Cardioprotective and survival benefits of long-term combined therapy with beta2 adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction.
We have reported therapeutic effectiveness of pharmacological stimulation of beta2 adrenoreceptors (ARs) to attenuate the cardiac remodeling and myocardial infarction (MI) expansion in a rat model of dilated cardiomyopathy (DCM) post-MI. Furthermore, the combination of beta2 AR stimulation with beta1 AR blockade exceeded the therapeutic effectiveness of beta1 AR blockade. However, these studies were relatively short (6 weeks). In this study, in the same experimental model, we compared different effects, including survival benefit, of combined therapy with the beta1 AR blocker, metoprolol, plus the beta2 AR agonist, fenoterol (beta1-beta2+), and either therapy alone (beta1- or beta2+) during the 1-year study. Therapy was started 2 weeks after permanent ligation of the left coronary artery. Cardiac remodeling, MI expansion, and left ventricular function were assessed by serial echocardiography and compared with untreated animals (nT). Sixty-seven percent mortality in nT was reduced to 33% in the beta1-beta2+ (p < 0.01). Progressive cardiac remodeling observed in nT and beta1- was significantly attenuated in beta1-beta2+ during the first 6 months of treatment. In beta1-beta2+, MI expansion was completely prevented, and functional decline was significantly attenuated during the entire year. Myocardial apoptosis was significantly reduced in both beta1-beta2+ and beta1-. A reduction of cardiac beta1 AR density and decreases in chronotropic and contractile responses to beta2 AR-specific stimulation in the absence of a reduction of beta2 AR density in nT were precluded in rats receiving combined therapy. The results demonstrate the cardioprotective and survival benefit of long-term combination therapy of beta2 AR agonists and beta1 AR blockers in a model of DCM.
Ahmet
Ismayil
I
National Institute on Aging, Intramural Research Program, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825, USA.
Krawczyk
Melissa
M
Zhu
Weizhong
W
Woo
Anthony Yiu-Ho
AY
Morrell
Christopher
C
Poosala
Suresh
S
Xiao
Riu-Ping
RP
Lakatta
Edward G
EG
Talan
Mark I
MI
D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D002306:Cardiac Volume / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005280:Fenoterol / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects
D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005280:Fenoterol; D008790:Metoprolol