM, Fung PC, Chan G, et al. Plasma nitric oxide level in heart failure secondary to left ventricular diastolic dysfunction. Am J Cardiol. 2001; 88: 867–870.[CrossRef][Medline] [Order article via Infotrieve]

22. Tonduangu D, Hittinger L, Ghaleh B, et al. Chronic infusion of bradykinin delays the progression of heart failure and preserves vascular endothelium-mediated vasodilation in conscious dogs. Circulation. 2004; 109: 114–119.[Abstract/Free Full Text]

23. Katz SD, Khan T, Zeballos GA, et al. Decreased activity of the L-arginine-nitric oxide metabolic pathway in patients with congestive heart failure. Circulation. 1999; 99: 2113–2117.[Abstract/Free Full Text]

24. Agnoletti L, Curello S, Bachetti T, et al. Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-. Circulation. 1999; 100: 1983–1991.[Abstract/Free Full Text]

25. Kobayashi N, Mori Y, Nakano S, et al. Celiprolol stimulates endothelial nitric oxide synthase expression and improves myocardial remodeling in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens. 2001; 19: 795–801.[CrossRef][Medline] [Order article via Infotrieve]

26. Jones SP, Greer JJ, van Haperen R, et al. Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci U S A. 2003; 100: 4891–4896.[Abstract/Free Full Text]

27. Balligand JL, Kelly RA, Marsden PA, et al. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci U S A. 1993; 90: 347–351.[Abstract/Free Full Text]

28. Hare JM, Keaney JF Jr, Balligand JL, et al. Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs. J Clin Invest. 1995; 95: 360–366.[Medline] [Order article via Infotrieve]

29. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996; 334: 374–381.[Free Full Text]

30. Jaffrey SR, Snyder SH. PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science. 1996; 274: 774–777.[Abstract/Free Full Text]

31. Hemmens B, Woschitz S, Pitters E, et al. The protein inhibitor of neuronal nitric oxide synthase (PIN): characterization of its action on pure nitric oxide synthases. FEBS Lett. 1998; 430: 397–400.[CrossRef][Medline] [Order article via Infotrieve]

32. Patel KP, Zhang K, Zucker IH, et al. Decreased gene expression of neuronal nitric oxide synthase in hypothalamus and brainstem of rats in heart failure. Brain Res. 1996; 734: 109–115.[Medline] [Order article via Infotrieve]

33. Dixon LJ, Morgan DR, Hughes SM, et al. Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation. 2003; 107: 1725–1728.[Abstract/Free Full Text]

34. Zhang K, Li YF, Patel KP. Blunted nitric oxide-mediated inhibition of renal nerve discharge within PVN of rats with heart failure. Am J Physiol. 2001; 281: H995–H1004.

35. Hirooka Y, Shigematsu H, Kishi T, et al. Reduced nitric oxide synthase in the brainstem contributes to enhanced sympathetic drive in rats with heart failure. J Cardiovasc Pharmacol. 2003; 42 (suppl 1): S111–S115.[Medline] [Order article via Infotrieve]

36. Witchitz S, Cohen-Solal A, Dartois N, et al. Treatment of heart failure with celiprolol, a cardioselective beta blocker with beta-2 agonist vasodilatory properties. The CELICARD Group. Am J Cardiol. 2000; 85: 1467–1471.[CrossRef][Medline] [Order article via Infotrieve]

37. Pietila M, Malminiemi K, Huupponen R, et al. Celiprolol augments the effect of physical exercise on insulin sensitivity and serum lipid levels in chronic heart failure. Eur J Heart Fail. 2000; 2: 81–90.[CrossRef][Medline] [Order article via Infotrieve]

38. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet. 1993; 342: 1441–1446.[CrossRef][Medline] [Order article via Infotrieve]

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