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Chronic β₂-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca²⁺-ATPase protein and activity

¹Basic and Clinical Myology Laboratory and ²Central Cardiovascular Regulation Group, Department of Physiology, University of Melbourne, Victoria, Australia

Submitted 26 August 2007 ; accepted in final form 7 April 2008

We determined the cardiovascular effects of chronic β₂-adrenoceptor (β₂-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 β₂-AR agonist formoterol (25 µg·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 β₂-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 β₂-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 β₂-AR stimulation was associated with a 30% decrease in the maximal rate (V_max) of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) activity, likely attributed to a 50% decrease in SERCA2a protein (P < 0.05). glycogen synthase kinase-3β (GSK-3β) has been implicated as a negative regulator of SERCA2 gene transcription, and we observed a 60% decrease (P < 0.05) in phosphorylated GSK-3β protein after chronic β₂-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 β₂-AR-mediated cardiac relaxation. These findings highlight some detrimental cardiovascular effects of chronic β₂-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.

β-agonist; glycogen synthase kinase-3β; sarco(endo)plasmic reticulum Ca²⁺-ATPase; A kinase anchoring protein