Robert E. Ten Eick

Are increases in cyclic GMP levels responsible for the negative inotropic effects of acetylcholine in the heart

Abstract It has been suggested that increases in cyclic GMP levels are responsible for the negative inotropic effects of acetylcholine in the heart. This hypothesis was tested by monitoring the effects of acetylcholine and sodium nitroprusside on tension and cyclic nucleotide levels in strips of cat atrial appendage. Sodium nitroprusside markedly increased atrial cyclic GMP levels but did not decrease the twitch tension developed by the atrial strips. Low concentrations of acetylcholine, on the other hand, decreased twitch tension without increasing myocardial cyclic GMP levels. No significant change in cyclic AMP levels was observed in any of these experiments. These results are not consistent with the proposed role for cyclic GMP as the mediator of the negative inotropic effects of acetylcholine.

Aberrancy: Electrophysiologic aspects

Abstract Possible electrophysiologic causes of aberrancy are discussed on the basis of data derived from studies on transmembrane potentials of single cardiac cells. Aberrancy is considered to result from impulse spread in fibers of the His-Purkinje system (1) in which membrane potential at excitation is reduced (that is, it is less negative than the normal resting potential) due to incomplete repolarization, enhanced automaticity (phase 4 depolarization) of latent pacemakers and low resting potential; (2) in which responsiveness is depressed; or (3) in which some combination of these conditions prevails. For purposes of this discussion aberrancy is classified into 3 general groups: (1) aberrancy occurring in conjunction with shortening of the cycle; (2) aberrancy occurring in conjunction with prolongation of the cycle; and (3) aberrancy occurring in the absence of changes in cycle length. Comparisons are made between data derived from studies on animals and from studies on human cardiac tissues in order to assess the extent to which hypotheses and predictions based on the former are applicable to considerations of aberrancy in man. Such comparisons also provide clues as to the greater incidence of aberrancy in the diseased as compared to the normal heart.

Glass Microelectrode Studies on Intramural Papillary Muscle Cells Description of Preparation and Studies on Normal Dog Papillary Muscle

Although the electrophysiological properties of intramural ventricular myocardial cells are important to an understanding of cardiac excitation and conduction, they have not been well defined. The paucity of information stems from limitations on the depth of penetration by glass microelectrodes and from difficulties in perfusing the deep layers. Therefore, a tissue slicing technique that satisfactorily exposes all the layers of a papillary muscle specimen from the endocardium to the epicardium was developed for electrophysiological examination. Glass microelectrodes were then used to explore these slice preparations to define the electrophysiological characteristics of intramural cells in the normal dog. Transmem-brane potentials recorded from subendocardial and deep myocardial cells in the papillary muscle slices were comparable to those recorded from standard preparations. Similarities included action potential duration and configuration, relationships among resting potential, action potential configuration, and extracellular potassium concentration, and dependency of action potential duration on cycle length. However, the average magnitudes of measured electrophysiological characteristics were consistently greater in the subsurface cells tested in papillary muscle slices than they were in the surface cells tested in the standard preparations, i.e., resting potential was 2–4 my more negative, action potential amplitude was 7–9 my larger, and maximum rate of voltage change (maximum dV/dt) was 40–140 v/sec larger. Deep myocardial tissues also exhibited enhanced responsiveness (the curve relating activation potential to maximum dV/dt of the response shifted up and to the left), cell populations with large maximum dV/dt, and estimated conduction velocities in excess of three times those in the surface cell layers. These findings provide a reasonable explanation for (1) discrepancies between previously reported values for ventricular conduction velocity, (2) rapid impulse spread to the papillary muscle tip, and (3) bidirectional activation of the papillary muscle and large trabeculae. They also suggest the possibility of functional pathways that facilitate rapid activation of the deep myocardial lavers.

Enhanced functional expression of transient outward current in hypertrophied feline myocytes.

SummaryCardiac 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 (Ito). However, it was not clear if the change in Ito 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 Ito. A kinetic comparison of Ito 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 Ito 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 Ito could explain the hypertrophy-induced changes in plateau voltage and action potential duration suggest that a change in Ito 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 Ito.

Familial Atrial Dysrhythmia with A-V Block Intracellular Microelectrode, Clinical Electrophysiologic, and Morphologic Observations

This study is of a family with a syndrome of atrial fibrillation or flutter with advanced or complete atrioventricular (A-V) block, involving four members in two generations. Less serious arrhythmias were documented in another 15 members (three generations). Inheritance was by autosomal dominance with varying degrees of expression. An atrial biopsy was obtained in one of the members, a 40-year-old female who had atrial flutter with advanced A-V block proximal to the His bundle (H-V interval of 39 msec). Intracellular action potential (IAP) recordings from this tissue revealed: 1) partially depolarized cells with depressed IAP amplitude, 2) phase IV diastolic depolarization with spontaneous firing, 3) diminished excitability and responsiveness, and 4) decremental conduction with local block and re-entry. Histological findings revealed vacuolar degeneration, hypertrophy, and early necrosis of atrial cells.In conclusion, the multiple IAP and pathologic abnormalities provide a basis for atrial dysrhythmia in this family. The etiology of the disease is unknown.

Comparison of the effects of internal [Mg2+] on IK1 in cat and guinea-pig cardiac ventricular myocytes

The effects of internal Mg2+ (Mg2+i) on processes underlying the inward rectification of the cardiac IK1 in enzymatically isolated cardiac ventricular myocytes (CVM) obtained from cat, guinea pig and rabbit were compared using the whole-cell and excised inside-out patch configurations of the voltage-clamp technique. In confirmation of the findings of other investigators, Mg(2+)i-sensitive outward IK1 currents could be elicited from guinea pig CVM at 15 degrees C when Mg2+i was reduced from 1 mM to less than 1 microM, suggesting that Mg2+i has an important role in the inward rectification of IK1 in guinea pig CVM at unphysiologically low temperatures. However, as temperature was raised to more physiological levels (e.g., 30 degrees C), Mg(2+)i-sensitive outward IK1 currents could no longer be evoked. In contrast with the results obtained with guinea pig CVM, IK1 remained inwardly rectifying in cat and rabbit CVM independent of the Mg2+i concentration ([Mg2+]i) at 37 degrees, 15 degrees, 10 degrees, and 5 degrees C. Reduced [Mg2+]i at low temperature (15 degrees C), shifted the voltage dependence of guinea pig IK1 activation in the depolarizing direction; this resulted in an apparent linearization of IK1 conductance. When the range of the membrane potential examined was expanded to include voltages up to +80 mV, the guinea pig IK1 was found to exhibit inward rectification with the inflection in the I-V relationship that is found at approximately EK at normal temperature, also shifted 80 mV or more to much less negative voltages at low temperatures. In contrast, irrespective of [Mg2+]i or temperature, the voltage dependencies of the IK1 activation curves for both cat and rabbit myocytes were not changed from that defined when [Mg2+]i was 1 mM and temperature was 37 degrees C. We propose that Mg2+i affects inward rectification of IK1 in cold guinea pig CVM by altering the voltage dependence of activation.

Dual Microcomputer Analysis of Cardiac Transmembrane Action Potentials

A dual microcomputer system has been developed for automating the analysis of cardiac transmembrane action potentials. This system consists of two microcomputers and supporting function modules which digitize, detect, analyze, and plot the transmembrane action potentials from a cardiac cell impaled with a microelectrode. The action potentials are digitized at two sampling rates for computer processing; a sampling rate of 10 kHz is used to obtain the rapid initial upstroke, while a rate of 100 Hz is used to obtain the slower repolarization phase. The action potentials are characterized by graphic displays using the derived measurements. The system measures the resting potential, overshoot amplitude, dV/dtmax and time for 50, 70, and 95 percent repolarization of the action potential.