Temporal dynamics of inotropic, chronotropic, and metabolic responses during β1- and β2-AR stimulation in the isolated, perfused rat heart

During the beta- adrenergic receptor ( beta- AR)- mediated stress response in the heart, the relations between functional responses and metabolism are ill defined, with the distinction between beta(1)- and beta(2)- AR subtypes creating further complexity. Specific outstanding questions include the temporal relation between inotropic and chronotropic responses and their metabolic correlates. We sought to elucidate the relative magnitudes and temporal dynamics of the response to beta(1)- and beta(2)- AR stimulation and the energy expenditure and bioenergetic state related to these responses in the isolated perfused rat heart. Inotropic [ left ventricular developed pressure ( LVDP) and dP/ dt], chronotropic [ heart rate ( HR)], and metabolic responses were measured during beta(1)- ( n = 9; agonist: norepinephrine) and beta(2)- ( n = 9; agonist: zinterol) AR stimulation. Myocardial oxygen consumption ( MV. O-2) was measured using fiberoptic oximetry, and high- energy phosphate levels and intracellular pH were measured using P-31 NMR spectroscopy. A multiple- dose protocol was used, with near- maximal beta-AR stimulation at the highest doses. In both beta(1) and beta(2) groups, there were dose- dependent increases in LVDP, dP/ dt, HR, and MVO2. The inotropic response showed more rapid onset, washout, and variation during dose than did the chronotropic response and was closely correlated with MVO2. This suggests that the myocardial bioenergetic state is more closely related to the inotropic response than to the chronotropic response. In addition, beta(1)- AR stimulation resulted in a greater magnitude and rate of onset of inotropic and MVO2 responses than did beta(2)- AR stimulation during maximal stimulation. However, a similar decrease in intracellular energy charge was seen in the two groups, consistent with a greater rate of oxidative phosphorylation during beta(1)- than during beta(2)- AR stimulation.