Rate dependency of {szligbeta}-adrenergic modulation of repolarizing currents in the guinea-pig ventricle

{szligbeta}-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 mu M Iso (I sub(Iso)); (2) the L-type Ca super(2+) current I sub(CaL) and slow delayed rectifier current I sub(Ks) components of I sub(Iso) (I sub(IsoCa) and I sub(IsoK)), identified as the Iso-induced current sensitive to nifedipine and HMR1556, respectively; and (3) I sub(Iso) persisting after inhibition of both I sub(Ca) and I sub(Ks) (I sub(isoR)). The pause dependency of I sub(Ks) and its modulation were evaluated in voltage-clamp experiments. The rate dependency of the duration of the action potential at 90% repolarization (APD sub(90)) and its modulation by isoprenaline were tested in current-clamp experiments. At a CL of 250 ms I sub(Iso) was inward during initial repolarization and reversed at 59% of APD sub(90). At a CL of 1000 ms I sub(Iso) became mostly inward in all cells. Switching to shorter CL did not change I sub(IsoCa) and I sub(IsoK) amplitudes, but moved their peak amplitudes to earlier repolarization; I sub(IsoR) was independent of CL. Acceleration of I sub(IsoK) at shorter CL was based on faster pause dependency of I sub(Ks) activation rate. The 'restitution' of activation rates was modulated by isoprenaline. The APD sub(90)-CL relation was rotated anticlockwise by isoprenaline and crossed the control curve at a CL of 150 ms (400 beats min super(-1)). We conclude that: (1) isoprenaline induced markedly different current profiles according to pacing rate, involving CL-dependent I sub(Ca) and I sub(Ks) modulation; (2) the effect of isoprenaline on APD sub(90) was CL dependent, and negligible during tachycardia; and (3) during sympathetic activation, repolarization stability may involve matched modulation of sinus rate and repolarizing currents.