Rate dependency of β‐adrenergic modulation of repolarizing currents in the guinea‐pig ventricle

β‐Adrenergic stimulation modulates ventricular currents and sinus cycle length (CL). We investigated how changes in CL affect the current induced by isoprenaline (Iso) during the action potential (AP) of guinea‐pig ventricular myocytes. Action‐potential clamp was applied at CLs of 250 and 1000 ms to measure: (1) the net current induced by 0.1 μm Iso (IIso); (2) the L‐type Ca2+ current ICaL and slow delayed rectifier current IKs components of IIso (IIsoCa and IIsoK), identified as the Iso‐induced current sensitive to nifedipine and HMR1556, respectively; and (3) IIso persisting after inhibition of both ICa and IKs (IisoR). The pause dependency of IKs and its modulation were evaluated in voltage‐clamp experiments. The rate dependency of the duration of the action potential at 90% repolarization (APD90) and its modulation by isoprenaline were tested in current‐clamp experiments. At a CL of 250 ms IIso was inward during initial repolarization and reversed at 59% of APD90. At a CL of 1000 ms IIso became mostly inward in all cells. Switching to shorter CL did not change IIsoCa and IIsoK amplitudes, but moved their peak amplitudes to earlier repolarization; IIsoR was independent of CL. Acceleration of IIsoK at shorter CL was based on faster pause dependency of IKs activation rate. The ‘restitution’ of activation rates was modulated by isoprenaline. The APD90–CL relation was rotated anticlockwise by isoprenaline and crossed the control curve at a CL of 150 ms (400 beats min−1). We conclude that: (1) isoprenaline induced markedly different current profiles according to pacing rate, involving CL‐dependent ICa and IKs modulation; (2) the effect of isoprenaline on APD90 was CL dependent, and negligible during tachycardia; and (3) during sympathetic activation, repolarization stability may involve matched modulation of sinus rate and repolarizing currents.