Beta-adrenergic modulation of IKs in the guinea-pig ventricle

The slowly activating delayed rectifier potassium current, IKs, is strongly upregulated by PKA-mediated phosphorylation and it has been indicated to have a central role in maintaining repolarization stability during sympathetic activation in man. In vivo, sympathetic activation modulates repolarization currents by the concurrence of direct action on adrenergic receptors and heart rate changes. Until recently, rate-dependent increase in IKs has been generally attributed to incomplete channel deactivation during short diastolic intervals. This should lead to accumulation of channels in the open state, resulting in a larger "instantaneous" IKs appearing at the action potential upstroke. This view was disputed by our observation that high rates enhance IKs by accelerating the onset of its time-dependent component, rather than only by increasing its instantaneous one [1, 2]. This was tentatively interpreted as rate-dependent accumulation of channels in a non-conductive state from which activation may occur more rapidly. This interpretation has been elegantly formalized by Silva and Rudy [3] in a numerical model of IKs. The purpose of the work was to test whether the effects of β-adrenergic modulations of IKs can be interpreted within the framework of the same kinetic computational model. To this aim, IKs kinetics and its adrenergic and rate-dependent modulations were extensively evaluated in guinea-pig ventricular myocytes and subsequently used as the reference for the identification of a mathematical description of the IKs kinetic with and without adrenergic stimulation. The computational model was then used to analyse the mechanisms regulating the ß-adrenergic modulation of the current.