Cardiac electrophysiological actions and interactions of ethanol, cocaine, and the metabolite ethylcocaine.

The influence of ethanol on the actions of cocaine and ethylcocaine on rat sinoatrial preparations was studied. Ethanol did not modify the depressant effect of cocaine or ethylcocaine on sinoatrial rate (SR) in preparations with spontaneous activity. Cocaine produced sinoatrial block only in the presence of ethanol, and the latter accentuated the sinoatrial block produced by ethylcocaine. Ethanol did not modify the depressant effect of cocaine or ethylcocaine on membrane potentials of atrial fibers in preparations driven at a constant rate. In conclusion, ethanol, in a concentration that did not by itself affect SR or produce sinoatrial block, accentuated the effects of cocaine and ethylcocaine on sinoatrial conduction, without modifying the effects on SR. It is proposed that the accentuation of the block was the consequence of the combination of a depressant action on the fast sodium system and a deterioration of the cell-to-cell coupling.

Temperature-dependent inotropic effects of lignocaine and ethanol on rat heart papillary muscles.

1. The main objective of the present study was to investigate the temperature dependence of the cardiac inotropic effects of lignocaine and ethanol (EtOH). 2. We studied the in vitro inotropic actions and interactions of EtOH (2.4 g/L) and lignocaine (25 mg/L) on rat papillary muscles superfused with Tyrode's solution and stimulated at 1 Hz at either 37 or 30 degrees C. Peak tension developed (PTD), maximum velocity of development of tension (VmaxT) and time to peak tension (TPT) were measured. 3. At 37 degrees C, EtOH depressed PTD, while VmaxT and TPT remained unchanged. At 37 degrees C, lignocaine alone or in combination with EtOH depressed all three parameters. 4. At 30 degrees C, EtOH did not modify PTD or VmaxT, whereas TPT decreased. At 30 degrees C, lignocaine decreased TPT, but VmaxT did not change and the effect of lignocaine on PTD was smaller at 30 degrees C than at 37 degrees C. Ethanol and lignocaine in combination decreased all three parameters at 30 degrees C. However, the depression of VmaxT by the combination of lignocaine and EtOH was less at 30 degrees C than at 37 degrees C. 5. Hypothermia (30 degrees C) protected the myocardium against the depressant actions of EtOH and lignocaine, alone or in combination. With EtOH alone, the protection resulted in no change in PTD. When lignocaine was involved, the protection resulted in a weaker action on PTD and VmaxT. The temperature dependence of the action of lignocaine may explain, at least in part, the development of ventricular failure in cardiac surgical patients exposed to lignocaine during hypothermia and rewarming.

Adrenergic-mediated effects of cocaine on the myocardial force-frequency relationship.

We studied the role of sarcolemmal alpha- and beta-adrenoceptors activation in the effects of cocaine on the positive force staircase in isolated guinea pig atria. The preparations were superfused with Tyrode's solution at 31 degrees C while attached to a force transducer to measure peak tension developed (PTD), maximum velocity of development of tension (Vmax T) and time to peak tension (TPT). The positive force staircase was not affected by propranolol or phentolamine, but it was abolished by nifedipine. Cocaine 1 mg/l (2.9 microM) enhanced PTD and Vmax T, while TPT remained unchanged. On the other hand, cocaine did not modify the increase in PTD induced by the increase in frequency of stimulation, but significantly reduced the magnitude of the increase in Vmax T. The cocaine-induced attenuation of the increase in Vmax T in response to changes in the frequency of stimulation was abolished by both propranolol and phentolamine. It is concluded that the effect of cocaine on the force-frequency relationship required background activation of alpha- and beta-adrenergic receptors.

Actions and interactions of ethanol and imipramine on the rat sinus node.

We studied the actions and interactions of ethanol and imipramine on the sinus node. Strips of the right rat atrium including the sinus node were superfused with Tyrode's solution at 37 degrees C while beating spontaneously. The preparations were exposed to imipramine or ethanol alone as well as to the two drugs in combination while recording membrane potentials with standard intracellular microelectrodes. The results obtained show that ethanol 0.8 and 2.4 g/l exerted a positive chronotropic action. On the other hand, imipramine 0.25 mg/l did not modify the sinus node rate. However, it reduced significantly the positive chronotropic action of ethanol. The sinus node rate decreased under the action of a higher concentration of imipramine (1 mg/l). When ethanol was tested in combination with this concentration of imipramine, the effect of the latter prevailed. In conclusion, a concentration of imipramine that did not affect the sinus node rate antagonized the positive chronotropic action of ethanol. In addition, the negative chronotropic action of a higher concentration of imipramine prevailed over the positive action of ethanol. The results obtained provide additional support to the notion that the use of ethanol and cardioactive drugs in combination may result in significant changes in the actions of either of the two, or both. This is of clinical relevance, since at least some of the individuals under treatment with cardioactive drugs will be alcoholics and/or social drinkers.

Arrhythmogenic and antiarrhythmic actions of substances of abuse: effects on triggered activity.

Substances of abuse exert adrenergic and/or depressant actions on the cellular processes responsible for cytosolic calcium overload. This investigation attempted to determine whether substances of abuse, through catechol-mediated effects or cellular actions, elicit or inhibit the production of arrhythmias caused by delayed afterdepolarizations (DADs) and triggered activity (TA). The papillary muscles of rats and Purkinje fibers of dogs were superfused in vitro with Tyrode's solution at 37 degrees C. Intracellular microelectrodes were used to record membrane potentials. Overdrives failed to induce DADs and TA in the canine Purkinje fibers exposed to either Tyrode's solution alone, or containing ethanol or harmine. Instead, ethanol and harmine inhibited DADs and TA induced by overdrives in the presence of strophanthidin. On the contrary, in the presence of acetaldehyde and amphetamine, overdrives did produce TA, which was inhibited by propranolol. In conclusion, substances of abuse may either elicit or inhibit the production of DADs and TA, depending on the balance between adrenergic and depressant actions on the cellular mechanisms responsible for the calcium overload of the cytosol.

Mechanisms of the in vitro effects of amphetamine on rat sinus node automaticity and membrane potentials of atrial fibers.

The main objective of this investigation was to clarify the mechanisms of the acute in vitro actions of amphetamine (AMP) on cardiac electrophysiology. Concentrations of AMP ranging from those considered clinically therapeutic to those considered toxic were tested in isolated rat sinoatrial tissues while recording membrane potentials with intracellular microelectrodes. In preparations beating spontaneously, 6.8 nM-2.71 microM AMP exerted a positive chronotropic action that was blocked by propranolol. The positive chronotropic action of 5.43 microM AMP was smaller than that of 2.7 microM AMP and was reversed by propranolol. Neither phentolamine nor atropine blocked this depressant action of AMP. It is concluded that the positive chronotropic action of AMP was beta-adrenergic and that beta-adrenergic block unmasked a negative chronotropic action of a high concentration of AMP, which was neither alpha-adrenergic nor muscarinic. In atrial fibers driven at a constant rate, 54.3 nM AMP prolonged the action potential duration (APD), without affecting the resting membrane potential (RMP), the action potential amplitude (APA), or the maximum velocity of phase 0, while 5.43 microM AMP reduced RMP, APA, and the maximum velocity of phase 0, and increased APD. The prolongation of APD, as well as the decreases of RMP and APA, was not abolished by propranolol, phentolamine, or 4-aminopyridine. Conversely, nifedipine abolished the effects of AMP on all three parameters. In general, AMP produced mainly a prolongation of the action potential. Only a high concentration of AMP decreased RMP and depressed phase 0 of the action potential. The effect of AMP on APD, RMP, and APA essentially involved increasing the influx of calcium through the L-type channels in the sarcolemma.

Mechanism of the positive inotropic action of cocaine in the guinea pig atrium.

We studied the mechanism of the positive inotropic action of cocaine in isolated guinea pig atria superfused with Tyrode's solution at 31 degrees C while attached to a force transducer to measure peak tension developed, maximum velocity of development of tension, and time to peak tension. Cocaine 2.9 microM enhanced peak tension developed and velocity of development of tension, and prolonged time to peak tension. The increase in peak tension developed produced by cocaine was not affected by propranolol. On the other hand, the cocaine-induced increase in velocity of development of tension was reduced, but not abolished. In the presence of propranolol and phentolamine combined, the cocaine-induced prolongation of time to peak tension was abolished and the increases of both peak tension developed and velocity of development of tension were significantly smaller than those observed in the absence of the two adrenergic blockers. For all practical purposes, nifedipine completely abolished the increase in peak tension developed induced by cocaine. It is concluded that the positive inotropic effect of cocaine in the guinea pig atrial muscle is predominantly the result of adrenergic-dependent, both alpha- and beta- receptor mediated, as well as adrenergic-independent increases in calcium influx through the L-type calcium channels in the sarcolemma.

Electrophysiologic in-vitro effects of cocaine and its metabolites.

We studied the in-vitro electrophysiologic effects of equimolar concentrations of cocaine and its metabolites on rat cardiac tissues. The effects on the sinus node rate were studied in spontaneously active sinoatrial preparations. The order of magnitude of the effects was: ethylcocaine > cocaine > benzoylecgonine and ecgonine methyl ester > ecgonine. The effects of cocaine and ethylcocaine were not additive. The actions of cocaine and ethylcocaine on membrane potentials were studied in papillary muscles driven at 5 Hz. Both compounds depressed to similar degrees the resting potential and the amplitude of the action potential, and increased the duration of the action potential. Simultaneous exposure to the two drugs did not result in effects greater than those of ethylcocaine or cocaine alone. It is concluded that (a) cocaine and its metabolites depressed the sinus node rate. Only cocaine and ethylcocaine exerted actions that may be of clinical significance. (b) Ethylcocaine had an effect greater than that of cocaine on the sinus node rate, and similar to that of the parent compound on ventricular membrane potentials. Thus, ethylcocaine may play a significant role in the cardiac electrophysiologic actions of cocaine, when the latter is used in combination with ethanol. (c) The effects of cocaine and ethylcocaine were not additive.

Cocaine suppression of triggered activity. A possible mechanism of antiarrhythmic action.

The cellular mechanisms of cocaine-induced arrhythmias are not clear. Production of early afterdepolarizations (EADs) in single myocytes have been proposed as a possible mechanism of cocaine arrhythmogenesis. The objective of this investigation was to determine whether cocaine exerts arrhythmogenic or antiarrhythmic actions related to the production or inhibition of afterdepolarizations in multicellular preparations. Rat and guinea pig papillary muscles superfused in vitro with Tyrode's solution at 37 degrees C were stimulated at 1 Hz. Standard intracellular microelectrodes were used to record membrane potentials. Cocaine administered at 2.9-58 microM never induced EADs; also, overdrive in the presence of cocaine never induced delayed afterdepolarizations (DADs). On the other hand, cocaine administered at 58 microM suppressed DADs and triggered activity induced by overdrive in the presence of ouabain octahydrate and isoproterenol. Thus, cocaine acting on multicellular ventricular preparations in vitro did not induce EADs or DADs. On the contrary, cocaine inhibited DADs and triggered activity induced by other drugs.

Mechanism of the negative inotropic action of cocaine in rat papillary muscle.

We studied the mechanism of the negative inotropic action of cocaine in isolated rat papillary muscles superfused with Tyrode's solution at 31 degrees C while attached to a force transducer to measure peak tension developed (PTD), maximum velocity of development of tension (Vmax T), and time to peak tension (TPT). The results show that in preparations driven at 1 Hz, 5 and 10 mg/liter cocaine had a significant negative effect only on PTD, while 20 mg/liter (58 microM) significantly depressed all three measured parameters. Similar results were obtained in preparations driven at 0.5 Hz, which developed a greater control active tension than those driven at 1 Hz. In preparations driven at 0.5 Hz, propranolol (1 microM) had no significant effect on the active tension developed nor did it modify the negative inotropic action of cocaine. Both nifedipine (1 microM) and caffeine (1.5 mM), on the other hand, significantly reduced PTD, Vmax T, and TPT. The depressant inotropic action of cocaine was accentuated by nifedipine, but was blocked by caffeine. These observations suggest that the primary site of action of cocaine was at the level of the sarcoplasmic reticulum rather than at the sarcolemma.

Cocaine enhances postrest and paired-stimulation potentiation in rat papillary muscle.

We studied the effects of cocaine (20 mg/l; 58 microM) on paired-stimulation potentiation and rest-potentiation in isolated rat papillary muscles superfused with Tyrode's solution at 31 degrees C. A force transducer was used to measure peak tension developed, maximum velocity of development of tension and time to peak tension. The results show that, in preparations driven at a basic constant rate (0.5 Hz), cocaine had a depressant effect on peak tension developed and maximum velocity of development of tension and shortened time to peak tension. Propranolol or nifedipine did not modify the negative inotropic action of cocaine, whereas this action was blocked by caffeine. The results also show that cocaine enhanced rest-potentiation and paired-stimulation potentiation. In the presence of propranolol, the enhancement of paired-stimulation potentiation caused by cocaine remained intact, whereas it failed to do so under the influence of nifedipine. On the other hand, nifedipine did not affect the enhancing action of cocaine on rest-potentiation. Caffeine reversed both rest-potentiation and paired-stimulation potentiation; this action was not modified by cocaine. Thus, even though cocaine exerted a negative inotropic action on rat papillary muscles driven at a constant rate, it enhanced the potentiating action of maneuvers which modify the force-interval relation. Cocaine appears to cause these effects by acting at various levels of electro-mechanical coupling, such as the sarcolemma, the sarcoplasmic reticulum and the myofilaments sensitivity to calcium.

Cardiac beta-adrenergic mediated chrono- and inotropic effects of imipramine in vitro.

Clinical and experimental studies show that tricyclic antidepressants in "therapeutic plasma concentrations" can increase heart rate, myocardial contractility and blood pressure. Our study was undertaken to analyze the role of beta-adrenergic stimulation in the chronotropic and inotropic effects of imipramine. Strips of rat right atrium including the sinus node, which were beating spontaneously, were used to study chronotropism. Strips of the left atrium, electrically stimulated to beat at 1 Hz, were used to study inotropism. The preparations were superfused in vitro with Tyrode's solution at 37 degrees C and exposed to imipramine while recording membrane potentials or force of contraction. Imipramine exerted dose-dependent biphasic actions. Imipramine 0.8 microM produced positive chronotropic and inotropic actions which were blocked by propranolol. Imipramine 1.6 microM depressed the sinus node automaticity, but it did not modify the force of contraction. Imipramine 3.2 microM depressed both the sinus node automaticity and the myocardial contractility. In conclusion, imipramine in "therapeutic plasma concentrations" produces beta-adrenergic mediated cardiac positive chronotropic and inotropic actions. The possible mechanisms of the depressant effects of imipramine itself on automaticity and contractility are still not clear. The results presented can explain stimulatory and depressant cardiac effects of therapeutic doses and overdoses of tricyclic antidepressants.

Clinical relevance of distal arterial compliance.

AIM: To calculate the compliance of resistance vessels. METHODS: Pressure-flow data (plethysmographic and sphygmomanometric) were obtained non-invasively from six normal and six hypertensive subjects, and the results were compared with similar data obtained previously from large blood vessels. The parameter used to represent compliance was extensibility (E), defined as the percentage change in radius for a given change in pressure. RESULTS: The hand vessels of hypertensive subjects (E = 0.126 +/- 0.034/mmHg) were significantly stiffer (P < 0.02) than those of the normotensive subjects (E = 0.272 +/- 0.047/mmHg); and the values of E for the resistance vessels were larger than those for the large arteries.

Cardiac inotropic effects of ethanol and calcium-channel modulators.

Our objective was to analyze the influence of ethanol ingestion on the in vitro inotropic effects of dihydropyridines alone, or in combination with ethanol, on atrial muscle from rats offered a liquid diet with ethanol ("ethanol rats," ER) or without ethanol ("normal rats," NR). Left atria from NR or ER were superfused with Tyrode's solution (36 degrees C) and driven at 1.5 Hz while recording tension. Bay K 8644 (BAYK) increased, while nimodipine or ethanol decreased, the tension developed and the velocity of development of tension. The preparations recovered rapidly from the effects of ethanol, but not from those of the dihydropyridines. The effects of ethanol and dihydropyridines in combination were the result of the additive or counteractive actions of the drugs. The effects of ethanol and nimodipine on ER preparations were not different from those observed in NR. The action of BAYK was significantly smaller in ER than in NR. In other words, chronic ingestion of ethanol reduced the positive inotropic effect of BAYK, but it did not modify the negative inotropic action of nimodipine or ethanol.

Effects of nicotine and ethanol on rat atrial membrane potentials.

The purpose of this research was to study the effects of nicotine and ethanol, alone and in combination, on cardiac membrane potentials (MP). Rat atrial preparations driven at 5 Hz were superfused with Tyrode's solution (37 degrees C) while recording MP with intracellular microelectrodes. Nicotine concentrations below and including 6.2 x 10(-5) M did not affect MP. Within 15 s, nicotine 3.1 x 10(-3) M shortened the action potential duration (APD) and depressed the overshoot of the action potential (OS). This action was blocked by atropine. After 3 min, nicotine prolonged the APD and depressed Vmax of phase O, OS and the amplitude of the action potential (AAP), without affecting the resting membrane potential (RMP). Nifedipine blocked the depression of the OS while tetraethylammonium chloride blocked the prolongation of the APD. Acute exposure to ethanol depressed OS and AAP and shortened APD, but it did not affect RMP or Vmax of phase O. When nicotine and ethanol were administered simultaneously, the APD-prolonging effects of nicotine prevailed. The influence of chronic ethanol ingestion on the acute action of nicotine and/or ethanol was studied in rats pair-fed a liquid diet with (ER) or without (NR) ethanol (35% of total caloric intake) for 24 weeks. Chronic ethanol ingestion accentuated the depressant effect of nicotine 3.1 x 10(-3) M on OS and AAP, but it did not modify the APD-prolonging action of nicotine. The same results were observed when ER and NR were exposed to nicotine and ethanol simultaneously.

Mechanisms of the inotropic actions of MPTP and MPP+ on isolated atria of rat.

Besides having toxic actions, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (1-methyl-4-phenyl-pyridinium ion) produce the release of catecholamines in the peripheral and central nervous systems. This paper reports on the effects of MPTP and MPP+ on isolated left atria of rats and their mechanisms. MPP+ and MPTP produced a concentration-dependent positive inotropic effect. This action was blocked by propranolol and nomifensine; however, inhibition of monoamine oxidase had no effect on the response. In atria from reserpinized rats, the positive inotropic effect of MPTP was also blocked and a negative inotropic effect was unmasked which continued to increase in magnitude during wash. The negative inotropic effect was markedly reduced by superoxide dismutase and catalase. These results indicate that MPTP and MPP+ produce a catecholamine-mediated positive inotropic effect that is not MAO-dependent, unlike the toxic actions of MPTP. These results also suggest that MPTP may directly damage cardiac muscle by generating free radicals which might explain why high doses of MPTP are lethal to animals.

Electrophysiological mechanisms of cocaine-induced cardiac arrest. A possible cause of sudden cardiac death.

The hypothesis that cocaine intoxication results in cardiac arrest by producing a block of the propagation of the action potential, without loss of pacemaker function, was tested in rat cardiac tissues. In spontaneously active sinoatrial preparations, cocaine exerted a dose-dependent negative chronotropic action, which was not modified by atropine or propranolol. Sinus node arrest was never observed. Instead, cocaine produced sinoatrial block. The mechanism of this block involved a fall in the resting potential and a decrease in the amplitude and Vmax of phase 0 of the action potential of atrial fibers. In sinoatrial preparations and papillary muscles driven at 5 Hz., cocaine depressed the resting potential, the total amplitude, the overshoot of the action potential, and the Vmax of phase 0. Cocaine had a biphasic effect on the atrial action potential duration. The initial shortening was muscarinic. The prolongation was alpha-adrenergic mediated and probably the result of the inhibition of the transient outward current Ito. In papillary muscles, only the prolongation of the action potential occurred. In conclusion, the electrophysiological actions of cocaine can explain cardiac sudden death. The fall in the resting potential associated with the decrease in the amplitude of the action potential of contractile fibers will result in a block of the propagation of the action potential. Quiescence of the contractile fibers will occur while the sinus node is still generating action potentials at a rate compatible with life.

Cardiac chronotropic effects of nicotine and ethanol in the rat.

The purpose of this research was to study the chronotropic effects of ethanol (ETOH) and nicotine (NIC), alone and in combination, on the heart. Rat sinoatrial preparations superfused with Tyrode's solution (37 degrees C) were used. The sinoatrial rate (SAR) was monitored using intracellular microelectrodes. NIC concentrations below and including 6.2 x 10(-5) M did not affect the SAR. NIC 6.2 x 10(-4) M and above depressed the SAR. This chronotropic effect of NIC was in part muscarinic. Acute in vitro exposure to ETOH diminished the chronotropic effect of NIC. Chronic ingestion of ETOH (35% of total caloric intake) for 24 weeks did not modify the effect of NIC on the SAR. In summary, there is no positive component in the chronotropic effect of NIC on the rat heart, which is probably due to absence of NIC receptors for the release of norepinephrine. Acute in vitro exposure to ETOH, but not chronic ingestion of ETOH, diminished the negative chronotropic action of NIC.

Physicochemical characteristics of the terbium-adriamycin complex and its effects on the sinus node automaticity.

The physicochemical characteristics of the terbium-adriamycin complex (terbomycin) were studied. Perturbations in the visible absorption spectrum of adriamycin by terbium (Tb3+) was indicative of formation of the terbomycin complex. The absorption maximum of free adriamycin at 479 nm shifted towards the absorption maximum of terbomycin at 539 nm. The binding of Tb3+ to adriamycin was negligible at acidic pH. At alkaline pH, the affinity of Tb3+ for adriamycin increased. The stoichiometry of binding was estimated to be 0.5; one Tb3+ ion per two adriamycin molecules. Thermodynamic analysis revealed that the spontaneous formation of terbomycin was due to an increase in the entropy of the system. The effects of adriamycin, Tb3+ and terbomycin on sinus node automaticity were studied using sinus node from rats, superfused with modified mammalian Tris-Tyrode's solution (37 degrees C). The sinus node rate was monitored with intracellular microelectrodes. 25 microM Tb3+ increased the sinus node rate. Adriamycin (50 microM) depressed sinus node automaticity. Terbomycin also reduced the sinus node rate. There was no difference between the effects of adriamycin and terbomycin. The chronotropic effect of terbomycin persisted in the presence of atropine.

Actions and interactions of calcium modulators and ethanol on rat atrial membrane potentials.

The effects of ethanol and dihydropyridines on atrial membrane potentials (MP) were studied. Rat atrial strips superfused with Tyrode's solution (36 degrees C) were driven at 5 Hz while recording MP with intracellular microelectrodes. Bay K 8644 7 X 10(-7) M (BAYK) increased the amplitude of the action potential (AAP) without affecting the resting membrane potential (RMP) or the Vmax of phase 0 (Vmax 0). The velocity of change in voltage decreased at the beginning of the repolarization, causing an increase in the action potential duration (APD), but it was not modified at negative voltages. Nimodipine 4.2 X 10(-6) M reduced the AAP without affecting RMP or Vmax 0. The velocity of change in voltage increased at the beginning of the repolarization, causing a decrease in the APD, but was not modified at negative voltages. Ethanol 5.3 X 10(-2) M exerted actions similar to those of nimodipine. Simultaneous exposure to ethanol and nimodipine resulted in changes not different from those obtained with each of the two compounds. The MP remained unchanged when the preparations were exposed to ethanol and BAYK simultaneously. In summary, ethanol and nimodipine exerted similar actions on the atrial MP while BAYK had opposite actions. The effects of ethanol and BAYK cancelled each other.