Biomedical subjects

U Borchard

Publications and source records attributed to U Borchard.

At least 37 records · Page 2Linked to original sources

PubMed1992

Electrophysiological characterization of histamine receptor subtypes in sheep cardiac Purkinje fibers.

The histamine-receptor-subtype-mediated effects on action potentials of electrically driven and spontaneously active isolated sheep cardiac Purkinje fibers were investigated using H1- and H2-selective agonists and antagonists. In electrically stimulated Purkinje fibers, histamine (3 mumol/l) increased the action potential plateau height, decreased the action potential duration measured at a repolarization level of -60 mV and enhanced the pacemaker activity. These effects were abolished by the H2-selective antagonist cimetidine (30 mumol/l), but were not impaired by the H1-selective antagonist dimetindene (0.3 mumol/l). In spontaneously active Purkinje fibers, histamine (10 mumol/l) increased the spontaneous rate by 24%, the slope of diastolic depolarization by 45% and shortened the duration of the diastole by 32% of the respective control measurements. These effects were blocked by 30 mumol/l cimetidine, but remained unchanged in the presence of 0.3 mumol/l dimetindene. Concentration-response curves of histamine were shifted to the right by approximately 2 logarithmic units in the presence of 30 mumol/l cimetidine, but were not influenced in the presence of 0.3 mumol/l dimetindene. The H2-selective agonist impromidine (0.001-0.3 mumol/l) had similar actions as histamine on spontaneously active Purkinje fibers, while the H1-selective agonist 2-(2-pyridyl-)ethylamine was ineffective. It is concluded that the pronounced stimulatory action of histamine on spontaneous activity in sheep cardiac Purkinje fibers is exclusively mediated by H2 receptors.

Action Potentials↗

PubMed1991

Inhibition of potassium outward currents and pacemaker current in sheep cardiac Purkinje fibres by the verapamil derivative YS 035.

The electrophysiologic mode of action and potency of the verapamil derivative YS 035 (N,N-bis-(3,4-dimethoxyphenethyl)-N-methyl amine) were investigated in sheep cardiac Purkinje fibres. Action potential duration measured at a repolarization level of -60 mV (APD-60) and membrane currents recorded with the two-microelectrode voltage-clamp technique were evaluated. At 10 mumols/l YS 035 APD-60 was increased to about 115% of reference. Prolongation measured as percentage of the respective control exhibited on the average no dependence on stimulation frequency (0.17-2 Hz). At 100 mumols/l membrane became depolarized to about -50 mV and action potentials could no longer be elicited. Further study was focussed on effects on outward currents, mostly activated at a frequency of 0.05 Hz. Transient outward current (ito) was completely blocked at 100 mumols/l and half-maximal inhibition occurred at about 14 mumols/l. Inwardly rectifying potassium current (ik1) was reduced to 47% of reference at 100 mumols/l. An initially activating outward current at positive membrane potentials (iinst) was reduced to 73% at 100 mumols/l. Time-dependent (delayed) outward current (iK) was on the average not affected up to 100 mumols/l. Besides inhibition of repolarizing outward currents YS 035 completely blocked pacemaker current (if) at 100 mumols/l and half-maximal reduction was achieved at 5 mumols/l. YS 035 (1-100 mumols/l) did not clearly affect time constants of activation at selected test potentials (IK: +35 mV; if: -90 mV) or inactivation (ito: 0 mV). Voltage-dependent control mechanisms of currents (ito, if) were not influenced by YS 035 but the amount of available current was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1991

Positive and negative contractile effects of neuropeptide Y on ventricular cardiomyocytes.

The potency of neuropeptide Y (NPY) to cause negative and positive contractile responses in rat ventricular cardiomyocytes was investigated. In these cells, NPY was found to activate the transient outward K+ current (Ito) and the slow inward Ca2+ current (Isi). As reported before (H. M. Piper, B. C. Millar, and J. R. McDermott, Naunyn Schmiedeberg's Arch. Pharmacol. 340: 333-337, 1989), NPY attenuated the increase in the contractile response induced by isoprenaline (10(-7) M). This effect of NPY could be abolished by 1) the presence of the inhibitor of Ito, 4-aminopyridine (4-AP, 0.5 mM); 2) pretreatment of the cells with pertussis toxin (1 microgram/ml for 6 h); and 3) the presence of the 19-amino acid COOH-terminal fragment of NPY, NPY-(18-36) (10(-6) M). In the absence of isoprenaline, but in the presence of 4-AP, NPY exerted a stimulatory effect on the cardiomyocytes. This effect could be abolished 1) by using the inhibitor of the Isi, verapamil (10(-8) M), but not 2) by pretreatment with pertussis toxin, nor 3) by coincubation with NPY-(18-36). The results indicate that in the rat the antiadrenergic negative contractile effect of NPY results from its action on the Ito. Blockade of this current by 4-AP unmasks a positive contractile effect of NPY that is related to activation of the Isi.

4-Aminopyridine↗

PubMed1991

[Ibopamine--pharmacologic principles].

Ibopamine is the 3,4-diisobutyrylester of N-methyl-dopamine (epinine). Oral ibopamine is transferred during and after resorption (first-pass effect) to the active metabolite epinine by blood and tissue esterases. 200 mg ibopamine lead to maximal plasma concentrations of 60 to 100 nmol/l. The ratio of total epinine to free epinine is about 10:1. Epinine is intensively metabolized so that less than 1% of the oral dosage is eliminated via the kidneys. The plasma half-life of epinine amounts to about 45 min. Epinine activates dopamine (DA1, DA2)-, beta 1- and beta 2- as well as alpha-receptors. The affinity is of the other: DA1, DA2 greater than beta 1, beta 2 greater than alpha. Stimulation of postsynaptic DA1-receptors predominantly induces renal vasodilation and increase in diuresis. Stimulation of presynaptic DA2-receptors leads to a reduced liberation of noradrenaline (NA) from its presynaptic storage vesicles. This effects a decrease in NA-plasma concentration, peripheral resistance, and it is partly responsible for diuresis and natriuresis. Investigations in isolated organs have shown that the action on DA1, DA2-receptors occurs in the range of 100-700 nmol/l), whereas stimulation of beta 1- and beta 2-receptors affords significantly higher levels (affinity to human cardiac beta 1- and beta 2-receptors 5-10 mumol/l). alpha-receptors are only stimulated at still higher concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiotonic Agents↗

PubMed1991

[Adverse drug effects and their clinical importance within the scope of intensive care and emergency medicine].

Patients in intensive care often receive various drugs. Many of these patients have received previous treatment for chronic diseases. When different drugs are administered the possibility of unwanted drug interactions has to be considered. A short review is presented, dealing with clinically relevant interaction with sympathomimetic, antiarrhythmic, analgesic, neuroleptic and diuretic drugs, plasma expanders and electrolytes. Knowledge of the limited number of unwanted drug interactions helps to correct loss of drug action or intoxication.

Analgesics↗

PubMed1990

Pharmacokinetics of beta-adrenoceptor blocking agents: clinical significance of hepatic and/or renal clearance.

A great number of beta-adrenoceptor blocking drugs are now available for clinical use which show great differences with respect to their pharmacokinetic properties. Bioavailability might be low because of a low absorption rate after oral application in the case of hydrophilic drugs like atenolol or might be low because of a high first-pass effect in the liver in the case of metoprolol or propranolol. Plasma levels of these latter drugs may vary considerably and inhibition of their oxidative metabolism by cimetidine may lead to an increase of peak plasma concentrations. In general, lipophilic beta-blockers are metabolized in the liver whereas hydrophilic agents are eliminated in the kidneys as unchanged drugs. Dose has to be adjusted according to renal function in the case of atenolol, carteolol, nadolol, sotalol and acebutolol, which is transformed into the active metabolite diacetolol. Drugs like bisoprolol, betaxolol and pindolol are eliminated via the liver and the kidneys. Bisoprolol, for example, shows a balanced clearance as it is eliminated to about 50% in the liver and 50% via the kidneys. Failure of one clearance organ (liver, kidney) leads to a maximally twofold increase in plasma half-life of bisoprolol. Being aware of the observation that some drugs show a long terminal half-life, it has been demonstrated that plasma levels correlate to duration of action. This is of major importance for the treatment of coronary heart disease as a once-daily dose should be active for 24 h.

Adrenergic beta-Antagonists↗

PubMed1989

Effects of the calcium entry blocker bepridil on repolarizing and pacemaker currents in sheep cardiac Purkinje fibres.

(1) Effects of bepridil (0.3-100 mumol/l) on transmembrane currents which are active during the repolarization of the cardiac action potential were studied in sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique. Transmembrane currents were activated at a frequency of 0.03 Hz. (2) The initial inwardly rectifying current (iK1) was reduced by 1.8 mumol/l bepridil to 70% of the reference iK1-current in the absence of the drug. (3) An initial outward current, which is activated at positive membrane potentials (iinst) was depressed to 70% of reference by 14 mumol/l bepridil. (4) The time-dependent outward current (iK) was decreased by 1.8 mumol/l bepridil to 70% of its amplitude in the absence of bepridil. The biexponential time course of iK-current activation changed to be monoexponential with 100 mumol/l bepridil. The effect of bepridil on iK-current resulted in a shift of the activation curve of iK-current to more positive membrane potentials (10 mumol/l bepridil) and an additional decrease of driving force and/or conductance of the iK-channels with higher bepridil concentrations (100 mumol/l). (5) The transient outward current (ito) was completely blocked by 30 mumol/l bepridil. Inhibition to 70% of reference occurred with 1 mumol/l bepridil. The voltage-dependent inactivation of ito-current was affected by bepridil: the amplitude of the steady-state inactivation curve was reduced and ito-current was inactivated faster after application of bepridil. Bepridil caused no pronounced shift of the steady-state inactivation curve along the voltage axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Effects of (+)- and (+/-)-sotalol on repolarizing outward currents and pacemaker current in sheep cardiac Purkinje fibres.

This study was aimed to differentiate the action of (+)- and (+/-)-sotalol (10-1000 mumol/l) on membrane currents which are active during the repolarization of cardiac action potentials. Effects where studied in shortened sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique. Action potentials were activated at a frequency of 0.25 Hz and membrane currents at 0.03 Hz or 0.05 Hz in most experiments. Out of the currents investigated the transient outward current (ito) reacted most sensitively to (+)- and (+/-)-sotalol. Ito-amplitude was decreased on the average to 77% of reference at 10 mumol/l and to 53% at 1000 mumol/l (+)- or (+/-)-sotalol. The maximally available ito-current was decreased but the voltage-dependent control of inactivation was left nearly unchanged. The initial inwardly rectifying current (iK1), which propels the last repolarization phase of the action potential and controls resting potential to a large extent was reduced on the average to 93% of reference at 10 mumol/l and to 62% at 1000 mumol/l (+)- or (+/-)-sotalol. Time-dependent (delayed) outward current (iK) was on the average not affected by (+)- or (+/-)-sotalol up to 100 mumol/l and was decreased to 84% of reference current under the influence of 1000 mumol/l. An initial outward current, which is activated at positive membrane potentials (iinst) was not clearly affected by (+)- or (+/-)-sotalol at concentrations up to 1000 mumol/l. Pacemaker current (if) was not influenced by the drugs up to 100 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1989

H1-receptor reserves in guinea-pig left atria, trachea and pig coronary artery as identified by phenoxybenzamine.

H1-receptor reserves in guinea-pig left atria, trachea and pig coronary arteries were calculated by the use of phenoxybenzamine (Pba), a beta-haloalkylamine that irreversibly blocks the H1-receptor response to histamine or 2-(2-pyridyl)-ethylamine (PEA). Equieffective concentrations of the H1-agonist in the absence (A) and presence (A') of Pba were evaluated from concentration-response curves. By plotting the reciprocal values 1/A versus 1/A' the amount of H1-receptors not occupied by the agonist was calculated. The size of the H1-receptor reserve could be estimated by comparison of the receptor occupation with the corresponding effect. Furthermore, the dissociation constants for histamine, PEA, Pba and the pD'2-values for Pba were determined for the different tissues. 5% and 6% H1-receptor occupation is necessary to achieve a half maximal contraction of the trachea with the agonists histamine and PEA, respectively. Only 0.5% H1-receptor occupation is needed for the half maximal positive inotropic effect of histamine in left atria, while 5.5% of the H1-receptors have to be occupied using PEA as an agonist in this tissue. In the coronary artery of the pig 50% of the maximal contraction can be achieved by stimulation of 15.1% of the H1-receptors with histamine.

Animals↗

PubMed1989

Classification and action of antiarrhythmic drugs.

A great number of antiarrhythmic drugs is available for the treatment of tachyarrhythmias. The classification of these drugs according to their action on different ionic channels of cardiac cells is discussed and summarized. Furthermore, drugs are characterized with respect to their mechanism of action on membrane currents and their action in different cardiac tissues. From the results, strategies may be developed which represent the basis for clinical application of antiarrhythmic drugs.

Action Potentials↗

PubMed1988

Electrophysiological characterization of the class III activity of sotalol and its enantiomers. New interpretation of use-dependent effects.

1. Sotalol (Sotalex) and both its optical isomers were studied in electrophysiological experiments with respect to their class III activity of antiarrhythmic drugs. The three substances prolonged action potentials (AP) of guinea-pig papillary muscle and left atrium in concentrations greater than or equal to 3 mumol/l, whereas other AP parameters (resting potential, amplitude and upstroke velocity) remained unchanged. Similar results were observed if papillary muscles were partially depolarized by elevating the extracellular potassium concentration from 4.7 mmol/l to 10-12 mmol/l. 2. The effects of sotalol showed marked frequency dependence (0.017-2 Hz): At slow driving rates sotalol brought about an enhanced AP prolongation as measured by APD30 and APD90. 3. The results were compatible with numerical AP simulation studies on the basis of the assumption that sotalol inhibits time-dependent K-outward current. This leads to the consequence that longer control APs (at low driving rates) are prolonged more effectively by sotalol than shorter ones (at high driving rates). 4. Sotalol effects dynamically followed APD changes due to alterations of driving rate: If APD was decreased under increasing driving frequencies, AP prolongation was diminished. 5. Paired pulse experiments showed that class III activity of sotalol was preserved in premature or delayed single action potentials.

Action Potentials↗

PubMed1986

Beta-adrenoceptor antagonists (non-selective as well as beta 1-selective) with partial agonistic activity decrease beta 2-adrenoceptor density in human lymphocytes. Evidence for a beta 2-agonistic component of the partial agonistic activity.

In the present study the effects of pindolol [non-selective beta-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on beta 2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the beta 1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA. Administration of pindolol (2 X 5 mg/day) caused an about 25% decrease in lymphocyte beta 2-adrenoceptor density after 2 days; during treatment beta 2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte beta 2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The KD-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte beta 2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3 X 40 mg/day) indicating that the PAA of pindolol is the cause of its beta-adrenoceptor decreasing effect. Administration of the non-selective beta-adrenoceptor antagonist bopindolol (1 X 2 mg/day) with PAA caused decreases in lymphocyte beta 2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 mumol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the beta-adrenoceptor antagonist-induced decrease in beta-adrenoceptor density is accompanied by a loss in beta-adrenoceptor function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗

PubMed1986

Electrophysiological characterization of histamine receptor subtypes in mammalian heart preparations.

Histamine-induced electrophysiological effects have been investigated in guinea-pig left atria, papillary muscles and rabbit AV-nodal preparations by means of intracellular recording of action potentials, slow responses in the presence of 27 mmol/l (K+)o and voltage clamp experiments. Differentiation of the H-receptor subtypes was performed by the use of the H2-selective agonists dimaprit and impromidine and the H1- and H2-selective antagonists dimetindene and cimetidine, respectively. The following results were obtained: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium. Histamine at concentrations less than 1 mumol/l leads to a small increase in APD30 and APD90, but to a marked decrease at concentrations greater than or equal to 1 mumol/l, whereas Vmax, resting potential and amplitude remain nearly unchanged. The effects on ADP are completely blocked by cimetidine and not changed by dimetindene. Changes in action potential may be explained by an increased in slow inward current and outward currents as shown by voltage clamp experiments. In left atria histamine increases APD30 and APD90, whereas there is only a minor increase in amplitude with no changes in Vmax and resting potential. These effects are completely reversed by the H1-antagonist dimetindene but not by cimetidine. IBMX decreases APD90 and does not potentiate the action of histamine. Vmax of slow responses is increased in left atria by stimulation of H1-receptors and in papillary muscles by stimulation of H2-receptors. The results suggest that stimulation of atrial H1-receptors directly causes an increase in Ca-channel conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1986

Electrophysiological actions of histamine and H1-, H2-receptor antagonists in cardiac tissue.

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results: Histamine and the H2-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD90) in atria. Histamine effects in atrial myocardium are completely reversed by the H1-antagonist dimetindene. Stimulation of atrial H1-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content. Histamine reduces AH-interval, increases V max of NH-cells and may induce AV-node arrhythmias (at concentrations greater than or equal to 3 mumol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV-nodal conduction via H2-receptors. Unspecific membrane actions of cimetidine are not observed up to 100 mumol/l. Dimetindene increases action potential duration (APD) in left atria and decreases Vmax at concentrations greater than or equal to 10 mumol/l. However, H1-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA2-values 8.39-9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Differential changes in lymphocyte beta 2-adrenoceptor density by beta-blocker administration: role of intrinsic sympathomimetic activity.

To study the role of intrinsic sympathomimetic activity (ISA) in beta-blocker-induced changes of beta-adrenoceptors, the effects of administration of several beta-blockers for 9 days on lymphocyte beta 2-adrenoceptor density--assessed by 125iodocyanopindolol binding--were investigated in 47 normotensive volunteers. Propranolol (unselective; no ISA; 4 X 40 mg/day) increased beta 2-adrenoceptor density by 25-40%; after withdrawal beta 2-adrenoceptor density declined slowly, being still elevated for 3 days. In contrast, the unselective beta-blockers pindolol (ISA (isoprenaline = 1.0) = 0.39; 2 X 5 mg/day) and mepindolol (ISA = 0.27; 2 X 5 mg/day) decreased beta 2-adrenoceptor density by 50% and 35%, respectively, while alprenolol with weak ISA (=0.066; 4 X 100 mg/day) had no effect. Among the beta 1-selective blockers studied, celiprolol with ISA (=0.32; 1 X 200 mg/day) decreased beta 2-adrenoceptor density by 30% whereas bisoprolol without ISA (1 X 10 mg/day) had no effect. It is concluded that the ISA determines the direction and amount of beta-adrenoceptor alterations induced by beta-blockers. Furthermore, changes in human lymphocyte beta-adrenoceptors reflect subtype-selective changes in beta 2-adrenoceptors, since the beta 1-selective blocker bisoprolol without ISA--in contrast to propranolol--did not affect lymphocyte beta 2-adrenoceptors. Accordingly, the fact that the beta 1-selective blocker celiprolol with ISA decreased lymphocyte beta 2-adrenoceptors, is consistent with the hypothesis that celiprolol possesses in addition to its beta 1-antagonistic activity a beta 2-agonistic activity.

Adrenergic beta-Antagonists↗

PubMed1985

Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity".

Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1985

In vitro studies on the pharmacological properties of diacetolol, the major metabolite of acebutolol in man.

The cardioselectivity and specificity of diacetolol, the major metabolite of the beta-adrenoceptor blocking drug acebutolol, was studied in the isolated right atrium of the guinea-pig and rat and the papillary muscle and trachea of the guinea-pig. The beta-adrenoceptor blocking potency of diacetolol is about ten times lower than that of acebutolol. Like acebutolol, diacetolol was a more effective isoprenaline antagonist in the heart than in the trachea, thus showing relative cardioselectivity. The high water solubility of diacetolol and acebutolol led to a much faster disappearance of the beta-blockade after washout than the blockade by the lipid soluble agents propranolol and penbutolol. Like acebutolol, diacetolol had a weak intrinsic sympathomimetic activity. Cardiac depressant effects, e.g. decrease of maximum upstroke velocity and duration of the action potential and reduction in force of contraction, occurred with concentrations 100-1000 times higher than those needed for beta-blockade, thus indicating relative specificity.

Acebutolol↗

PubMed1985

Antiarrhythmic and electrophysiological actions of flecainide, bepridil and amiodarone on isolated heart preparations during controlled hypoxia.

A model of arrhythmias based on the application of sinusoidal alternating current (ac) to isolated heart preparations has been employed to determine the effects of hypoxia (30 vol % O2 in the perfusion medium) on the threshold of arrhythmia and asystole. With this method three representatives of different classes of antiarrhythmic drugs, flecainide, bepridil and amiodarone, have been investigated in isolated papillary muscles and left atria from guinea-pigs. Hypoxia reduces both the threshold for ac-arrhythmia and the threshold for ac-asystole. Flecainide (3 and 10 mumol/l) elevates both thresholds under normoxia and has a protective effect against the hypoxia-induced reduction of threshold. Bepridil (10 mumol/l) is without effect on the threshold of ac-arrhythmia in papillary muscle, prevents the hypoxia-induced decline of the threshold of ac-arrhythmia in left atria and depresses the threshold of ac-asystole both in normoxia and hypoxia. amiodarone (10 mumol/l) elevates the threshold of ac-arrhythmia both during normoxia and hypoxia in papillary muscle but only during the second hour of hypoxia in left atria. The results may be interpreted with respect to the inhibitory action on Na+-channels (flecainide), Ca2+-channels (bepridil) or protective effects against hypoxia-induced changes in action potential duration (amiodarone, but also flecainide and bepridil) as shown by additional electrophysiological experiments.

Action Potentials↗