Cardioprotective Effects of Beta3-Adrenergic Receptor (β3-AR) Pre-, Per-, and Post-treatment in Ischemia–Reperfusion

  • Ruduwaan SalieEmail author
  • Aisha Khlani Hassan Alsalhin
  • Erna Marais
  • Amanda Lochner


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).


To investigate whether selective modulation of β3-AR prior to or during ischemia and/or reperfusion may be cardioprotective.


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).


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.


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.


Myocardial ischemia Reperfusion injury Cardioprotection β3-AR modulation 


Compliance with Ethical Standards

Experimental Animals

Male Wistar rats (230 to 250 g) were used in this study. The handling of laboratory animals was in accordance with the ethical guidelines as set out by the University of Stellenbosch, Faculty of Medicine and Health Sciences Ethics Committee and the South African National Standard for Care and Use of Animals for Scientific Purpose (SANS 10386: 2008). The rats had free access to food and water prior to experimentation. Rats were anesthetized with sodium pentobarbital (30 mg/rat) by intraperitoneal injection before removal of hearts.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10557_2019_6861_MOESM1_ESM.docx (31 kb)
ESM 1 (DOCX 30 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ruduwaan Salie
    • 1
    • 2
    Email author
  • Aisha Khlani Hassan Alsalhin
    • 2
  • Erna Marais
    • 2
  • Amanda Lochner
    • 2
  1. 1.Biomedical Research and Innovation PlatformSouth African Medical Research CouncilCape TownSouth Africa
  2. 2.Faculty of Medicine and Health Sciences, Division of Medical PhysiologyUniversity of StellenboschCape TownSouth Africa

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