Effects of AHR-2666 on electrical activity of canine cardiac tissues: possible inhibition of slow inward current.
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Biomedical subjects
Publications and source records attributed to B F Hoffman.
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We have identified extracell potential changes associated with the electrical activity of the canine sinoatrial pacemaker. Small nonpolarizable electrodes and low frequency high gain amplification were used to record unipolar electrograms from both the epicardial and the endocardial surfaces of the canine sinus node. Initially in vitro studies were performed so that transmembrane action potential changes could be recorded simultaneously with the extracell potentials. The sinus nodal electrogram showed two characteristic potentials when the electrode was in immediate proximity to pacemaking cells: (1) During phase 4 there was a steady slope of about -30 to -100 muv/sec, and (2) during the transition from phase 4 to phase 0 of the transmembrane action potential the slope of the electrogram increased smoothly to approximately -400 to -1,000 muv/sec. These potentials were followed by high frequency deflections as cells in the surrounding atrium depolarized. Tetrodotoxin (5 mg/liter) rendered the atrial muscle inexcitable and delayed and then abolished the high frequency activity in the sinus electrogram, which then appeared as a continuous smooth tracing similar to the sinus pacemaker action potential but reversed in polarity. We then recorded these small localized potentials from the in situ canine heart. Sinus nodal electrograms could be obtained from beating hearts with hand held probes on the epicardial surface and with conventional recording catheters on the endocardial surface. The results demonstrate that the canine sinus node gives rise to detectable and characteristic changes in extracell potential and suggest that similar potentials can be recorded from man to evaluate sinus nodal function.
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We have compared the effects of lidocaine (L) to those of several derivatives in an attempt to determine the sites of action and active forms of the molecules. We studied cardiac Purkinje fibers with intracellular microelectrodes, and drugs were administered by superfusion or by iontophoretic intracellular injection. We compared to L the effects of QX-314 and QX-572, two quaternary derivatives, and also compound 6603, a tertiary analogue with a pKa of 9.81. When administered by superfusion in concentrations of 10(-5) and 10(-4) M, all four agents exerted qualitatively similar effects on the transmembrane action potential. The rate of onset of action of the quaternary derivatives was considerably slower than that of L and their actions were not reversed by superfusion for 1 hour with drug-free solution. Comparison of effects of L and QX-314 after intracellular injection showed that attenuation of Vmax, and thus of the fast inward current, results from interaction of the charged form acting form acting from the inner surface of the sarcolemma. After intracellular injection, QX-314 diffused readily along the long axis of fiber bundles, and it was thus possible to expose the inner surface of a large number of contiguous cells to drug. Comparison of results of extracellular and intracellular application suggests that effects on the voltate during phase 2 result from the charged form acting from the inner surface, but effects on total action potential duration result only from drug acting from the outer surface of the sarcolemma. Unlike L, the three derivatives did not decrease the slope of normal phase 4 depolarization. The results may help relate antiarrhythmic action to specific effects on transmembrane potentials.
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To determine whether the ureter is innervated by the autonomic nervous system, isolated canine ureters were superfused with modified Tyrode solution, and force developed in response to 100-msec duration stimuli at a rate of 3 per min was monitored. Norepinephrine and phenylephrine significantly increased developed force; the latter more than the former. These increases in developed force were blocked by phentolamine, and propranolol enhanced the stimulatory effect of norepinephrine. In the presence of phentolamine, norepinephrine significantly decreased developed force. Isoproterenol significantly decreased developed force and this significant decrease in contractility was not observed in the presence of propranolol. High intensity, high frequency, short duration stimuli which in themselves were unable to excite quiescent rabbit and canine ureteral segments potentiated contractile force of segments contracting at the basal rate of 3 per min in response to long duration stimuli. When these same high intensity, high frequency, short duration stimuli were applied to ureteral segments pretreated with phentolamine, the developed force of the basally driven preparations decreased. These data suggest the presence of alpha-stimulatory and beta-inhibitory adrenergic receptors in canine and rabbit ureter and provide evidence for adrenergic tissue within the wall of the ureter that can influence contractile force.
Effects of the phenothiazine analog, EN-313, on ventricular electrical activity were studied using isolated blood-superfused canine Purkinje fibers and conscious dogs with sustained ventricular arrhythmias following a 2-stage ligation of the left anterior descending coronary artery, EN-313, less than 3 mg/kg, i.v., had no significant effect on transmembrane potentials of Purkinje fibers. At 3 mg/kg, EN-313 significantly decreased maximum upstroke velocity of phase 0 depolarization and action potential duration. In conscious dogs, EN-313 (1-3 mg/kg i.v.; 10-20 mg/kg p.o.) reduced arrhythmias that occured larger than or equal to 24 h after coronary artery ligation. No excessive changes in electrocardiographic parameters were observed following EN-313. These studies demonstrate that EN-313 suppresses ventricular arrhythmias in doses which have little effect on cellular electrophysiologic properties of normal Purkinje fibers and suggest that EN-313 should be useful in treating cardiac arrhythmias arising as a result of coronary occlusion.
The effects of epinephrine on the electrophysiologic properties of human right atrail tissue, obtained at cardiac surgery, were evaluated utilizing standard microelectrode techniques. In studies of electrophysiology, epinephrine had little effect on the resting membrane potential and transmembrane action potentials of normal atrial fibers. Epinephrine enhanced phase-4 depolarization and increased automaticity in normal fibers but hyperpolarized partially depolarized atrial fibers and decreased automaticity. The hyperpolarizing action of epinephrine resulted in an increase in action potential amplitude and dV/dt and enhanced conduction. Active force increased 40-230% in depressed tissues when exposed to epinephrine. Epinephrine-induced hyperpolarization of depressed atrail fibers may have a beneficial effect on atrial arrhythmias and depressed contractility encountered clinically.
We used open tip microelectrodes containing a K+-sensitive liquid ion exchanger to determine directly the intracellular K+ activity in beating canine cardiac Purkinje fibers. For preparations superfused with Tyrode's solution in which the K+ concentration was 4.0 mM, intracellular K+ activity (ak) was 130.0+/-2.3 mM (mean+/-SE) at 37 degrees C. The calculated K+ equilibrium potential (EK) was -100.6+/-0.5 mV. Maximum diastolic potential (ED) and resting transmembrane potential (EM) were measured with conventional microelectrodes filled with 3 M KCl and were -90.6+/-0.3 and -84.4+/-0.4 mV, respectively. When [K+]o was decreased to 2.0 mM or increased to 6.0, 10.0, and 16.0 mM, ak remained the same. At [K+]o=2.0, ED was -97.3+/-0.4 and Em -86.0+/-0.7 mV; at [K+]o=16.0, ED fell to -53.8+/-0.4 mV and Em to the same value. Over this range of values for [K+]o, EK changed from -119.0+/-0.3 to -63.6+/-0.2 mV. These values for EK are consistent with those previously estimated indirectly by other techniques.
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Two cases with XYY chromosome complement are presented and compared with 153 cases described in the literature. Some patients with abnormalities of personality development and manifest psychopathology may have sex chromosome abnormalities and should be studied further for the interaction of genetic and environmental factors in personality development. In particular, tall, schizoid impulsive men with a history of criminality, arson or sexual offences should be screened for this particular genetic configuration. Because of the biased manner by which most of the cases are found, it is not yet known whether an XYY genotype results in a characteristic phenotype. What is needed is a genetic study of a normal population and a prospective study of newborns with various genotypes which would, unfortunately, create complex research and ethical problems.
A method for signal enhancement of electrograms of the specialized atrioventricular conduction system is presented. This method allows a single electrogram to replace the tracings of bipolar electrograms previously required to ensure recognition of the specialezed conduction system and yet maintains the safety afforded by use of three pairs of recording electrodes. In addition, this new signal is enhanced in magnitude and is always unidirectional (positive). These features are desirable for automated signal recognition. This method therefore provides an important step toward future automation and signal recognition of specialized conduction system electrograms during open-heart surgery.