Robert G. Carpentier

Acute and Chronic Effects of Ethanol on Sinoatrial Electrophysiology in the Rat Heart

Summary: The influence of moderate chronic ethanol ingestion (CEI) on the acute effects of ethanol upon sinoatrial electrophysiology was studied in rats maintained on a liquid diet for 24 weeks. Rats on ethanol (E-R) received 14A of the caloric intake as ethanol. Controls (N-Rl received the same diet, except for isocaloric substitution of carbohydrates for ethanol. The rats were sacrificed at the end of the 24 weeks and sinoatrial preparations were isolated and supervised with Tyrodes solution at 36OC. Intracellular microelectrodes were used to monitor: (a) sinus node automaticity (SNA) in preparations spontaneously active: (b) atrial membrane potentials (AMP) in preparations driven at a constant rate. Ethanol 40–80 mg/100 ml enhanced SNA in N-R. while 240 mg/100 ml were required to obtain a similar effect in E-R. This positive chronotropic effect was not blocked by propranolol. CEI did no modify the effects of carbachol or isoproterenol on SNA. Ethaol 240 mg/100 ml shortened the atrial action potentials in N-R. CEI did not modify the effects of ethanol. carbachol. or isoproterenol on AMP. In summary. smal concentrations of ethaol enhanced the SNA in vitro. CEI resulted in development of tolerance to the chronotropic effect of ethanol, without modifying: (a) the acute in vitro effects of carbachol or isoproterenol on SNA and AMP; and (b) the effects of ethanol on AMP.

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.

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 Tyrodes 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 Tyrodes 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.

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 Tyrodes 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.

Effects of acetaldehyde on the automaticity of the guinea pig sinus node.

The objective of this investigation was to characterize the effects of acetaldehyde (ACA) on sinus node automaticity (SNA). Guinea pig sinoatrial preparations superfused with Tyrodes solution at 37 degrees C were used. Intracellular microelectrodes were used to monitor SN rate (SNR). Acetaldehyde 3 X 10(-5) M had no effect on SNR, while 3 X 10(-3) M had a positive chronotropic action. The increase in SNR was associated with an increase in the slope of the slow diastolic depolarization (SDD) of subsidiary pacemaker fibers, with no change in the maximum diastolic potential (MDP). Acetaldehyde 3 X 10(-2) M exerted a biphasic effect: the SNR was enhanced and then depressed. Propranolol blocked the positive component of this chronotropic action. The negative component was not modified by propranolol, phentolamine, or atropine. It is concluded that ACA exerts both positive and negative chronotropic actions on the guinea pig sinus node. The positive component of this biphasic effect is mediated through a beta-adrenergic mechanism and it is associated with an increase in the SDD. The negative component is not due to alpha- or beta-adrenergic or muscarinic stimulation.

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.

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 Tyrodes 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.

Effects of acetaldehyde on membrane potentials of sinus node pacemaker fibers

The experiments reported here were performed to characterize the effects of acetaldehyde on membrane potentials (MP) of sinus node subsidiary pacemaker fibers in the absence and presence of adrenergic and cholinergic blockade. Guinea pig sinoatrial preparations were superfused with Tyrodes solution at 37 degrees C while electrically stimulated at 5 Hz. Intracellular microelectrodes were used to record the MP of sinus node subsidiary pacemaker fibers. Acetaldehyde 3 x 10(-6) M and 3 x 10(-3) M had no effect on maximum diastolic potential (MDP), while 3 x 10(-5) M and 3 x 10(-2) M exerted a depolarizing effect on the MDP, without affecting the overshoot (OS). The fall in MDP was associated with a reduction in the amplitude of the action potential (AAP) and the maximum velocity of phase 0 (Vmax 0). The depressant effect of acetaldehyde on MDP was not abolished by adrenergic blockers or atropine. Concentrations of acetaldehyde between 3 x 10(-5) and 3 x 10(-2) M prolonged the action potential duration (APD). Acetaldehyde 3 x 10(-3) M did not affect MDP even in the presence of atropine or propranolol. The APD-prolonging effect of acetaldehyde was not abolished by adrenergic blockers. In summary, the actions of acetaldehyde on MDP and APD were independent of adrenergic and cholinergic mechanisms.

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.

Effect of ethanol on guinea pig ventricular action potentials

The effects of low concentrations of ethanol on transmembrane potentials of guinea pig ventricular muscle were analyzed. Papillary muscles were superfused with Tyrode solution in vitro at 30 degree C while driven at 60 min-1. Transmembrane potentials were recorded by means of intracellular microelectrodes before, during and after a 15 min exposure to ethanol. Ethanol 2,5 mg/100 ml (0.55mM) did not affect transmembrane potentials. Ethanol 5 mg/100 ml enhanced the amplitude of the action potential (AAP) without affecting the membrane resting potential (MRP) and the maximum velocity of the upstroke (dV/dt). Ethanol 40 mg/100 ml also enhanced AAP without modifying MRP and dV/dt. Verapamil and propranolol blocked the augmenting effect of ethanol on AAP. Ethanol 40 mg/100 ml also enhanced the amplitude of responses restored by norepinephrine in fibers depolarized by high [K]0 to a level of resting potential at which the fast component of the upstroke was abolished. The enhancement of AAP was accompanied by a shift of the plateau to more positive values, but the duration of the action potential measured at 50% of repolarization was not affected. The results indicate that ethanol in low concentrations augments, through a catechol-mediated effect, the slow component of the upstroke of ventricular action potentials.