Published online before print August 16, 2004, doi: 10.1161/01.CIR.0000139844.15045.F9
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;110:1083-1090.)
© 2004 American Heart Association, Inc.
Original Articles |
Beneficial Effects of Chronic Pharmacological Manipulation of ß-Adrenoreceptor Subtype Signaling in Rodent Dilated Ischemic Cardiomyopathy
From the Gerontology Research Center, Baltimore, Md.
Correspondence to Mark I. Talan, MD, PhD, Gerontology Research Center, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail talanm{at}grc.nia.nih.gov
Received October 14, 2003; de novo received January 30, 2004; revision received March 13, 2004; accepted March 26, 2004.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Studies in isolated cardiac myocytes have demonstrated that signaling via specific ß1-adrenergic receptor subtypes (ß1ARs) promotes but that signaling via ß2ARs protects from cell death. We hypothesized that prolonged ß2AR stimulation or ß1AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure.
Methods and Results— A large myocardial infarction (MI) induced in rats by coronary artery ligation resulted in a dilated cardiomyopathy (DCM) characterized by infarct expansion and a progressive increase in left ventricular (LV) end-diastolic volume, accompanied by a reduction in ejection fraction (EF), as assessed by repeated echocardiography. Pressure-volume analysis at 8 weeks after ligation showed that diastolic stiffness (Eed) and arterial elastance (Ea) were increased, end-systolic elastance (Ees) was decreased, and arterioventricular (AV) coupling (Ea/Ees) had deteriorated. Apoptosis was present in both peri-infarct and remote myocardium. Chronic (6-week) administration of the ß2AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The ß1AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the ß2AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by ß2AR agonists than by the ß1AR blocker. Both ß2AR agonists and the ß1AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the ß2AR agonists reduced the Eed and the MI size by reducing infarct expansion.
Conclusions— These results provide proof of concept for the efficacy of chronic ß2AR stimulation in this DCM model.
Key Words: receptors, adrenergic, beta • heart failure • pharmacology • myocardial infarction • remodeling
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Dilated cardiomyopathy (DCM), characterized by compromised systolic and diastolic function, increased arterial elastance (Ea), and inefficient arterioventricular (AV) coupling, is the final common outcome of multiple cardiac disease states. Myocyte death resulting in part from apoptosis1,2 has been implicated in the evolution of DCM.3,4 Thus, protection of myocytes from cell death due to apoptosis holds promise as a therapeutic strategy with respect to delaying the initiation or progression of DCM.
Enhanced ventricular wall stress, due in part to an increased left ventricular (LV) cavity size, an increase in Ea (afterload), and excessive elaboration of catecholamines, angiotensin II, or cytokines, has been implicated in initiating or accelerating cell death. Catecholamines are elaborated excessively in chronic heart failure (CHF), and chronic exogenous administration of the mixed ß-adrenergic receptor (ßAR) agonist isoproterenol to rodents without heart disease results in DCM5 accompanied by cell death.6 Multiple ßAR subtypes are expressed in the adult myocardium. Recent advances in ß-adrenergic subtype signaling in isolated cardiac cell models indicate that stimulation of ß1AR is proapoptotic,7 whereas stimulation of ß2AR protects from apoptosis.8–10 Thus, there is a rationale to suggest that ß2AR agonists may reduce cell death and attenuate DCM progression.
The attractive theoretical benefits of ß2AR signaling with respect to direct cellular effects in protection from apoptosis, combined with its potential hemodynamic effect in reducing afterload and thus, in indirectly reducing apoptosis by reducing Ea and LV dilation, have yet to be tested in a cardiomyopathic model in the intact organism. We hypothesized that chronic stimulation of ß2AR would attenuate the increase in Ea, LV dilatation, and functional decline that ensue after a large myocardial infarction (MI) as a result of permanent coronary artery ligation in rats and that these effects would be accompanied by a reduction in the extent of apoptosis. Because ß1AR stimulation causes apoptosis in isolated cardiac myocytes and drugs with predominately ß1AR-blocking properties have already been demonstrated to be effective in the treatment of CHF, we also compared the effects of ß2AR agonists to those of a ß1AR blocker.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Experimental Design
After baseline echocardiographic assessment, the left descending coronary artery was ligated in 95 male Wistar rats, weighing 350 to 380 g (Charles River Inc, Wilmington, Mass), as described elsewhere.11 An additional 5 rats underwent sham operation without actual coronary ligation. One week after surgery, LV function and MI size in survivors were evaluated by echocardiography. Eight randomly selected, ligated animals were also euthanized at this time to assess the comparability of the echocardiographic estimate of MI size with a histological measure of MI size (see online-only Data Supplement for details). Then all remaining MI rats were divided into 4 groups of similar average MI size and variability: (1) untreated (LNT, n=13); (2) treated with a selective ß2AR agonist (fenoterol, n=10); (3) treated with another selective ß2AR agonist (zinterol, n=9); or (4) treated with a selective ß1AR blocker (metoprolol, n=7). Echocardiographic indices of LV structure and function at this time were considered the pretreatment baseline values for each group. Beginning 2 weeks after surgery, drugs were dissolved in the drinking water. The daily dose was 250 µg/kg, 1 mg/kg, and 250 mg/kg for fenoterol, zinterol, and metoprolol, respectively. Metoprolol was started at one fourth of the full dose for the first week of treatment, increased to a half dose for the second week, and increased to a full dose thereafter.12 Echocardiography was repeated at 2 and 6 weeks after initiation of treatment (ie, 4 and 8 weeks after surgery). After the final echocardiogram, all rats underwent an invasive hemodynamic study, and hearts were harvested for histological evaluation. Fenoterol and metoprolol were purchased from Sigma; zinterol was a gift from Bristol-Myers Inc (Evansville, Ind).
Echocardiography and Hemodynamics
Rats were anesthetized with sodium pentobarbital, and standard echocardiographic measurements were made (see online-only Data Supplement [available at http://www.circulationaha.org] for details). Hemodynamic measurements by pressure-volume (PV) loop analyses were conducted as described previously.13
Histology
Myocardial sections (5 µm thick) were obtained at the midpapillary muscle level, and MI size was calculated as previously described13 (also see online-only Data Supplement [available at http://www.circulationaha.org] for details). Hematoxylin and eosin staining was used to measure myocyte diameters across the nucleus in transverse sections. Terminal dUTP nick end-labeling (TUNEL) staining (Cardio TACS, R&D Systems), followed by eosin counterstaining of the cytoplasm, was used to assess apoptosis.
Statistical Analysis
All data are expressed as mean±SEM. Echocardiographically derived indices were compared by 2-way ANOVAs for repeated measures. Group differences at specific time points were assessed by a Bonferroni test. Differences in hemodynamic or histological data among sham or LNT, ß2AR agonist, and ß1AR blocker groups were assessed by 1-way ANOVAs, followed by a Bonferroni test. A value of P<0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Treatment Group Assignment
The 24-hour mortality rate after coronary ligation surgery was 50%. There was no later mortality. Figure 1A illustrates representative 2D, short-axis echocardiographic images of ligated rats 1 week after surgery, divided into 4 groups of equal MI size. Neither the mean nor the variance about the mean of this pretreatment echocardiographic estimate of MI size differed among groups (Table 1). Echocardiographic LV dimensions and ejection fraction (EF) also did not differ among groups (Figure 3 legend).
|
|
|
P<0.05 versus LNT; 
P<0.05 versus sham. Post hoc comparison at different time points: *P<0.05 versus LNT; #P<0.05 versus metoprolol.
DCM Progression in the Absence of Treatment
LV Dimensions
The findings in Figure 2 illustrate the progression of LV remodeling during an 8-week period after coronary artery ligation in the absence of treatment. Both end-diastolic volume (EDV) and end-systolic volume (ESV) had increased significantly 1 week after surgery, and these increases were progressive until the study was terminated.
|
, LNT; and 
, sham. ANOVA for repeated measures revealed statistically significant (P<0.05) groupxtime interaction. *P<0.05 for post hoc comparison at different time points.
Infarct Expansion
The results shown in Figure 1B illustrate representative echocardiographic images before the rats were euthanized. The average echocardiographic estimate of MI size increased from the pretreatment values by 32±5% (Table 1). The actual endocardial circumferential infarct length increased by 52±8%. Thus, infarct expansion occurred between 1 and 8 weeks after surgery.
Histological Infarct Size
Representative cardiac gross morphology (cross sections of hearts) at sacrifice is illustrated in Figure 1C. The histological MI size at 8 weeks after ligation in the absence of treatment averaged 32.2±4.0% of the LV circumference (Table 1). In the group of animals euthanized at 1 week after surgery (Figure 4, 1 week after MI), histological MI size averaged 26.1±2.1% (P<0.05 versus MI size at 8 weeks after ligation) and confirmed the echocardiographic estimate of infarct expansion between 1 and 8 weeks after surgery.
|
, zinterol; and 
, metoprolol.
Relative Heart Weight and Myocyte Size
The heart weight–to–body weight ratio and average LV posterior wall myocyte diameter also were significantly increased (Table 1), indicating the presence of myocardial and myocyte hypertrophy.
Myocardial Apoptosis
The findings in Figure 5 illustrate representative examples of TUNEL staining of the MI border and remote areas of the myocardium. A markedly increased number of TUNEL-positive myocytes was evident in both the MI border and remote areas.
|
LV Function
Within 1 week after coronary artery ligation, EF markedly declined (by about half) and by 8 weeks showed a modest further decline. Figure 6 illustrates representative LV PV loops recorded before euthanization at 8 weeks after coronary ligation. The average values of hemodynamic parameters are listed in Table 2. All indices of LV performance were significantly affected: EF and preload recruitable stroke work (PRSW) were reduced by 50%; dP/dt was reduced by 40%; end-systolic elastance (Ees) fell by 70%; end-diastolic elastance (Eed) increased by 300%; the isovolumic relaxation time increased by 50%; and Ea increased by 30%. As a result, the Ea-Ees ratio increased by 5-fold, indicating a marked decline in the efficiency of AV coupling.
|
|
Effect of Treatment on DCM Progression
Before the beginning of treatment (2 weeks after ligation), substantial LV dilation and functional decline had occurred, ie; post-MI DCM had already became manifest (Figure 2), and its severity did not differ among ligated groups (Table 1 and Figure 3 legend).
LV Dimensions
The results in Figure 3 illustrate the average effects of treatment on the changes in chamber dimensions from the pretreatment measurement at 1 week after ligation. The progressive increases in EDV and ESV that occurred in the absence of treatment were reduced by both ß2AR agonists but not by the ß1AR blocker.
Infarct Expansion
In the metoprolol group, echocardiographic MI size, measured as a percentage of the LV, had increased over 6 weeks from the pretreatment value by 27±14%, ie, similar to that of the LNT group. The endocardial circumferential infarct length also increased in the metoprolol group, similar to the LNT group. In the fenoterol and zinterol groups, MI size, measured as a percentage of the LV, was reduced, but endocardial circumferential infarct length did not change during the treatment period (Table 1). Considering the enlargement of the LV cavity size during the treatment period (Figure 3), the increased relative echocardiographic MI size in both LNT and metoprolol groups likely indicates infarct expansion; on the contrary, there was no evidence of infarct expansion in the fenoterol and zinterol groups.
Histological Infarct Size
Histological MI size was highly correlated with the echocardiographic estimate of MI size (Figure 4; R2=0.88) and was significantly smaller in the fenoterol group than in the LNT or metoprolol group (Table 1).
Relative Heart Weight and Myocyte Size
The heart weight–to–body weight ratio was not affected by treatment (Table 1). LV posterior wall myocyte diameter was significantly increased in the metoprolol group compared with the sham-operated group, was significantly reduced in both fenoterol and zinterol groups in comparison with the LNT or metoprolol group (Table 1), and did not significantly differ among sham-operated, fenoterol, and zinterol groups.
Myocardial Apoptosis
The number of TUNEL-positive–stained myocytes in both fenoterol and zinterol groups was significantly less than in the LNT group, in both the MI border and remote areas (Figure 5). In the metoprolol group, TUNEL staining was also significantly less than in the LNT group in remote areas but not in the MI border area. Compared with the metoprolol group, TUNEL staining was significantly reduced in both fenoterol and zinterol groups in the MI border area but not within remote areas.
LV Function (Echocardiography)
The findings in Figure 3 illustrate the average effect of treatment on the change in EF from pretreatment baseline. In LNT and metoprolol groups, EF declined and was unchanged, respectively. In contrast, EF was improved by both ß2AR agonists: with fenoterol, from 34±2% to 43±2% (P<0.05) and with zinterol, from 32±2% to 37±2% (P<0.05).
LV Function (PV Loops)
Representative PV loops for each group are illustrated in Figure 6, and average values of hemodynamic parameters in each group are listed in Table 2. In the fenoterol group compared with the LNT group, LV systolic pump function parameters PRSW, +dP/dt, and EF significantly increased; Ees also increased, but this increase did not reach statistical significance (P<0.10). For the same 2 groups, the diastolic functional parameters Eed, EDP, and isovolumic relaxation time were significantly reduced; –dP/dt was increased; the vascular afterload parameters peripheral vascular resistance (PVR) and Ea were significantly reduced; and AV coupling (Ea/Ees) was significantly improved (reduced ratio), on the basis of a reduction in Ea and the trend for Ees to increase. The profile of functional improvement in the LNT group versus the zinterol group was similar to that of fenoterol for most parameters (Table 2). In the metoprolol group compared with the LNT group, the systolic functional parameters PRSW, +dP/dt, and Ees were significantly improved, but the diastolic functional parameters Eed, EDP, isovolumic relaxation time, and –dP/dt did not differ; the vascular loading parameters PVR and Ea also did not statistically differ; and AV coupling (Ea/Ees) significantly improved, largely on the basis of an increase in Ees.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study compared the therapeutic effects of chronic pharmacological ßAR subtype manipulation on DCM induced by a large MI in rats. This DCM model is characterized by apoptosis, infarct expansion, myocyte hypertrophy in the area remote from the MI, progressive LV dilation, and systolic and diastolic functional decline in the context of an increased Ea and inefficient AV coupling. The rationale for the study stems from previous experimental observations that signaling pathways and biological consequences of ß1AR and ß2AR stimulation differ and therefore, that ßAR subtype stimulation potentially has different effects in the context of DCM.
Cardiac-specific overexpression of ß2AR at moderate levels (30 to 
200 times) leads to increased basal adenylyl cyclase activity and elevated contractile function without obvious cardiotoxicity, ie, hypertrophy and failure, whereas only when receptor overexpression is maintained at very high levels (350 to 1000 times) does it lead to these sequelae.14 In contrast to the relatively wide therapeutic window for ß2AR overexpression, even low levels of ß1AR overexpression (5 to 40 times) lead to progressive cardiac deterioration with prominent fibrosis, myocyte apoptosis, and hypertrophy.15 ß2AR signaling distinctly differs from that of the ß1AR.16 The ß2AR is dually coupled to both Gs and Gi in many species.17 When activated, Gi signaling counteracts that of Gs, eg, on phospholamban and myofilament phospholyration,18,19 plausible reasons why most ß2AR agonists induce a weaker positive inotropic effect than do ß1AR agonists. Most important, ß2AR stimulation protects cardiac myocytes from apoptosis, whereas ß1AR stimulation is proapoptotic.8–10
The most important novel finding of our study is that fenoterol and zinterol, both selective ß2AR agonists, attenuated the progression of DCM: Both reduced apoptosis and infarct expansion, attenuated LV dilatation, reduced Ea, and improved both LV systolic and diastolic functions and AV coupling. Fenoterol improved AV coupling (Ea/Ees) by reducing Ea and slightly increasing Ees. Although zinterol reduced Ea, it also slightly reduced Ees, and as a result, the improvement in AV coupling did not reach statistical significance. The reduction of the progressive LV chamber dilatation after treatment by either ß2AR agonist was accompanied by both reduced myocyte apoptosis in the MI border zone, an effect likely linked to the prevention of MI expansion, and a reduction of apoptosis in the myocardium remote from the MI. These effects of both ß2AR agonists were accompanied by a lack of myocyte hypertrophy within the myocardium remote from the MI.
Although the present study does not address specific pathways by which ß2AR agonists protect from apoptosis, previous studies indicate that the potent antiapoptotic effect of zinterol is mediated through ß2AR-Gi coupling.8 Among ß2AR agonists, fenoterol specifically is the most potent in enhancing contractility in isolated cardiac myocytes, and its effect is not pertussis toxin sensitive.20 Fenoterol, however, is unique in that, unlike other ß2AR selective agonists (eg, zinterol), it does not couple to Gi;20 Intriguingly, the potent antiapoptotic effect of fenoterol is also not pertussis toxin–sensitive (R.P. Xiao, MD, PhD, Senior Investigator, Laboratory of Cardiovascular Sciences, NIA, NIH, oral communication, 2004).
The effects of ß2AR agonists to attenuate LV remodeling and improve LV function in the context of DCM are likely realized through activation of both peripheral vascular and cardiac ß2AR signaling pathways. The vasodilating property of ß2AR agonists contributes to an improvement of LV function by reduction of vascular afterload, as evidenced by reductions in Ea and PVR. The resulting reduction in LV wall stress might be an additional contributory mechanism to the reduction of apoptosis effected by ß2AR agonists. This "indirect" antiapoptotic effect of ß2AR agonists might be shared by carvedilol, which has proven to be beneficial in the treatment of CHF21 and exhibits an antiapoptotic effect independent of ß1AR blockade.22
Metoprolol and other drugs with prominent ß1AR blocker properties are widely used in the treatment of clinical CHF. Their beneficial effects on cardiac function and survival have been well documented by various large-scale clinical studies.23,24 Metoprolol, at the dose used in the present study, improved cardiac systolic function and reduced apoptosis. However, it was not as effective as ß2AR agonists in this regard and did not attenuate LV chamber dilatation or improve diastolic function. Thus, after metoprolol treatment, whereas LV Ees was greater than in untreated DCM, LV Eed remained as high as in untreated DCM. Metoprolol, like fenoterol, improved AV coupling but achieved this mainly by an increase in Ees without significantly reducing Ea, as did the ß2AR agonists. Although metoprolol reduced myocardial apoptosis in the LV remote from the MI, it neither reduced MI border zone apoptosis nor prevented infarct expansion or an increase in myocyte size in the myocardium remote from the MI.
In summary, the present study provides proof of concept that chronic ß2AR stimulation is beneficial with regard to progressive LV dilatation and functional decline in DCM induced by coronary artery ligation. The overall results of chronic pharmacological stimulation of ß2AR signaling in the present study, ie, reduced apoptosis and deleterious LV remodeling, and improved function in the context of a reduced LV afterload provide a rationale for additional studies to evaluate the effectiveness of ß2AR stimulation in other CHF models. The complementary beneficial effects of ß2AR stimulation and ß1AR blockade on LV afterload and contractility, as well as additive effects on apoptosis demonstrated by the present results, also provide a rationale for studies to gauge whether additive myocardial protection could be achieved when these agents are used combination.
|
Footnotes |
|---|
The online-only Data Supplement, which contains additional information about Methods used in this study, is available with this article at http://www.circulationaha.org.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med. 1997; 336: 1131–1141.
[Abstract/Free Full Text]
- Sam F, Sawyer DB, Chang DL, et al. Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol. 2000; 279: H422–H428.
- Wencker D, Chandra M, Nguyen K, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest. 2003; 111: 1497–1504.[CrossRef][Medline]
[Order article via Infotrieve]
- Yamamoto S, Yang G, Zablocki D, et al. Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. J Clin Invest. 2003; 111: 1463–1474.[CrossRef][Medline]
[Order article via Infotrieve]
- Muders F, Friedrich E, Luchner A, et al. Hemodynamic changes and neurohumoral regulation during development of congestive heart failure in a model of epinephrine-induced cardiomyopathy in conscious rabbits. J Card Fail. 1999; 5: 109–116.[CrossRef][Medline]
[Order article via Infotrieve]
- Shizukuda Y, Buttrick PM, Geenen DL, et al. ß-Adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. Am J Physiol. 1998; 275: H961–H968.[Medline]
[Order article via Infotrieve]
- Zhu WZ, Wang SQ, Chakir K, et al. Linkage of ß1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II. J Clin Invest. 2003; 111: 617–625.[CrossRef][Medline]
[Order article via Infotrieve]
- Communal C, Singh K, Sawyer DB, et al. Opposing effects of ß1- and ß2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin–sensitive G protein. Circulation. 1999; 100: 2210–2212.
[Abstract/Free Full Text]
- Chesley A, Lundberg MS, Asai T, et al. The ß2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3'-kinase. Circ Res. 2000; 87: 1172–1179.
[Abstract/Free Full Text]
- Zhu WZ, Zheng M, Koch WJ, et al. Dual modulation of cell survival and cell death by ß2-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001; 98: 1607–1612.
[Abstract/Free Full Text]
- Hochman JS, Bulkley BH. Expansion of acute myocardial infarction: an experimental study. Circulation. 1982; 65: 1446–1450.
[Abstract/Free Full Text]
- Wei S, Chow LT, Sanderson JE. Effect of carvedilol in comparison with metoprolol on myocardial collagen postinfarction. J Am Coll Cardiol. 2000; 36: 276–281.
[Abstract/Free Full Text]
- Ahn D, Cheng L, Moon C, et al. Induction of myocardial infarcts of a predictable size and location by branch pattern probability assisted coronary ligation in C57BL/6 mice. Am J Physiol. 2004; 286: H1201–H1207.
- Liggett SB, Tepe NM, Lorenz JN, et al. Early and delayed consequences of ß2-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation. 2000; 101: 1707–1714.
[Abstract/Free Full Text]
- Engelhardt S, Hein L, Wiesmann F, et al. Progressive hypertrophy and heart failure in ß1-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A. 1999; 96: 7059–7064.
[Abstract/Free Full Text]
- Wenzel-Seifert K, Liu HY, Seifert R. Similarities and differences in the coupling of human ß1- and ß2-adrenoceptors to Gsalpha splice variants. Biochem Pharmacol. 2002; 64: 9–20.[CrossRef][Medline]
[Order article via Infotrieve]
- Xiao RP, Avdonin P, Zhou YY, et al. Coupling of ß2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res. 1999; 84: 43–52.
[Abstract/Free Full Text]
- Xiao RP, Ji X, Lakatta EG. Functional coupling of the ß2-adrenoceptor to a pertussis toxin–sensitive G protein in cardiac myocytes. Mol Pharmacol. 1995; 47: 322–329.[Abstract]
- Kuschel M, Zhou YY, Spurgeon HA, et al. ß2-Adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart. Circulation. 1999; 99: 2458–2465.
[Abstract/Free Full Text]
- Xiao RP, Zhang SJ, Chakir K, et al. Enhanced Gi signaling selectively negates ß2-AR, but not ß1-AR, mediated positive inotropic effect in myocytes from failing rat hearts. Circulation. 2003; 108: 1633–1639.
[Abstract/Free Full Text]
- Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003; 362: 7–13.[CrossRef][Medline]
[Order article via Infotrieve]
- Schwarz ER, Kersting PH, Reffelmann T, et al. Cardioprotection by carvedilol: antiapoptosis is independent of ß-adrenergic blockage in the rat heart. J Cardiovasc Pharmacol. 2003; 8: 207–215.
- Groenning BA, Nilsson JC, Sondergaard L, et al. Antiremodeling effects on the left ventricle during ß-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol. 2000; 36: 2072–2080.
[Abstract/Free Full Text]
- Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). JAMA. 2000; 283: 1295–1302.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  J. G. Ryall, J. D. Schertzer, K. T. Murphy, A. M. Allen, and G. S. Lynch Chronic {beta}2-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca2+-ATPase protein and activity Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2587 - H2595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ahmet, M. Krawczyk, W. Zhu, A. Y.-H. Woo, C. Morrell, S. Poosala, R.-p. Xiao, E. G. Lakatta, and M. I. Talan Cardioprotective and Survival Benefits of Long-Term Combined Therapy with {beta}2 Adrenoreceptor (AR) Agonist and {beta}1 AR Blocker in Dilated Cardiomyopathy Postmyocardial Infarction J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K.R. Soppa, J. Lee, M. A. Stagg, L. E. Felkin, P. J.R. Barton, U. Siedlecka, S. Youssef, M. H. Yacoub, and C. M.N. Terracciano Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure Cardiovasc Res, March 1, 2008; 77(4): 695 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Pleger, P. Most, M. Boucher, S. Soltys, J. K. Chuprun, W. Pleger, E. Gao, A. Dasgupta, G. Rengo, A. Remppis, et al. Stable Myocardial-Specific AAV6-S100A1 Gene Therapy Results in Chronic Functional Heart Failure Rescue Circulation, May 15, 2007; 115(19): 2506 - 2515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Birks, P. D. Tansley, J. Hardy, R. S. George, C. T. Bowles, M. Burke, N. R. Banner, A. Khaghani, and M. H. Yacoub Left Ventricular Assist Device and Drug Therapy for the Reversal of Heart Failure N. Engl. J. Med., November 2, 2006; 355(18): 1873 - 1884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Burniston, L.-B. Tan, and D. F. Goldspink Relative myotoxic and haemodynamic effects of the {beta}-agonists fenoterol and clenbuterol measured in conscious unrestrained rats Exp Physiol, November 1, 2006; 91(6): 1041 - 1049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Xydas, A. R. Kherani, J. S. Chang, S. Klotz, I. Hay, C. J. Mutrie, G. W. Moss, A. Gu, A. R. Schulman, D. Gao, et al. beta2-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 553 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rota, A. Boni, K. Urbanek, M. E. Padin-Iruegas, T. J. Kajstura, G. Fiore, H. Kubo, E. H. Sonnenblick, E. Musso, S. R. Houser, et al. Nuclear Targeting of Akt Enhances Ventricular Function and Myocyte Contractility Circ. Res., December 9, 2005; 97(12): 1332 - 1341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bernstein, G. Fajardo, M. Zhao, T. Urashima, J. Powers, G. Berry, and B. K. Kobilka Differential cardioprotective/cardiotoxic effects mediated by {beta}-adrenergic receptor subtypes Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2441 - H2449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ahmet, R. Wan, M. P. Mattson, E. G. Lakatta, and M. Talan Cardioprotection by Intermittent Fasting in Rats Circulation, November 15, 2005; 112(20): 3115 - 3121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhu, X. Zeng, M. Zheng, and R.-P. Xiao The Enigma of {beta}2-Adrenergic Receptor Gi Signaling in the Heart: The Good, the Bad, and the Ugly Circ. Res., September 16, 2005; 97(6): 507 - 509. [Full Text] [PDF]
|
|
|
|
|
|
J.-Q. He, R. C. Balijepalli, R. A. Haworth, and T. J. Kamp Crosstalk of {beta}-Adrenergic Receptor Subtypes Through Gi Blunts {beta}-Adrenergic Stimulation of L-Type Ca2+ Channels in Canine Heart Failure Circ. Res., September 16, 2005; 97(6): 566 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tsuneyoshi, W. Oriyanhan, H. Kanemitsu, R. Shiina, T. Nishina, S. Matsuoka, T. Ikeda, and M. Komeda Does the {beta}2-Agonist Clenbuterol Help to Maintain Myocardial Potential to Recover During Mechanical Unloading? Circulation, August 30, 2005; 112(9_suppl): I-51 - I-56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. R. Soppa, R. T. Smolenski, N. Latif, A. H. Y. Yuen, A. Malik, J. Karbowska, Z. Kochan, C. M. N. Terracciano, and M. H. Yacoub Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1468 - H1476. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||