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

Abstract

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.