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

Abstract We previously found that isoproterenol activates apamin‐sensitive small‐conductance Ca 2+ ‐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 Ca 2 + (Ca i ) during atrial pacing. Study I (six females and six males): baseline – 1 µ m denopamine (specific β1‐AR agonist) – 100 n m apamin. Study II (seven females and six males): baseline – pirbuterol 1 or 10 µ m (specific β2‐AR agonist) – 100 n m apamin. Study III (three females): baseline – 1 µ m mirabegron (specific β3‐AR agonist) – 100 n m 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 (APD 25 ) and 80% repolarization (APD 80 ) 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 APD 25 and APD 80 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 APD 80 . 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. image Key points β1‐adrenoceptor (AR) agonist denopamine activates the apamin‐sensitive small‐conductance Ca 2+ ‐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 Ca 2+ (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.