Selective β2-adrenoreceptor stimulation attenuates myocardial cell death and preserves cardiac function after ischemia-reperfusion injury.
OBJECTIVE
β(2)-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β(2)-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability.


RESULTS
Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 µg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr(308) (P<0.001) and Ser(473) (P<0.01), and eNOS phosphorylation at Ser(1177) (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS(-/-) mice.


CONCLUSIONS
Our results indicate that β(2)-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.
Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30308, USA.
Shashi
S
Bhushan
Kazuhisa
K
Kondo
Benjamin L
BL
Predmore
Maxim
M
Zlatopolsky
Adrienne L
AL
King
Claire
C
Pearce
Hui
H
Huang
Ya-Xiong
YX
Tao
Marah E
ME
Condit
David J
DJ
Lefer
D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004983:Ethanolamines / Q000627:therapeutic use*; D000068759:Formoterol Fumarate; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D004983:Ethanolamines; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D000068759:Formoterol Fumarate