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

We determined the cardiovascular effects of chronic beta(2)- adrenoceptor (beta(2)-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 beta(2)-AR agonist formoterol (25 mu g . 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 beta(2)-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 beta(2)-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 beta 2-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-3 beta (GSK- 3 beta) has been implicated as a negative regulator of SERCA2 gene transcription, and we observed a similar to 60% decrease (P < 0.05) in phosphorylated GSK-3 beta protein after chronic beta(2)-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 beta(2)-AR-mediated cardiac relaxation. These findings highlight some detrimental cardiovascular effects of chronic beta(2)-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.