Contribution of quinidine metabolites to electrophysiologic responses in human subjects.

The quinidine metabolites 3-hydroxyquinidine, 2'-oxoquinidione, and quinidine-N-oxide and the contaminant dihydroquinidine have been shown to have electrophysiologic activity. This study investigated the time-dependent contributions of quinidine, dihydroquinidine, and the quinidine metabolites to the electrophysiologic effects of a prolonged quinidine infusion in 14 patients referred for management of symptomatic ventricular tachyarrhythmias. Electrophysiologic testing and blood sampling were done at baseline and every 5 minutes throughout a 110-minute quinidine infusion. Changes in ventricular effective refractory periods correlated significantly with serum concentrations of quinidine-N-oxide (r = 0.54; p less than 0.001), 3-hydroxyquinidine (r = 0.50; p less than 0.001), and time (r = 0.52; p less than 0.001) but did not correlate with the quinidine concentrations (r = 0.19). Multiple linear regression revealed that only 3-hydroxyquinidine and time contributed independently to changes in the ventricular effective refractory period. Quinidine concentration was the only variable that contributed independently to changes in ventricular tachycardiac cycle lengths. Time was the only variable that correlated independently with changes in QRS and QTc durations. These data indicate that active metabolites accumulate during an intravenous infusion that attains therapeutic quinidine levels and that quinidine and its metabolites may have different electrophysiologic effects.

Thyrotropin-releasing hormone enhances event-related brain potentials and growth hormone release in man.

Changes in contingent negative variation (CNV), a brain-evoked potential related in arousal, as well as in serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), prolactin (PRL), cortisol and growth hormone (GH) levels were recorded in 12 male volunteers receiving either thyrotropin-releasing hormone (TRH) or saline infusion. Only during TRH administration an increase in CNV (P less than 0.02) and, 30 min later, in GH (P less than 0.05) occurred; thyroid hormones and PRL increased as well, in the absence of any correlation with CNV areas. Cortisol was not affected by TRH. As dopamine (DA) agonistic drugs notoriously increase both CNV areas and GH levels and experimental evidence for prodopaminergic properties of TRH has accumulated in animal models, a possible explanation of the results here presented might be the activation of DA pathways by TRH also in the human.

Acute effects of ethanol on motor performance and movement-related brain potentials.

The acute effects of ethanol on skilled motor functions were examined in male social drinkers, under four doses ranging from 0 (placebo) to 1.05 g/kg lean body weight. The movement entailed a forewarned choice transitive motion of the arm and hand, aimed at a flanking target. Performance measures disclosed only small effects of ethanol on speed and accuracy of movement. The simultaneously-recorded movement-related brain potentials disclosed decreased involvement of frontal and posterior brain areas, suggesting that ethanol disrupted the planning and regulation of movement despite the overall preservation of reaction speed.

Inhibitory influence of oxytocin infusion on contingent negative variation and some memory tasks in normal men.

A double-blind study combining electrophysiological and psychometrical approaches was carried out to investigate the central effects of an intravenous oxytocin (OT) infusion in normal men. Contingent negative variation (CNV) was selected as the measure of central cognitive evoked potential, and the psychometric tests measured mood, vigilance and memory. OT infusion induced a significant decrease of CNV amplitude and an increase of post-imperative positive potentials in vertex derivations. A similar effect was still evidenced one week after treatment in frontal derivations, suggesting a long time effect of OT on human brain. No significant influence of OT on mood or vigilance tests was apparent; only one item of a memory test revealed a significant impairment of some mnesic performances. These observations provide new electrophysiological arguments supporting a central action of peripheral OT administration in man.

Alteration of intestinal tight junction structure and permeability by cytoskeletal contraction.

Permeabilized intestinal absorptive cell brush borders contain a perijunctional ring of actin and myosin (PAMR) that can be induced to contract. Recently, morphological changes suggestive of PAMR contraction were shown to occur in absorptive cells of ileal epithelium after exposure to cytochalasin D (CD) (J. Cell Biol. 102: 2125-2136, 1986). With this response, altered tight junction structure and enhanced tight junction permeability also occur. To further assess the relationship between PAMR contraction and enhanced tight junction permeability, we examined the effect of the uncoupler 2,4-dinitrophenol (DNP) on this CD response. Progressive depletion of functionally defined intraepithelial energy stores occurred with DNP concentrations of 0.1-1 mM. Such DNP concentrations did not independently impair tight junction barrier function. Depletion of energy stores before CD exposure ablated the ability of CD to induce abnormalities of tight junction permeability. Similarly, PAMR condensation and alterations in tight junction structure could be dissociated from CD exposure by prior depletion of functional energy reserves. These data tie CD elicited alterations in tight junction structure and permeability to an energy dependent event that appears to be PAMR contraction. We speculate that tensile forces within the PAMR regulate tight junction structure and function.

[Changes in slow evoked potentials in depressed patients treated with amitriptyline and oxaprotiline]. / La modification des potentiels évoqués lents chez les déprimés sous amitriptyline et oxaprotiline.

Using a simple S1S2-R paradigm, acoustically evoked potentials, CNV, and PINV were recorded in 59 patients with major depressive disorder before and during a 4 week double blind pharmacological treatment with either amitriptyline (AT) or oxaprotiline (OT). In parallel, 30 healthy subjects were investigated 3 times, in identical intervals of 2 weeks. In the depressed state patients exhibited significantly smaller CNVs than the controls. In the AT-group clinical improvement and drug plasma levels of nortriptyline (NT, the principal metabolite of AT and an active antidepressant by itself) were positively related to increases in CNV-area; in the OT-group the reverse was true: increase in CNV-area was related to smaller OT plasma levels and less favourable outcome. The control group displayed a steady decline in CNV area during the 3 test sessions. N1P2 amplitude and PINV were not significantly different between groups and exhibited only minor variations during treatment.

Long-term intracoronary ethanol administration electrophysiologic and morphologic effects.

The long-term intracoronary infusion of ethanol was used to evaluate the potential of ethanol to produce myocardial injury and cardiac rhythm disturbances. In 22 dogs, electrophysiologic testing was performed 48 hr after cessation of alcohol administration. Multiple premature ventricular beats occurred spontaneously in 3 dogs with spontaneous sustained monomorphic ventricular tachycardia observed in 1 dog. Provocative ventricular pacing produced ventricular tachycardia lasting 20 or more beats in 13 animals with sustained tachycardia observed in 3 animals. Provocative ventricular pacing in the presence of lidocaine or epinephrine produced sustained ventricular tachycardia in an additional 4 dogs. The electrophysiologic properties of Purkinje fibers from the zone receiving ethanol were altered when compared to the control zone. The resting membrane potential was decreased (-76 +/- 2 mV vs. -85 +/- mV, p less than 0.001) with a decrease in action potential amplitude (91 +/- 4 vs. 109 +/- 2 mV, p less than 0.001) and phase 0 upstroke (231 +/- 27 vs. 456 +/- 25 V/sec, p less than 0.02). Prolonged refractoriness was observed in the ethanol zone without a prolongation of action potential duration. Intramural lesions observed within the left circumflex distribution varied from focal acute myofibrillar degeneration and necrosis to severe local scarring. The data suggest that intracoronary ethanol administration at human abuse levels of blood alcohol concentrations produces histologic and electrophysiologic injury in the canine heart. The electrophysiologic ch changes provide a substrate sufficient for the induction and maintenance of ventricular arrhythmia.

Quinidine-induced inhibition of transient outward current in cardiac muscle.

Quinidine is frequently used as a class I antiarrhythmic agent in the management of cardiac rhythm disturbances. It depresses the rapid initial depolarization of the action potential by blocking the sodium current, INa. In addition, quinidine increases the duration of the action potential and lengthens the refractory period. We have used a whole cell voltage-clamp technique to study the ionic mechanism underlying the lengthening of the action potential in single cells from the atrium and ventricle of the rabbit heart. Our data show that quinidine at therapeutic doses (3-10 microM) is a potent and selective inhibitor of a transient outward current, which controls the early repolarization of the action potential. In contrast, neither the calcium current, ICa, nor the time-independent background K+ current, IK1, is changed significantly by 10 microM quinidine. The reduction in the transient outward current can explain the lengthening of action potential and provides new insight into the mechanism of action of quinidine as an antiarrhythmic agent.

Age-related variation of EEG responses to clonidine, prazosin and yohimbine in rats.

The EEG-effects induced by intraperitoneal administration of clonidine, prazosin and yohimbine to 8 and 22 month old rats were compared. Clonidine (0.01 mg/kg) and prazosin (1 mg/kg) increased spectral powers, yohimbine (0.5 mg/kg) decreased them. In the older rats, EEG variations were smaller for prazosin and yohimbine, but larger for clonidine. These findings show that alpha receptor mediated influences on EEG are changed during aging and show that quantified EEG gives a picture of age related changes in the functional state of the neurotransmitter systems.

Contingent negative variation and efficacy of beta-blocking agents in migraine.

Thirty-three patients with common migraine underwent contingent negative variation (CNV) recordings before receiving prophylactic beta-blocker treatment with either metoprolol (27 patients) or propranolol (6 patients) at mean daily dosages of 110 mg and 122 mg, respectively. After 3 months the therapeutic efficacy of the beta-blocker was assessed in each patient by means of a global severity score and compared with the initial CNV recordings. The mean clinical improvement was 62%. A significant positive correlation was found between CNV amplitude before prophylaxis and the clinical response to beta-blockers: patients with higher CNV tended to respond better to therapy. Eight of 10 patients with a CNV amplitude higher than -25 microV had a more than 50% reduction of the severity score--that is, a good or excellent response to the beta-blocking agent--whereas only 2 of 9 patients with an amplitude lower than -20 microV had a good response.

Developmental changes in the interactions of cholinergic and beta-adrenergic agonists on electrophysiologic properties of canine cardiac Purkinje fibers.

The parasympathetic nervous system attenuates the effects of sympathetic interventions on the hearts of mature animals. Whereas the vagal mediator, acetylcholine (ACh), alone has minor effects on electrophysiologic properties of the ventricular conducting system, in the presence of sympathetic amines, it induces an accentuated antagonism. Because there are developmental changes in both sympathetic and parasympathetic effects on the heart we studied the parasympathetic and sympathetic interaction in isolated neonatal canine Purkinje fibers (PF), and compared the results to those in adult PF. PF were exposed to isoproterenol (Iso) alone (1 X 10(-9), 1 X 10(-7) and 1 X 10(-5) M) to ACh alone (1 X 10(-7) or 1 X 10(-5) M) and to Iso in the presence of ACh. In adult PF, superfusion with Iso, 10(-5) M, alone shortened action potential duration to 50% repolarization from a control value of 215 +/- 9 to 200 +/- 9 ms (p less than 0.01). Simultaneous superfusion of adult PF with Iso 10(-5) and Ach 10(-5) M decreased the extent of action potential shortening produced by Iso, so that action potential duration to 50% repolarization shortened from a control value of 221 +/- 8 to only 214 +/- 12 ms (p less than 0.01). The response to superfusion with Iso and Ach (10(-5) M) differed significantly from that with Iso alone (p less than 0.01). In contrast, exposure of neonatal PF to Iso (10(-5) M) prolonged action potential duration to 50% repolarization from a control value of 157 +/- 7 to 180 +/- 5 ms (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Intraraphedorsal kainic acid induces paroxysmal electroencephalographic changes in some brain structures of cats.

In acute experiments on cats the effect of kainic acid microinjected into the raphe dorsal nucleus on the EEG activity recorded from various brain structures was investigated. Kainic acid in doses of 0.2 to 32.0 nmol was injected by glass micropipets and an air-pressure system. The analysis of the EEG and the EEG power analysis in the usual frequency bands (delta, theta, alpha, and beta) revealed an activating to hyperexcitatory effect of kainic acid. This hyperexcitatory effect was manifested by the appearance of paroxysmal EEG patterns of different types which developed in some cases into seizure episodes or an epileptic state. Abnormal EEG changes occurred first in the thalamus and mesencephalic reticular formation. A dose-response relationship existed: the duration of the EEG with pathological patterns increased whereas the latency of their appearance decreased with increase of the dose of kainic acid. Five to seven hours after the injection there were no severe histopathologic changes in the region of the raphe dorsal nucleus. The hyperexcitatory effect of kainic acid on brain excitability might be a result of the excitatory action of kainic acid and of triggering of circuits of neuronal hyperactivity in structures connected with the raphe dorsal nucleus.

Noxiustoxin, a short-chain toxin from the Mexican scorpion Centruroides noxius, induces transmitter release by blocking K+ permeability.

Noxiustoxin (NTX), a 39 amino acid peptide purified from the venom of the Mexican scorpion Centruroides noxius, has been shown to block voltage-dependent K+ currents in the squid giant axon (Possani et al., 1982; Carbone et al., 1982). Although several other drugs known as K+ channel blockers in the squid axon also act on isolated nerve terminals to produce an increase in transmitter release, these releasing effects have not been shown to be related to a decrease of K+ permeability in synaptosomes (Vizi et al., 1977; Tapia and Sitges, 1982). In this work we show that NTX increases 3H-GABA release from perfused mouse brain synaptosomes. This effect was not blocked by TTX. Ca2+ channel blockers (verapamil or Co2+) or the absence of external Ca2+ prevents the releasing effect of this toxin. NTX does not seem to induce transmitter release by directly increasing Ca2+ permeability: The K+ ionophore valinomycin completely inhibits the release induced by NTX, as well as that evoked by the K+ channel blocker 4-aminopyridine; in contrast, the release evoked by a Ca2+ ionophore is not blocked by valinomycin. These findings strongly suggest that the releasing effect of NTX is mediated by a decrease in K+ permeability. External Ca2+ is needed only in order to couple this stimulus with the release process. Consistent with this hypothesis, we present evidence that NTX blocks the efflux of 86Rb+ from synaptosomes. An extended comparison of the effect of 4-aminopyridine with that of NTX is also reported.

The electrophysiological effects of calcium channel blockade during standard hyperkalemic hypothermic cardioplegic arrest.

The addition of calcium channel-blocking agents to a standard hyperkalemic hypothermic cardioplegic solution has been examined both experimentally and clinically. None of these studies, however, have investigated the effect of calcium blockade during cardioplegic arrest on the specialized cardiac conduction tissues and on the subsequent development of arrhythmias after arrest. The present study examined the effect of adding nifedipine to standard cardioplegic solution administered in a canine experimental preparation modeled on routine clinical techniques. The time to and duration of electrical arrest following the administration of cardioplegia and the functional electrophysiological variables before and after arrest were measured using a 32-channel data acquisition system. The addition of nifedipine shortened the time to electrical arrest and prolonged the duration of arrest compared with standard potassium cardioplegic solution alone, without a deleterious effect on conduction function immediately after arrest. The occurrence of low-amplitude electrical activity (LEA) in both atria and ventricles during arrest was significantly reduced by the addition of nifedipine, thereby suggesting a possible correlation between LEA and calcium-mediated conduction occurring under conditions of standard cardioplegic arrest.