Sex‐dependent activation of apamin‐sensitive small‐conductance Ca ²⁺ ‐activated K ⁺ current by β1‐adrenergic stimulation in rabbit ventricles

We previously found that isoproterenol activates apamin-sensitive small-conductance Ca²⁺-activated K⁺ currents (I_KAS) more in female than male rabbit ventricles. Isoproterenol activates all β-adrenoceptors (ARs). It remains unknown which AR is responsible for I_KAS activation. We studied Langendorff-perfused rabbit hearts with dual optical mapping to determine the action potential duration and intracellular Ca² ⁺ (Ca_i) 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 Ca_i time-to-peak duration was significantly shortened by denopamine only in females, but not in males. At aPCL of 250 ms, Ca_i 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 Ca_i time-to-peak duration. Subsequent administration of apamin did not prolong APD₈₀. We conclude that β1-AR, but not β2 or β3-AR, activates I_KAS in rabbit ventricles. This rate-dependent effect exhibits a sex difference and is associated with a significant shortening of Ca_i time-to-peak duration. KEY POINTS: β1-adrenoceptor (AR) agonist denopamine activates the apamin-sensitive small-conductance Ca²⁺-activated K⁺ current (I_KAS) 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⁺ (Ca_i) transient is associated with I_KAS activation. β2-AR agonist pirbuterol and β3-AR agonist mirabegron do not activate I_KAS or shorten the Ca_i time-to-peak duration.