β(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification.
BACKGROUND
inhibition of L-type Ca(2+) current contributes to negative inotropy of β(3) adrenergic receptor (β(3) AR) activation, but effects on other determinants of excitation-contraction coupling are not known. Of these, the Na(+)-K(+) pump is of particular interest because of adverse effects attributed to high cardiac myocyte Na(+) levels and upregulation of the β(3) AR in heart failure.


RESULTS
we voltage clamped rabbit ventricular myocytes and identified electrogenic Na(+)-K(+) pump current (I(p)) as the shift in holding current induced by ouabain. The synthetic β(3) AR agonists BRL37344 and CL316,243 and the natural agonist norepinephrine increased I(p). Pump stimulation was insensitive to the β(1)/β(2) AR antagonist nadolol and the protein kinase A inhibitor H-89 but sensitive to the β(3) AR antagonist L-748,337. Blockade of nitric oxide synthase abolished pump stimulation and an increase in fluorescence of myocytes loaded with a nitric oxide-sensitive dye. Exposure of myocytes to β(3) AR agonists decreased β(1) Na(+)-K(+) pump subunit glutathionylation, an oxidative modification that causes pump inhibition. The in vivo relevance of this was indicated by an increase in myocardial β(1) pump subunit glutathionylation with elimination of β(3) AR-mediated signaling in β(3) AR(-/-) mice. The in vivo effect of BRL37344 on contractility of the nonfailing and failing heart in sheep was consistent with a beneficial effect of Na(+)-K(+) pump stimulation in heart failure.


CONCLUSIONS
the β(3) AR mediates decreased β(1) subunit glutathionylation and Na(+)-K(+) pump stimulation in the heart. Upregulation of the receptor in heart failure may be a beneficial mechanism that facilitates the export of excess Na(+).
North Shore Heart Research Group, Kolling Institute of Medical Research, University of Sydney, Australia.
Henning
H
Bundgaard
Chia-Chi
CC
Liu
Alvaro
A
Garcia
Elisha J
EJ
Hamilton
Yifei
Y
Huang
Karin K M
KK
Chia
Stephen N
SN
Hunyor
Gemma A
GA
Figtree
Helge H
HH
Rasmussen
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006333:Heart Failure / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009248:Nadolol / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004149:Dioxoles; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D009248:Nadolol; C057368:BRL 37344; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione