Sex-dependent activation of apamin-sensitive small-conductance Ca2+-activated K+ current by β1-adrenergic stimulation in rabbit ventricles.

We previously found that isoproterenol activates apamin-sensitive small-conductance Ca2+-activated K+ currents (IKAS) more in female than male rabbit ventricles. Isoproterenol activates all β-adrenoceptors (ARs). It remains unknown which AR is responsible for IKAS activation. We studied Langendorff-perfused rabbit hearts with dual optical mapping to determine the action potential duration and intracellular Ca2 + (Cai) during atrial pacing. Study I (six females and six males): baseline - 1 µm denopamine (specific β1-AR agonist) - 100 nm apamin. Study II (seven females and six males): baseline - pirbuterol 1 or 10 µm (specific β2-AR agonist) - 100 nm apamin. Study III (three females): baseline - 1 µm mirabegron (specific β3-AR agonist) - 100 nm apamin. During denopamine infusion, at a pacing cycle length (PCL) of 200 ms, apamin significantly prolonged action potential duration (APD) at the level of 25% repolarization (APD25) and 80% repolarization (APD80) in female ventricles, but not male ventricles. The Cai time-to-peak duration was significantly shortened by denopamine only in females, but not in males. At aPCL of 250 ms, Cai time-to-peak duration was significantly shortened following denopamine administration in both females and males. Subsequent administration of apamin significantly prolonged APD25 and APD80 in both females and males in the presence of denopamine. Neither pirbuterol nor mirabegron shortened Cai time-to-peak duration. Subsequent administration of apamin did not prolong APD80. We conclude that β1-AR, but not β2 or β3-AR, activates IKAS in rabbit ventricles. This rate-dependent effect exhibits a sex difference and is associated with a significant shortening of Cai time-to-peak duration. KEY POINTS: β1-adrenoceptor (AR) agonist denopamine activates the apamin-sensitive small-conductance Ca2+-activated K+ current (IKAS) in female rabbit ventricles at a pacing cycle length (PCL) of both 200 ms and 250 ms and in male ventricles only at a PCL of 250 ms. A significantly shortened time-to-peak of intracellular Ca2+ (Cai) transient is associated with IKAS activation. β2-AR agonist pirbuterol and β3-AR agonist mirabegron do not activate IKAS or shorten the Cai time-to-peak duration.