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

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Abstract
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 (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-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.

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