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Biomedical subjects

O Binah

Publications and source records attributed to O Binah.

53 records · Page 3Linked to original sources

Tetanus in the mammalian heart: studies in the shrew myocardium.

The purpose of the present study was to test the possibility that tetanus can occur in the shrew myocardium, in which the ventricular action potential is similar to that of skeletal muscle. Action potentials and tension were recorded from the right ventricular muscle using glass microelectrodes and a force transducer. When the regular twitch (at a cycle length of 2000 ms) was followed by a train of stimuli having an internal cycle length of less than 50 to 60 ms, unfused and fused tetanus readily developed. Action potentials were generated at the frequency of the stimuli within the train. With trains of sufficient duration, the tension during the tetanus usually reached a steady state and exceeded the tension of the regular twitch preceding the train. Tetanus with similar characteristics was also observed during an arrhythmic train which was occasionally triggered spontaneously by a regular stimulus. Simultaneous recordings of the action potential and the twitch demonstrated that the shrew ventricular muscle can be tetanized, since the action potential is very short (3 to 4 ms) and terminates before any signs of mechanical activity begin. The present study demonstrates that mammalian myocardium can be tetanized when action potential duration is much shorter than the duration of the mechanical event.

Action Potentials↗

Electrophysiological effects of a novel antiarrhythmic drug, EO-122, on guinea pig ventricular muscle and isolated myocytes.

EO-122, a newly developed structural analog of lidocaine, has recently been shown to suppress ventricular arrhythmias in a few clinical studies in patients and in experimental animals. In the present study, we investigated the effects of EO-122 on the electrophysiological properties of guinea pig papillary muscle and ventricular myocytes by means of standard microelectrode and whole-cell recording techniques, respectively, At the concentration range of 10(-7)-10(-4) M (cycle length, 2000 ms), resting potential and action potential duration (APD90) were not altered by the drug. Action potential amplitude and APD50 were reduced (p less than 0.01) by 10(-4) M, and Vmax was reduced (p less than 0.01) by EO-122 greater than or equal to 10(-5) M. The effect of EO-122 on Vmax was use-dependent. At 10(-6) and 10(-5) M (cycle length, 2000 ms), the time constant for onset of block (tau on) was 37.0 +/- 13.2 and 26.0 +/- 3.4 s, respectively. The recovery kinetics from use-dependent block was not monoexponential, and the estimated "time constant" for recovery was 76.5 s. We examined the effects of EO-122, 10(-5) M, on the membrane currents in ventricular myocytes and found that the drug attenuated the slow inward current (Isi). EO-122 reduced peak Isi by 68.6 +/- 5.2% (p less than 0.005), whereas the outward current was unchanged. The present study demonstrates that EO-122 blocks both the fast inward (Na+) and the slow inward (Ca2+) channels, and these effects are probably responsible for the antiarrhythmic effects of the drug.

Action Potentials↗

Effect of sodium pentobarbital on the transmembrane action potential and the slow inward current of guinea pig ventricular myocytes.

Barbiturates, which are widely used in clinical anesthesia, exert a negative inotropic effect on the myocardium. To investigate the mechanism for the negative inotropism, we studied the effect of sodium pentobarbital (SP) on the action potential and the slow inward current recorded from guinea pig ventricular myocytes. We found that SP at 0.6, 1.0, and 1.6 microM decreased action potential duration at 50% repolarization by 17 +/- 6, 25 +/- 11, and 29 +/- 8%, respectively (p less than 0.05, n = 4). At the concentration range of 0.6-1.6 microM, resting potential and action potential amplitude were unaffected. Voltage-clamp studies in ventricular myocytes demonstrated that SP at 0.6, 1.0, and 1.6 microM reduced the peak slow inward current by 30 +/- 4, 36 +/- 14, and 67 +/- 5%, respectively (p less than 0.005, n = 4). In conclusion, SP, a frequently used anesthetic, decreases the slow inward current in guinea pig ventricular myocytes at clinically relevant concentrations.

Action Potentials↗

Ventricular electrophysiological properties: is interspecies variability related to thyroid state?

Whereas action potential (AP) duration, area, and repolarization vary considerably, ventricular AP characteristics such as resting membrane potential, AP amplitude, and maximal upstroke velocity of phase 0 depolarization appear similar in a variety of mammalian species. As it has been shown that modifications of the thyroid state are associated with alterations in ventricular electrophysiological properties, we hypothesized that some variations in transmembrane potentials among mammalian species result in part from differences in the individual thyroid states. To test this hypothesis, we used standard microelectrode techniques to study ventricular APs in the dog, mole-rat, guinea pig, rat, mouse, and shrew, which encompass a wide range of thyroid states. In these species O2 consumption ranges from 0.38 (in the shrew) to 4.05 ml O2 X g-1 X h-1 (in the dog). We found that resting membrane potential and AP amplitude, duration, and area were inversely correlated with O2 consumption. The correlation coefficients between these parameters with O2 consumption were -0.92, -0.78, -0.91, and -0.92, respectively. We further tested the hypothesis in guinea pigs in which we modified the thyroid state in opposite directions by thyroxine administration and by propylthiouracil treatment. In the hypothyroid myocardium, AP duration (cycle length = 2,000 ms) markedly increased (P less than 0.001), whereas in the hyperthyroid myocardium, resting membrane potential and AP amplitude (P less than 0.01) and duration (P less than 0.001) decreased. We conclude that interspecies variations in ventricular electrophysiological properties can be correlated with the thyroid state, which may be an important determinant of these properties.

Action Potentials↗

Ultrastructure of the myocardium in dogs with induced jaundice.

Morphological aspects of the myocardium in dogs with experimentally induced jaundice were assessed ultrastructurally. Obstructive jaundice was produced by chronic bile-duct ligation and by choledochocaval anastomosis. The left ventricular myocardium and the papillary muscle were used. Statistical analysis of sarcomere length and of mitochondrial density showed no significant differences between jaundiced and sham-operated dogs. Qualitative evaluation of the mitochondria, the intercalated disc and other sarcoplasmic constituents revealed no damage to the jaundiced dogs.

Animals↗

Efficacy of transdermal scopolamine against seasickness: a 3-day study at sea.

Transdermal scopolamine has been reported to provide protection against motion sickness, both while sailing at sea (7-8 h) and under experimental conditions. In this study, we tested the efficacy of transdermal scopolamine and evaluated its side effects during a 72-h cruise at sea. We tested 38 male volunteers, 20-25 years old, who were located on a 3000-ton vessel. The presence of seasickness, defined by Graybiel's diagnostic criteria, was used to calculate percent protection. When sickness was considered as malaise II or more, the drug provided 74, 73, and 39% protection during the three sailing days, respectively. There were no significant differences in the magnitude of the side effects reported by experimental and placebo groups. We conclude that transdermal scopolamine's efficacy against seasickness during a 3-day cruise was not associated with significant side effects and, therefore, we find the drug suitable for long-term use by sailing crews.

Administration, Cutaneous↗

The inotropic effects of amrinone and milrinone on neonatal and young canine cardiac muscle.

Standard techniques were used to study developmental changes in the effects of amrinone and milrinone on contractile properties of isolated canine cardiac papillary and trabecular muscle. In contrast to milrinone, which induced a positive inotropic effect, amrinone had a negative inotropic effect on the neonatal canine muscles studied. For both drugs there was an age-dependent increase in contractility beyond the neonatal period. The negative inotropic effect of amrinone was not related to a change in phosphodiesterase inhibition, although developmental changes in phosphodiesterase inhibition did occur. These results highlight the differences in the mechanism of action of two similar molecules. They also suggest that use of amrinone as an inotropic agent in the early neonatal period should be viewed with caution.

Age Factors↗

Transdermal scopolamine: human performance and side effects.

The effect of transdermal scopolamine on performance was tested on 23 naval volunteers. Performance was evaluated by using a battery of professional (naval-related) and cognitive tests. For all tests performed there were no significant differences between the scores obtained in placebo and transdermal scopolamine conditions. These results were in close agreement with subjective estimations of performance. Transdermal scopolamine significantly reduced salivary flow, whereas mood state, visual acuity, and eye accommodation for near vision were not affected. We conclude that transdermal scopolamine administration is not accompanied by decrement in performance abilities and can safely be used by naval crews.

Accommodation, Ocular↗

Obstructive jaundice blunts myocardial contractile response to isoprenaline in the dog: a clue to the susceptibility of jaundiced patients to shock?

Patients with obstructive jaundice are susceptible to postoperative shock. To clarify the mechanism of this phenomenon, we compared the contractile response to isoprenaline of isolated ventricular preparations from three groups of dogs: (a) dogs with chronic bile-duct ligation (CBDL), (b) dogs with choledochocaval anastomosis (CDCA) and (c) sham-operated dogs (SO). Isolated ventricular muscles from CBDL and CDCA dogs showed a depressed contractile response to isoprenaline as compared with SO dogs. Mechanical performance was spared in the CBDL and CDCA dogs. There were no differences in the contractile responses of SO and CBDL dogs, either to ouabain or to changes in the rates of stimulation (force-frequency relationships). These data demonstrate that, in the dog, obstructive jaundice and/or cholaemia are associated with blunted contractile response to beta-adrenoreceptor stimulation in the face of intact basic mechanical performance. Similar inotropic refractoriness to beta-adrenoreceptor stimulation could contribute to the susceptibility to postoperative shock in patients with obstructive jaundice.

Alanine Transaminase↗

The cellular mechanisms of cardiac antiarrhythmic drug action.

In the preceding pages we have considered a number of mechanisms whereby drugs may modify arrhythmias and we also have demonstrated that certain types of action are specific to individual drugs. In addition, through the description of the use-dependence of drug effects, we have shown that the specificity of a drug's action often is attributable to its interactions with specific channels. As we learn more about the specificity of individual drug effects we should be better able not only to understand the actions of presently available drugs, but also to discover compounds that promise to be of use in the future.

Animals↗

Fetal canine cardiac Purkinje fibers: electrophysiology and ultrastructure.

We studied the ontogenesis of the transmembrane action potential and the ultrastructure of fetal canine Purkinje fibers. Fetal hearts were obtained from fetuses just after implantation to end gestation. Using standard microelectrode recording techniques, we found that action potential characteristics varied linearly over this period of development. Maximum diastolic potential (MDP) ranged from -65 to -85 mV; action potential amplitude (AMP) varied from 100 to 120 mV; maximum upstroke velocity (Vmax) increased from 200 to 550 V/s. Action potential duration measured to 50% repolarization (APD50) increased from 15 to 156 ms while duration measured at full repolarization (APD100) similarly increased from 75 to 236 ms. The relationship between external potassium concentration and membrane potential was equivalent across all stages of fetal development. Tetrodotoxin (TTX, 7.7 X 10(-7) to 1.6 X 10(-5) M) caused concentration-dependent decreases in AMP, Vmax, and APD50. Verapamil (1 X 10(-7) to 1 X 10(-5) M) decreased Vmax and APD50 in a concentration-dependent manner. The effects of both TTX and verapamil were statistically equivalent across all stages of fetal development. Ultrastructural studies of fetal Purkinje fibers showed that myocytes at the earliest stages of development (Purkinje fibers were not visually distinct at this time) were arranged as a tightly packed mosaic with a rounded shape, with a large amount of glycogen, small sparse mitochondria, and relatively large nuclei. Mitotic cells were observed frequently. Purkinje fibers when first identified grossly had fewer myofilaments than working myocardial cells and sarcomeres without M lines. By late gestation, intercalated disks appeared with an increase in surface areas; desmosomes occurred more frequently. Myofilaments are organized around Z bands into rudimentary sarcomeres that still lack M lines. These data indicate that, although the fetal canine Purkinje fiber undergoes marked developmental changes in ultrastructure, cellular electrophysiological changes are more subtle. The action potential has a qualitative appearance similar to those of the neonatal or adult fiber. At no time during fetal development could we find slow-response action potentials.

Action Potentials↗

Developmental changes in the interactions of amrinone and ouabain in canine ventricular muscle.

We studied the effects of amrinone on contractility and aftercontractions of ouabain-superfused ventricular muscle from neonatal and 3-month-old dogs. In 3-month ventricular muscle, amrinone, 5.3 X 10(-4) M, alone, increased active tension by 150%. When amrinone was superfused over ouabain-treated ventricular muscle, the increment in contraction was greatest for those muscles in which ouabain had induced a small positive inotropic effect and diminished as the positive inotropic effect of ouabain increased. Amrinone alone did not induce aftercontractions but increased the amplitude of those induced by ouabain by 92 +/- 6%. In neonatal ventricular muscle, amrinone alone was negatively inotropic and it decreased the increment in active tension induced by ouabain.

Aminopyridines↗

Developmental changes in the cardiac effects of amrinone in the dog.

Amrinone, a bipyridine compound, has been shown to exert a positive inotropic effect on the heart, without producing cardiac arrhythmias. Because of preliminary observations suggesting that the actions of amrinone might change significantly with growth and development, we studied its effects on the contractility and electrophysiology of isolated cardiac muscle of 0- to 96-day-old beagles and Purkinje fibers of 5-year-old beagles. Amrinone's effects on ventricular muscle contractility were age-related. A significant decrease in contractility of right ventricular trabeculae and papillary muscles (not associated with changes in action potential characteristics) was observed in the 0- to 3-day newborn, whereas, by day 4-10, amrinone increased contractility. The magnitude of the increase became greater through day 96 of life. The negative inotropic effect of amrinone is unassociated with changes in the action potential plateau, suggesting that the slow inward current is not involved in this mechanism.

Aging↗

The effects of adriamycin on normal and ouabain-toxic canine Purkinje and ventricular muscle fibers.

In the "Na+ lag hypothesis" of cardiac glycoside action, [Ca++]i increases through sodium-calcium exchange following block of the sodium-calcium ATPase. This accumulation of [Ca++]i has been suggested to be responsible for digitalis-induced delayed after depolarizations and arrhythmias. We used standard microelectrode techniques to study the effects of adriamycin, 10-200 microM, on the canine Purkinje fiber transmembrane potential. Adriamycin, 10 and 50 microM, had no effect on the action potential other than inducing a 28% increase in duration at 50 microM (p less than 0.01). Adriamycin, 100 and 200 microM, further prolonged action potential duration and decreased amplitude and Vmax. We then studied the effects of adriamycin, 50 microM (a concentration that purportedly blocks sodium-calcium exchange), on ouabain-induced delayed afterdepolarizations and aftercontractions in Purkinje fiber and ventricular muscle. After initially increasing delayed afterdepolarization amplitude in five of nine Purkinje fibers, adriamycin reversibly reduced their amplitude in all nine, by 78%, at a drive cycle length of 500 msec (P less than 0.01). Adriamycin, 50 microM, had no effect on calcium ion-induced slow response action potentials, suggesting this concentration does not significantly reduce the slow inward current. In ventricular muscle, adriamycin, 50 microM, did not significantly reduce contraction but did depress aftercontractions (P less than 0.025). In sum: in concentrations that have no effect on the AP other than prolonging duration, adriamycin, 50 microM, reversibly depresses ouabain-induced delayed afterdepolarizations and aftercontractions; however, adriamycin, 50 microM, does not depress calcium ion-dependent action potentials. Although the action of adriamycin on delayed afterdepolarizations and aftercontractions is consistent with direct inhibition of the transient inward current and/or an indirect reduction via reduced activity of sodium-calcium exchange, whether either or both of these mechanisms is involved must be defined by further experimentation.

Action Potentials↗

Potassium channels in the nodal membrane of rat myelinated fibres.

Following some preliminary reports, mammalian fibres from rabbit and rat have recently been successfully studied in detail by means of the voltage clamp. The early transient or sodium conductance system was found to be similar to that in frog and squid axons. However, the delayed conductance or potassium currents were found to be negligible. Only after chemical and osmotic manipulations, which were said to expose channels buried under the myelin, did Chiu and Ritchie find delayed currents in rabbit fibres. If confirmed, this would mean that the membrane conductance system of mammalian fibres is so different from that of invertebrate and amphibian axon models as to make the data base gathered from amphibian myelinated fibres (frog and toad) and invertebrate giant axons (squid and myxicola) irrelevant to human nd other mammalian fibres. However, we show here that it is possible to find in the normal nodal membrane of rat myelinated fibres potassium currents that flow through channels which are similar in many respects to those found in the frog node of squid axons.

Animals↗

The effects of HGCl2 and mersalyl on mechanisms regulating intracellular calcium and transmitter release.

HgCl2 and mersalyl increased and later decreased both the spontaneous and evoked transmitter liberation at the frog neuromuscular junction. Lower concentration of HgCl2 exhibited only an inhibitory effect on transmitter release. These mercurials inhibited calcium transport of mitochondria and synaptosomal vesicles. Lower concentrations of HgCl2 showed a stimulatory effect on mitochondrial calcium uptake. It is suggested that the effect of mercurials on transmitter release is mediated via changes of the intracellular calcium ion concentration.

Adenosine Triphosphate↗

Systemic hypotension and decreased pressor response in dogs with chronic bile duct ligation.

Vascular instability as defined by systemic hypotension and unresponsiveness to endogenous or exogenous vasoactive substances is a feature of both patients and experimental animals with obstructive jaundice. In this study, we have attempted to dissect the possible mechanisms for these abnormalities using both in vivo and in vitro methods. In vivo cumulative pressor responses (Rmax) to intravenous and intraarterial infusions of norepinephrine and angiotensin II and to intravenous infusion of angiotensin I were studied pre- and postoperatively in chronic bile duct-ligated dogs and compared to sham-operated dogs. Preoperatively, the pressor responses to the cumulative infusion of six doses of vasoactive substances in the pre-sham operated and pre-chronic bile duct-ligated dogs were not significantly different. Postoperatively, in the sham-operated dogs, there was no significant change in systemic blood pressure at 1 and 3 weeks, and only in isolated instances were significantly different pressor responses found compared to the preoperative result. In chronic bile duct-ligated dogs, the mean systemic blood pressure fell significantly from 117.2 +/- 3.1 to 107.2 +/- 3.0 mm Hg (p less than 0.01) at 1 week and remained significantly lower at 3 weeks [109.7 +/- 2.6 mm Hg (p less than 0.05)]. The Rmax to intravenous, but not intraarterial norepinephrine, was significantly decreased. In contrast, the Rmax to both intravenous and intraarterial angiotensin II infusions were significantly depressed at both 1 and 3 weeks. Similarly, the response to intravenous angiotensin I was significantly depressed. Cardiac output rose moderately in two sham-operated dogs from an average of 3.1 to 3.5 liters per min by 3 weeks associated with a decrease of 14.8% in peripheral vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗