Chronic beta2-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca2+-ATPase protein and activity.
We determined the cardiovascular effects of chronic beta2-adrenoceptor (beta2-AR) stimulation in vivo and examined the mechanism for the previously observed prolonged diastolic relaxation. Rats (3 mo old; n = 6), instrumented with implantable radiotelemeters, received the selective beta2-AR agonist formoterol (25 microg.kg(-1).day(-1) ip) for 4 wk, with selected cardiovascular parameters measured daily throughout this period, and for a further 7 days after cessation of treatment. Chronic beta2-AR stimulation was associated with an increase in heart rate (HR) of 17% (days 1-14) and 5% (days 15-28); a 11% (days 1-14) and 6% (days 15-28) decrease in mean arterial blood pressure; and a 24% (days 1-14) increase in the rate of cardiac relaxation (-dP/dt) compared with initial values (P < 0.05). Cessation of beta2-AR stimulation resulted in an 8% decrease in HR and a 7% decrease in -dP/dt, compared with initial values (P < 0.05). The prolonged cardiac relaxation with chronic beta2-AR stimulation was associated with a 30% decrease in the maximal rate (Vmax) of sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA) activity, likely attributed to a 50% decrease in SERCA2a protein (P < 0.05). glycogen synthase kinase-3beta (GSK-3beta) has been implicated as a negative regulator of SERCA2 gene transcription, and we observed a approximately 60% decrease (P < 0.05) in phosphorylated GSK-3beta protein after chronic beta2-AR stimulation. Finally, we found a 40% decrease (P < 0.05) in the mRNA expression of the novel A kinase anchoring protein AKAP18, also implicated in beta2-AR-mediated cardiac relaxation. These findings highlight some detrimental cardiovascular effects of chronic beta2-AR agonist administration and identify concerns for their current and future use for treating asthma or for conditions where muscle wasting and weakness are indicated.
Ryall
James G
JG
Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, Victoria, Australia.
Schertzer
Jonathan D
JD
Murphy
Kate T
KT
Allen
Andrew M
AM
Lynch
Gordon S
GS
D048868:Adaptor Proteins, Signal Transducing; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D013686:Telemetry; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; C526078:Akap7 protein, rat; C506948:Atp2a2 protein, rat; D002352:Carrier Proteins; D004983:Ethanolamines; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000068759:Formoterol Fumarate