Biomedical subjects

A Varró

Publications and source records attributed to A Varró.

At least 73 records · Page 4Linked to original sources

PubMed1991

Rate and concentration-dependent effects of UK-68,798, a potent new class III antiarrhythmic, on canine Purkinje fibre action potential duration and Vmax.

1. The frequency-dependent electrophysiological effects of UK-68,798 in concentrations of 1, 3, 10 and 30 nM were examined in isolated cardiac Purkinje fibres of the dog at both a number of constant rates of stimulation and following abrupt changes in pacing cycle length. 2. In all concentrations evaluated, UK-68,798 lengthened action potential duration in a concentration- and rate-dependent manner (e.g., at a cycle length = 500 ms, control APD90 = 234.0 +/- 3.3 ms, while after 10 nM UK-68,798, APD90 = 315.0 +/- 5.9 ms). 3. The duration of action potentials evoked following abrupt changes in pacing rate were also increased in a concentration-dependent manner at all diastolic intervals tested. 4. The fast and slow time constants for restitution of APD were not altered by UK-68,798. However, the amplitude terms for this relation were increased. 5. In addition, the maximum upstroke velocity (Vmax) was not significantly affected by exposure to UK-68,798 at any concentration or diastolic interval. The kinetics for recovery of Vmax were thus unaffected. 6. These findings are similar to those previously reported for recognized class III antiarrhythmic agents (e.g., bretylium, clofilium, and sotalol); however, UK-68,798 was 1,000 to 10,000 times more potent. 7. The combined potency and selectivity of this agent seem to make it an ideal tool for the investigation of cardiac potassium channels believed responsible for controlling the duration of the action potential. 8. This potent and highly selective compound may prove extremely useful in the control of cardiac arrhythmias.

Action Potentials↗

PubMed1991

Voltage-clamp characteristics of ventricular myocytes in rabbit.

Action potentials and ionic currents were measured by patch-clamp in single right ventricular myocytes isolated enzymatically from rabbits and guinea pigs at room temperature. Based upon the shape of their action potentials, the rabbit myocytes were divided into two groups. In group 1 (n = 15), a prominent phase of initial rapid repolarization (phase 1) occurred following the upstroke of the action potential. Action potentials recorded in the second group (n = 9) did not have a noticeable phase 1. In group 1, voltage-clamp protocols revealed a transient outward current (Ito) activated upon depolarization from a holding potential of -50 mV to potentials positive to -20 mV. This outward current inactivated rapidly (tau = 50 ms) in a voltage-independent manner. The transient outward current was not apparent in group 2. In all the rabbit myocytes, the inward calcium current (ICa) was activated between -30 and -20 mV, with a peak at 0 mV. The inactivation kinetics of the inward calcium current were dependent on the voltage. In 4 out of 11 cells, inactivation was best described by a single exponential relation, and in the remaining 7 cells by a double exponential relation. The recovery of the inward calcium current from inactivation and the restitution of the duration of the action potential showed similar time-courses of 132 +/- 11.6 ms (n = 8) and 163.7 +/- 23.0 ms (n = 6), respectively. In all the rabbit myocytes the relation between current and voltage, established at the end of 400 ms command pulses, displayed a negative slope conductance. In rabbit myocytes, unlike those of guinea pig, pulses as long as 5 s revealed the delayed rectifier outward current to be weak or absent. Our results suggest that two populations of ventricular myocytes exist in the rabbit; neither has a prominent delayed rectifier, at least at room temperature, while one group has a transient outward current and the other does not. The major currents controlling the duration of the action potential at room temperature in myocytes from the right ventricle of the rabbit, therefore, are the inward calcium current and the inward rectifier potassium current (IK1).

Action Potentials↗

PubMed1990

Use-dependent action of antiarrhythmic drugs in frog skeletal muscle and canine cardiac Purkinje fiber.

1. Conventional microelectrode techniques were used to study the effect of quinidine (10 microM), lidocaine (20 microM), and verapamil (3-10 microM) on action potential upstroke (V+ max) in frog skeletal muscle and dog Purkinje fiber. 2. The frequency-dependent nature of V+ max depression induced by these drugs was similar in both preparations, however, quinidine was more potent in skeletal muscle while lidocaine was in Purkinje fibers. 3. In skeletal muscle tetrodotoxin (3 and 15 nM) and low concentrations of antiarrhythmic drugs proportionally reduced the maximum velocity of depolarization and repolarization (V+ max and V- max, respectively), whereas V- max was more depressed than V+ max by high concentrations (50-200 microM) of antiarrhythmics. Decreases in the overshoot potential were proportional to the V+ max block in the case of each drug. 4. These results indicate that therapeutically relevant concentrations of quinidine and lidocaine inhibit skeletal muscle Na+ channels in a use-dependent manner similar to heart, while at higher concentrations the K+ channels may also be blocked. Therapeutic implications of the results are discussed.

Action Potentials↗

PubMed1990

Sotalol and mexiletine: combination of rate-dependent electrophysiological effects.

The rate-dependent electrophysiological effects of sotalol (30 microM), mexiletine (10 and 18 microM), and their coadministration were examined in isolated dog cardiac Purkinje fibers following abrupt changes in pacing cycle length. Combination of 30 microM sotalol with 10 microM mexiletine significantly lengthened premature action potential durations at diastolic intervals of less than 50 ms while the basic action potential duration evoked at a stimulus frequency of 2 Hz was not affected. This effect on the premature action potential duration was attenuated when the higher mexiletine concentration (18 microM) was coadministered with sotalol. The fast time constant for restitution of the action potential duration was significantly slowed by either combination. Coadministration of sotalol and mexiletine, like mexiletine alone, produced a rate-dependent depression of Vmax that displayed a second slow time component during recovery. This slow component for recovery of Vmax was not distinguished in the absence of drug or in the presence of sotalol alone. Sotalol-induced lengthening of the action potential duration observed at slow pacing frequencies was also attenuated by addition of mexiletine; and, under these conditions, Purkinje fiber early afterdepolarizations were prevented. In addition, the range of premature action potential durations was significantly decreased by mexiletine and by the combination, while sotalol alone increased this range slightly. These results indicate that coadministration of sotalol and mexiletine may provide beneficial electrophysiological effects expected to provide enhanced antiarrhythmic efficacy and fewer proarrhythmic complications in patients.

Action Potentials↗

PubMed1990

Effects of propranolol on premature action potentials in canine Purkinje and ventricular muscle.

We compared the effects of a low (0.09 microgram/ml) concentration of propranolol expected to produce only beta-adrenoceptor blockade and a high concentration (0.9 microgram/ml) expected to produce additional direct local anesthetic-like electrophysiological effects on basic and premature action potentials. Both isolated dog cardiac Purkinje and ventricular muscle fibers were examined using conventional microelectrode techniques. The low concentration of propranolol produced no significant electrophysiological change in either fiber type. The high concentration of propranolol shortened the action potential duration and refractoriness while decreasing the maximal upstroke velocity (Vmax) in both Purkinje and ventricular muscle fibers at a constant basic cycle length. In Purkinje fibers, the high concentration also slowed the kinetics of restitution of the action potential duration (tau c from 124.6 +/- 6.5 to 201.4 +/- 16.0 ms, p less than 0.01, n = 7), slowed the recovery kinetics of Vmax, and shifted the early portion of the normalized restitution curve toward longer action potential duration values in both fiber types. The range of premature action potential durations, defined as the difference between action potential durations during the first 100 ms of restitution, was decreased by the high concentration of propranolol in both Purkinje and ventricular muscle fibers by 39.5% and 33.9%, respectively. These findings indicate that (a) low concentrations of propranolol produced no direct electrophysiological effect, and (b) high concentrations of propranolol produced several potential antiarrhythmic effects in addition to the previously reported effects on Vmax and the action potential duration.

Action Potentials↗

PubMed1990

The combined electrophysiological effects of lignocaine and sotalol in canine isolated cardiac Purkinje fibres are rate-dependent.

1. The frequency-dependent electrophysiological effects of lignocaine, sotalol, and their combination were studied in dog isolated cardiac Purkinje fibres, both at various constant rates of stimulation and following abrupt changes in pacing cycle length. 2. The combined effect of 18 microM lignocaine and 30 microM sotalol selectively lengthened duration of premature action potentials evoked at a diastolic interval of 40 ms (from 172.2 +/- 5.4 to 201.7 +/- 4.9 ms, n = 6, P less than 0.01) without significantly changing the durations of action potentials evoked at the basic cycle length of 500 ms (259.1 +/- 7.7 vs 251.9 +/- 3.9 ms, n = 11). 3. The combination of lignocaine with sotalol, like lignocaine alone, displayed a use-dependent depression of Vmax and revealed a slow component for a recovery of Vmax (tau = 173.5 +/- 16.0 ms, n = 5). 4. The kinetics for restitution of action potential duration were also slowed by the combination of the two dwo drugs (tau f = 173.6 +/- 16.7, before, vs 268.5 +/- 8.5 ms, after; n = 5, P less than 0.01), while the maximum action potential duration attained in this relation was not increased as it was by sotalol alone. 5. Lignocaine, therefore, appeared to inhibit the sotalol-induced lengthening of action potential duration at slow pacing rates and at long diastolic intervals. The combination of lignocaine with sotalol also completely abolished the occurrence of sotalol-induced early after depolarizations. 6. Finally, sotalol alone moderately increased the range of premature action potential durations, while the combination of the two drugs significantly decreased this parameter. 7. These findings indicate that the combination of lignocaine with sotalol may provide important, and unique, beneficial electrophysiological alterations that might be expected to provide enhanced antiarrhythmic efficacy in patients.

Animals↗

PubMed1989

Rate-dependent electrophysiological effects of OPC-8212: comparison to sotalol.

The rate-dependent effects of OPC-8212 (6 microM), a new positive inotropic drug which lengthens cardiac action potential duration were studied in dog cardiac Purkinje fibers and compared to the effects of sotalol (30 microM), a class III antiarrhythmic using conventional microelectrode technique. Both OPC-8212 and sotalol lengthened action potential duration in a frequency-dependent manner. Both had a greater effect at slower pacing frequencies than at fast. The maximum rising velocity of the action potential upstroke was not affected by either compound at any of the pacing cycle lengths applied (300-2000 ms). The effects of OPC-8212 and sotalol on action potential duration and maximum rising velocity were also compared following abrupt changes in pacing cycle length (i.e. coupling intervals ranging between approximately 250-3000 ms). The effects of both OPC-8212 and sotalol following abrupt changes in pacing cycle length were similar to one another. Neither OPC-8212 nor sotalol altered the time constants for restitution of action potential duration or the kinetics for recovery of the maximum rising velocity of the action potential upstroke. These results indicate that the rate-dependent electrophysiological effects of OPC-8212 closely mimic those of sotalol and suggest that OPC-8212 may be an effective class III antiarrhythmic in addition to being a positive inotropic compound.

Action Potentials↗

PubMed1989

Age-related changes in electromechanical properties of canine ventricular muscle: effect of ouabain.

In this report, alterations between the electrical and mechanical responses of isolated neonatal and adult canine ventricular muscle preparations before and after ouabain exposure are described. No significant differences were observed between the two age groups in the concentration-dependent effects of ouabain on increasing contractile force or decreasing maximum diastolic transmembrane potential. The action potential plateau duration was decreased by high concentrations of ouabain (0.3-1 microM) in both neonatal and adult ventricular muscle. In addition, more adult preparations developed delayed afterdepolarizations associated with aftercontractions after exposure to ouabain than did neonatal preparations. These results suggest that the higher glycoside tolerance in neonatal dogs as compared with adults may be due in part to differences in the mechanisms responsible for development of abnormal ventricular automaticity. The results may also indicate that immature animals do not require higher glycoside levels to produce augmentation of cardiac contractility.

Aging↗

PubMed1989

Modulation of the effects of sotalol on Purkinje strand electromechanical characteristics.

The modulation of the effects of sotalol (30 microM) by two sodium channel blockers, tetrodotoxin (0.07 microM) and lidocaine (50 microM), and by a potassium channel activator, nicorandil (30 microM), were examined. Sotalol alone greatly increased Purkinje fiber transmembrane action potential duration and, in some preparations, induced early after depolarizations. Concurrent with the changes in action potential duration, sotalol also increased isolated Purkinje strand developed force paced at slow rates (0.33 Hz). These sotalol-induced alterations of Purkinje strand electromechanical characteristics were similar to those produced by either veratrine (0.6 or 1.0 micrograms/mL) or by tetraethylammonium (10 mM). The effects of sotalol on action potential duration and force development were reversed by exposure to either tetrodotoxin or nicorandil. Lidocaine also reversed the effects of sotalol on action potential duration and developed force. The sotalol-induced increase in action potential duration and development of early after depolarizations may, therefore, be abated by combination with drugs that either block cardiac sodium channels or that increase membrane potassium conductance. Combination with such drugs may help prevent the adverse arrhythmogenic effects of sotalol.

Animals↗

PubMed1989

Frequency-dependent and independent effects of tetrodotoxin on Vmax in cardiac fibers.

Superfusion with 3 microM tetrodotoxin (TTX) induced both a use-dependent and a frequency-independent depression of the rate rise of the action potential (Vmax) in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was fast and exponential with a time constant of 225.4 +/- 7.1 ms in dog Purkinje fibers (n = 6). The onset kinetics of the frequency-dependent Vmax block was rapid, i.e. reached steady state after 3.0 +/- 0.3 beats in guinea pig ventricular muscle (n = 6). The rapid use-dependent interactions with sodium channel make TTX similar to antiarrhythmic drugs with fast kinetics i.e. lidocaine, mexiletine, and tocainide, but unlike antiarrhythmic drugs, TTX-induces a large frequency-independent Vmax block at the same concentrations.

Action Potentials↗

PubMed1988

The effects of amiodarone on repolarization and refractoriness of cardiac fibers.

The effects of superfusion (acute) and chronic amiodarone pretreatment on repolarization in dog Purkinje and guinea pig papillary muscle fibers were studied using standard microelectrode techniques. In dog Purkinje fibers superfusion with 5 and 50 micrograms/ml amiodarone shortened action potential duration, slowed restitution of premature action duration, and decreased the range of premature action potential durations. In Purkinje fibers from pretreated dogs action potential duration and range of premature action potential durations did not differ significantly from the corresponding control values but restitution was slowed. In guinea pig papillary muscle superfusion with 20 micrograms/ml amiodarone did not change action potential duration and restitution kinetics but in the muscle fibers from pretreated animals both the action potential duration and the range of premature action potential durations were increased. We concluded that the designation of 'class III action' applied to chronic amiodarone treatment in ventricular but not to chronic treatment in Purkinje fibers, and not to acute treatment in either fibers.

Action Potentials↗

PubMed1988

Electrophysiological effects of GYKI-23 107, a new antiarrhythmic compound, in isolated rabbit and canine cardiac preparations.

The cellular cardiac electrophysiological effects of GYKI-23 107 (1-/2,6-dimethylamino/-2-dimethylaminopropane dihydrochloride), a new investigational antiarrhythmic drug, were studied in rabbit and canine ventricular muscle and Purkinje fibers. For comparison, mexiletine was used. GYKI-23 107, like mexiletine, did not affect the resting membrane potential and slightly reduced the action potential amplitude in both fiber types. The time for repolarization was shortened, but the ratio of effective refractory period to action potential duration was increased by both drugs. The maximum rate of depolarization (Vmax) was depressed by the drugs in a frequency-dependent ("use-dependent") manner. GYKI-23 107 slowed the recovery kinetics of Vmax in the canine ventricular muscle (Tc = 229.9 +/- 5.6 ms; n = 7) and Purkinje fiber (Tc = 149.6 +/- 33.8 ms; n = 7) in the same way as mexiletine. The kinetics of restitution of action potential duration during premature and postmature stimulation were slowed to similar degrees in the presence of both GYKI-23 107 and mexiletine in canine Purkinje fibers. It is concluded that, on the basis of its cardiac cellular electrophysiological effects, GYKI-23 107 can be categorized as a class Ib antiarrhythmic agent.

Animals↗

PubMed1987

Antiarrhythmic effect of desethylamiodarone in conscious rats.

The effect of desethylamiodarone, a metabolite of amiodarone, was studied in the early phase of arrhythmias induced by coronary artery ligation in conscious rats. Desethylamiodarone pretreatment improved survival without altering the occurrence of different types of arrhythmias during the first 20 min after coronary ligation. It was concluded that desethylamiodarone may contribute to the antiarrhythmic effect seen after chronic amiodarone treatment.

Amiodarone↗

PubMed1987

Use-dependent blockade of sodium channels induced by bencyclane in frog skeletal muscle and canine cardiac Purkinje fiber.

Applying conventional microelectrode technique, the effect of bencyclane was studied on the maximal rate of rise (Vmax) of the transmembrane action potential in frog skeletal muscle and canine cardiac Purkinje fiber. Bencyclane (10 microM) decreased the Vmax from 333.7 +/- 6.9 V/sec to 302.7 +/- 10.2 V/sec (n = 6, p less than 0.05) in skeletal muscle without changing the resting membrane potential. If repetitive stimulation with different constant cycle lengths was applied, a further, frequency-dependent decrease of Vmax developed in both tissues with similar frequency-dependence. In skeletal muscle bencyclane increased the time of 50% repolarization by 33.3 +/- 2.5% (n = 7, p less than 0.01) and decreased the overshoot potential by 11.3 +/- 0.72 mV (n = 7, p less than 0.01) measured at 250 msec cycle length. In cardiac Purkinje fiber bencyclane shortened the action potential duration (APD90) from 258.3 +/- 15.4 msec to 241.7 +/- 12.1 msec (n = 6, p less than 0.05) without changing the resting membrane potential and action potential amplitude measured at 500 msec cycle length. The comparable size of the Vmax-block at the same cycle lengths observed in skeletal muscle (short APD) and Purkinje fiber (long APD) suggests that the inhibition may by mainly attributed to the open sodium channel population. It was concluded that the antiarrhythmic action of bencyclane, based on the use-dependent blockade of sodium channels, might be an important component of the therapeutic effect of bencyclane.

Action Potentials↗

PubMed1987

Pharmacological investigation of a new anti-arrhythmic agent, GYKI-23 107.

GYKI-23 107 is a new antiarrhythmic substance with local anaesthetic activity. Its specific pharmacological and cardiovascular effects were studied in vivo and its efficacy was compared with that of lidocaine and mexiletine. GYKI-23 107 was effective against chemically (aconitine and ouabain) induced arrhythmias after both parenteral and oral administration. In aconitine-induced arrhythmia in mice the new compound was more active than either mexiletine or lidocaine after i.p. treatment. In ouabain-induced arrhythmia in dogs, the ED50 of GYKI-23 107 was approximately half that of mexiletine after i.v. injection. GYKI-23 107 and mexiletine produced similar elevation of the fibrillation threshold in anaesthetized cats. After oral pretreatment, GYKI-23 107 showed protective effects against coronary ligation-induced arrhythmia in conscious rats. The circulatory side-effects of GYKI-23 107 in anaesthetized and conscious dogs and cats were milder then those of mexiletine. In the antiarrhythmic dose range there were no adverse cardiovascular actions.

Aconitum↗

PubMed1986

Antiarrhythmic effect of acute and chronic amiodarone treatment in conscious rats.

The effect of amiodarone after acute and chronic pretreatment was studied in the early phase of arrhythmias induced by coronary artery ligation in conscious rats. Both acute and chronic amiodarone pretreatments improved survival during the first 20 min after coronary ligation. Only chronic amiodarone pretreatment reduced significantly the incidence of ventricular fibrillation. It was concluded that chronic amiodarone pretreatment seemed to be more effective than the acute one.

Amiodarone↗

PubMed1985

Use of immunoblockade to study the involvement of peptidergic afferent nerves in the intestinal vasodilatory response to capsaicin in the dog.

Capsaicin evokes intestinal vasodilatation when given by close arterial injection probably by acting on primary sensory neurons. Several peptides known to occur in primary afferents also have vasodilator effects. We have used immunoblockade to test the hypothesis that the vasodilator effect of capsaicin was mediated by release of these peptides. Antisera to substance P, cholecystokinin, vasoactive intestinal peptide and somatostatin inhibited specifically and dose dependently the effect of each of these peptides given alone. Graded doses of the antisera to substance P, cholecystokinin and vasoactive intestinal peptide also produced a dose dependent inhibition of the vasodilator response to capsaicin. In contrast, administration of somatostatin antiserum enhanced the vasodilator action of capsaicin. Prior administration of antibodies to substance P, cholecystokinin and vasoactive intestinal peptide produced an 80% inhibition of the response to capsaicin. In the presence of these antibodies, and of atropine, the response to capsaicin was reduced by more than 90%. The results suggest that capsaicin increases mesenteric blood flow due to release of substance P, cholecystokinin and vasoactive intestinal peptide. The precise cellular origins of these peptides is unknown, but they may well be released from the peripheral endings of primary afferent neurons.

Animals↗

PubMed1983

Regional differences in the development of cholecystokinin-like activity in rat brain.

The postnatal development of cholecystokinin (CCK) in rat brain was studied by radioimmunoassay and bioassay of tissue extracts. Marked differences were found in the patterns of development in different regions of the brain. In the cerebellum and brainstem of newborn rats the concentrations of CCK8-like immunoreactivity were 40-100% those in adults, whereas in more rostral regions the concentrations were 1-10% of those in adults. Between 0 and 14 days in concentrations of CCK-like activity measured by radioimmunoassay increased up to 30-fold in hypothalamus, cortex and olfactory bulb; in the cortex there were further increases up to 42 days. Cortical CCK was also measured by bioassay on rabbit gall bladder in vitro; bioactivity was identified in foetuses, and after birth showed a similar pattern of increase to that measured by radioimmunoassay. Immunoreactive material in extracts of neonatal cerebellum, brainstem and cortex was identified as CCK8 on the basis of cross-reactivity with different antisera, and chromatographic properties on gel filtration. The results raise the possibility of different rates of maturation of central CCKergic systems.

Animals↗