Beneficial effects of chronic pharmacological manipulation of beta-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy.
BACKGROUND
Studies in isolated cardiac myocytes have demonstrated that signaling via specific beta1-adrenergic receptor subtypes (beta1ARs) promotes but that signaling via beta2ARs protects from cell death. We hypothesized that prolonged beta(2)AR stimulation or beta1AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure.


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 beta2AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The beta1AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the beta2AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by beta2AR agonists than by the beta1AR blocker. Both beta2AR agonists and the beta1AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the beta2AR agonists reduced the Eed and the MI size by reducing infarct expansion.


CONCLUSIONS
These results provide proof of concept for the efficacy of chronic beta2AR stimulation in this DCM model.
Ahmet
Ismayil
I
Gerontology Research Center, Baltimore, MD 21224, USA.
Krawczyk
Melissa
M
Heller
Phillip
P
Moon
Chanil
C
Lakatta
Edward G
EG
Talan
Mark I
MI
D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005280:Fenoterol / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects
D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D005280:Fenoterol; C002904:zinterol; D008790:Metoprolol