A Local-Control Model of the Guinea Pig Ventricular Myocyte Allows Understanding of Force-Interval Relations at the Calcium Spark Level

Abstract

A local control model of the guinea pig ventricular myocytes was developed to explore the mechanisms governing Ca2+ dynamics. This dynamic balance is controlled by the model features including L-type Ca2+ channels (LCC), sarcolemmal sodium calcium exchangers (NCX) and ryanodine receptors, type 2 (RyR2s). We developed a new three state RyR2 model that simulates RyR2 adaptation in which the channels accumulate in a closed state when exposed to prolonged elevated subspace [Ca2+] (Gyorke and Fill Science. 1993 260:807-9). The model was tested for agreement with previous experimental and modeling studies on force-interval relations, i.e. the changes in calcium transient and action potential morphology at different pacing frequencies. Our local control model displays stable action potential trains at 7 Hz, unlike previous common pool models. The duration of the [Ca2+]i transient and the action potential (AP) decrease with increased pacing rates consistent with experiment. With increased pacing rate, the [Ca2+]i transient peak values increases up to 3Hz and decreases afterward, consistent with experimental force-frequency curves. The model predicts, in agreement with our previous modeling studies (Jafri et al., Biophys J. 1998 Mar;74(3):1149-68), that diastolic sarcoplasmic reticulum (SR) [Ca2+] and RyR2 adaptation increases with increased stimulation frequency giving rise to rising than falling amplitude of the myoplasmic [Ca2+] transients. The model also allows us to dissect these frequency dependent changes down to the spark level giving new insight into mechanism governing cardiac calcium dynamics.