Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing

The present study examined changes in electrophysiological properties of ventricular myocytes isolated from rabbit hearts after 2-3 weeks of rapid ventricular pacing. Left ventricular end-diastolic pressure at completion of the pacing period was nearly four-fold greater than in age-matched controls, although there was no significant change in heart weight/body weight ratio. Action potentials recorded in current-clamp mode at low stimulation frequencies were significantly longer in duration and phase 1 diminished in isolated myocytes from paced hearts compared with control. In voltage-clamp experiments, L-type Ca2+ current (I-Ca) density was not different between groups of myocytes, but the maximum current (at + 10 mV) elicited by 10 mu M isoproterenol was approximately 40% less in myocytes from paced hearts. In contrast, maximum I-Ca elicited by 10 mu M forskolin was similar in both groups. The 4-aminopyridine-sensitive, transient outward current (I-to) was 65% less (at + 60 mV) in myocytes from paced hearts than from control. However, after approximately 24 h in culture, I-to density in these myocytes returned toward control values. Despite marked reduction in I-to density, the inward rectifier current (I-k1) was not different between groups. These data demonstrate that I-to is significantly and reversibly decreased in myocytes from rapidly paced hearts, which may partly account for marked changes in action potential morphology. Although basal I-Ca was not altered in this group of myocytes compared with control, its modulation by beta-agonists was markedly blunted, probably through a decrease in receptor density or coupling to adenylyl cyclase. These changes in myocyte K+ and Ca2+ channel behavior in paced hearts may relate to impaired contractility and arrhythmogenesis that is characteristic of the intact failing heart. (C) 1997 Academic Press Limited.