Cells in many specimens of human ventricle can exhibit either of two stable levels of diastolic potential (DP) when exposed to 4 mM K' in vitro (i.e., -78±4 mV or -45±5 mV, mean±SEM). In this report we show that the DP of some partially depolarized human ventricular cells developed a sustained 25-35 mV hyperpolarization (n=28) when bath K' concentration (K+b) was raised from 4 to 7 mM. On return of K+b to 4 mM, the DP of most, but not all, of these cells returned to the original depolarized levels. In other cells, the transition between the two levels ofDP occurred at variable K+b ranging from 1 to 20 mM. We investigated the ionic mechanism(s) underlying the shifts between the two levels of potential by studying the K' dependence of the DP in partially depolarized cells in 22 specimens of human ventricle. DP hyperpolarized an average of 25.6 mV (from -44.4± 1.3 to -70.0+ 1.3 mV; n=25) when K+bwas increased from 4 to 7 mM. Intracellular K' activity, determined by K+-selective microelectrodes, was within the range of normal reported for other mammalian species (106.7+±4.4 mM in 4 mM K'; n=22) and was unaffected by increasing K'b to 7 mM (111.7+±6.6 mM; n=6). Ba2` (0.05 mM), a blocker of the inward rectifying K' current, reversibly prevented the hyperpolarization, whereas acetylstrophanthidin (9 ,uM) failed to inhibit it. These results suggest that the hyperpolarization was due to a K'-dependent increase in K' permeability and that electrogenic sodium pumping did not contribute significantly to the process. The ionic basis of the depolarization from a hyperpolarized level of DP also was investigated. Decreasing bath Na+ concentration and exposure to 30 ,lM tetrodotoxin did not prevent the depolarization. However, the depolarization could be inhibited by 2 mM Mn2'. These findings suggest that the depolarization may have been due to a Mn21-sensitive inward current. (Circulation Research 1990;66:191-201)

Cardiac hypertrophy can decrease myocardial contractility and alter the electrophysiological activity of the heart. It is well documented that action potentials recorded from hypertrophied feline ventricular cells can exhibit depressed plateau voltages and prolonged durations. Similar findings have been made by others in rabbit, rat, guinea pig, and human heart. Whole-cell patch voltage-clamp studies designed to explain these changes in the action potential suggest that the only component of the membrane current recorded from feline right ventricular (RV) myocytes found to be substantially different from normal is the 4-aminopyridine-sensitive transient outward current (I(to)). However. it was not clear if the change in I(to) could explain the changes in the action potential of hypertrophied cardiocytes, nor was it clear if these changes reflect an alteration in the electrophysiological character of the channels underlying I(to). A kinetic comparison of I(to) elicited by hypertrophied RV myocytes with that elicited by comparable normal RV myocytes previously revealed no differences, suggesting that the increased magnitude of the peak I(to) recorded from hypertrophied myocytes arises because the current density increases and not because of any alteration in the kinetic parameters governing the current. This finding suggests that in hypertrophy additional normal channels are expressed rather than a kinetically different channel subtype emerging. Investigations designed to determine if enhancement of I(to) could explain the.hypertrophy-induced changes in plateau voltage and action potential duration suggest that a change in I(to) density can indeed explain the entire effect of hypertrophy on RV action potentials. If this notion is correct, the likelihood of ''sudden death'' in patients with myocardial hypertrophy might be decreased by a blocker selective for cardiac I(to).

The myocardial cell hypertrophies in response to a sustained increase in workload including pressure overload due to ventricular or systemic hypertension; volume overload because of an AV fistula, other defects in the heart pump, or hypervolemia; and sustained increase in heart rate. It can be subsequent to regional damage brought about by acute or chronic ischemia and infarction, by nutritional and hormonal disturbances, and by dynamic {1} and isometric exercise {2}. There are numerous changes concomitant with, and perhaps associated with, myocardial hypertrophy, including recently described electrophysiological alterations. Hypertrophy may be compensatory, allowing the heart to meet the increased workload; if hypertrophy is insufficient, pump failure ensues {3, 4}. This review is limited to an examination of changes occurring in a common well-studied form of hypertrophy, that provoked by pressure overload. We describe and emphasize the electrophysiologic changes associated with this form of hypertrophy and also consider pertinent mechanical, structural, and biochemical findings. We refer to other models and to naturally occurring disease-induced hypertrophy when relevant.

Concentrations of ACh which reduced action potential twitch tensions by up to 30 or 40% (ED-30-ED-40) increased steady state outward currents but had no effect on the time dependent outward current, the slow inward current or voltage clamp tension. This indicates that in this dose range the negative inotropy during normal activity can be completely explained by an ‘indirect’ effect on the slow inward current, i.e. increased outward current shortens the action potential and prevents the slow inward current from running its normal time course.