Beta3 receptors mediate adrenergic stimulation of the sarcolemmal Na K pump

1
Beta-3 receptors mediate adrenergic
stimulation of the sarcolemmal Na-K
pump Henning Bundgaard3, Alvaro Garcia1, Elisha
Hamilton2, Caroline White1, Helge Rasmussen1,2 1
Royal North Shore Hospital, 2 University of
Sydney, Sydney, AUSTRALIA 3 Rigshospitalet,
Copenhagen, DENMARK
Summary
Results
Introduction

• The beta 3 AR agonist BRL 37344 stimulates the
  Na-K pump in cardiac myocytes
• The effect is mediated through the pathways
  indicated below
• The endogenous hormone norepinephrine
  stimulates the Na-K pump in cardiac myocytes
  via the beta 3 AR

Beta 3 adrenergic receptors (AR) are expressed in
the cardiac myocytes. It is widely accepted that
stimulation of beta 3 AR has a negative inotropic
effect. Since the receptor is coupled to
"endothelial" nitric oxide synthase (eNOS) and
since nitric oxide (NO) stimulates the Na-K pump
in cardiac myocytes we examined if beta 3 AR
activation stimulates the sarcolemmal Na-K pump.
Such pump stimulation might account for reports
of a negative inotropic effect of beta 3 AR
stimulation and be important for our
understanding of the pathophysiology of heart
failure (HF), a condition characterized by raised
intracellular levels Na and marked upregulation
of the myocardial beta 3 AR. Raised cytosolic
levels of Na make an important contribution to
the electro-mechanical phenotype of abnormal
cellular handling of Ca2, cardiac arrhythmia and
abnormalities of contraction in HF.
Clinical impact
Methods
We suggest that Na-K pump stimulation by beta 3
AR agonists represents a new clinical tool for
export of Nai from the cardiac myocytes in heart
failure and hypertrophy.
Isolated rabbit ventricular myocytes were voltage
clamped at 40 mV with wide-tipped patch pipettes
(1 m?) using the whole-cell patch clamp
technique. The pipette filling solution that
perfused the intracellular compartment included
10 mM Na. Electrogenic Na-K pump current (Ip,
arising from the 3Na 2K exchange ratio) was
identified from the shift in holding current
induced by pump blockade with 100 ?M ouabain.
Myocytes were exposed to compounds inclu-ded in
the superfusate or patch pipette filling
solutions.
References
1 Buhagiar, K. A. et al. (2001) Am J Physiol Cell
Physiol. 281, C1059-C1063. 2 Buhagiar, K. A. et
al (1999) Am J Physiol. 277, C461-C468.3 Hool, L.
et al (1996) Am J Physiol. 271, C172-C180. 4
Mihailidou, A. S. et al (2000) Circ Res. 86,
37-42. 5 William, M. et al (2005). J Physiol.
565815-25 . 6 Barouch, L. A. et al (2002).
Nature. 416337-339.
Ip measured in cardiac myocytes harvested from
rabbits. BRL 37344 is a beta 3 AR agonist.
Nadolol is a beta 1 and beta 2 AR antagonist.
HSP-90 Heat Shock Protein-90, Radicicol HSP-90
blocker, L-NAME nitric oxide synthase inhibitor,
NA noradrenaline (norepinephrine), H-89 Protein
Kinase A (PKA) inhibitor, ODQ cytosolic guanylyl
cyclase inhibitor. Figures () indicates number of
experiments.