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Cardioprotective Effects of Beta3-Adrenergic Receptor (β3-AR) Pre-, Per-, and Post-treatment in Ischemia-Reperfusion.
- Source :
-
Cardiovascular drugs and therapy [Cardiovasc Drugs Ther] 2019 Apr; Vol. 33 (2), pp. 163-177. - Publication Year :
- 2019
-
Abstract
- The β3-AR (beta3-adrenergic receptor) is resistant to short-term agonist-promoted desensitization and delivers a constant intracellular signal, making this receptor a potential target in acute myocardial infarction (AMI).<br />Aim: To investigate whether selective modulation of β3-AR prior to or during ischemia and/or reperfusion may be cardioprotective.<br />Methods: Isolated perfused rat hearts were exposed to 35-min regional ischemia (RI) and 60-min reperfusion. The β3-AR agonist (BRL37344, 1 μM) or antagonist (SR59230A, 0.1 μM) was applied: (i) before RI (PreT) or (ii) last 10 min of RI (PerT) or (iii) onset of reperfusion (PostT) or (iv) during both PerT+PostT. Nitric oxide (NO) involvement was assessed, using the NOS inhibitor, L-NAME (50 μM). Endpoints were functional recovery, infarct size (IS), cGMP levels, and Western blot analysis of eNOS, ERKp44/p42, PKB/Akt, and glycogen synthase kinase-3β (GSK-3β).<br />Results: Selective treatment with BRL significantly reduced IS. L-NAME abolished BRL-mediated cardioprotection. BRL (PreT) and BRL (PerT) significantly increased cGMP levels (which were reduced by L-NAME) and PKB/Akt phosphorylation. BRL (PostT) produced significantly increased cGMP levels, PKB/Akt, and ERKp44/p42 phosphorylation. BRL (PerT+PostT) caused significant eNOS, PKB/Akt, ERKp44/p42, and GSK-3β phosphorylation.<br />Conclusion: β3-AR activation by BRL37344 induced significant cardioprotection regardless of the experimental protocol. However, the pattern of intracellular signaling with each BRL treatment differed to some degree and suggests the involvement of cGMP, eNOS, ERK, GSK-3β, and particularly PKB/Akt activation. The data also suggest that clinical application of β3-AR stimulation should preferably be incorporated during late ischemia or/and early reperfusion.
- Subjects :
- Animals
Cyclic GMP metabolism
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases metabolism
Glycogen Synthase Kinase 3 beta metabolism
Hemodynamics drug effects
Isolated Heart Preparation
Male
Myocardial Infarction metabolism
Myocardial Infarction pathology
Myocardial Infarction physiopathology
Myocardial Reperfusion Injury metabolism
Myocardial Reperfusion Injury pathology
Myocardial Reperfusion Injury physiopathology
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Nitric Oxide metabolism
Nitric Oxide Synthase Type III metabolism
Phosphorylation
Rats, Wistar
Receptors, Adrenergic, beta-3 metabolism
Signal Transduction
Time Factors
Adrenergic beta-3 Receptor Agonists pharmacology
Adrenergic beta-3 Receptor Antagonists pharmacology
Myocardial Infarction prevention & control
Myocardial Reperfusion Injury prevention & control
Myocytes, Cardiac drug effects
Receptors, Adrenergic, beta-3 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1573-7241
- Volume :
- 33
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular drugs and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 30729348
- Full Text :
- https://doi.org/10.1007/s10557-019-06861-5