Cholinergic and adrenergic modulation of ionic membrane currents in a rabbit SA node cell model

We have modified our Hodgkin-Huxley (HH)-type compartmental model of the rabbit sinoatrial node (SAN) cell, to show the effects of cholinergic and adrenergic modulation on certain ionic membrane currents. This study centers on the direct and indirect effects of bath application of acetylcholine (ACh) in the presence or absence of isoprenaline (ISO). Specifically, the direct effect of ACh is on the muscarinic G-protein mediated K⁺ current I_K,ACh, while the indirect effect is mediated by the second messenger cyclic adenosine monophosphate (cAMP) which modulates four specific membrane currents: the hyperpolarization-activated inward current (I_f), the long-lasting Ca²⁺ current (I_CaL ), the delayed-rectifier K⁺ current (I_K) and the Na⁺-K⁺ pump current (I_NaK). The model also includes material balances on Na⁺, Ca²⁺, K⁺ and cAMP. The resulting model is capable of mimicking the response of the SAS cell to bath applications of these chemical agents (i.e. inhibitory effects of ACh and the excitatory effects of ISO upon the cycle length). In addition, the model is capable of mimicking the phase sensitivity of the SAN cell in response to both single and periodically-applied ACh stimuli in either the presence and absence of steady background levels of ISO. In these studies, the “ACh stimuli” used represent the local change in ACh concentration produced by the stimulation of a cluster of parasympathetic nerve terminal endings that surround individual pacemaking cells within the SA nodal region of the rabbit heart. Our simulation results for the single cell indicate that the model has a high degree of predictive value in that it can mimic data obtained from multicellular preparations, as well as provide biophysically based explanations for the well known phase-sensitivity of cardiac pacemaker cells to both single and periodically applied ACh stimuli