Effects Of Sodium Channel Blockers Research Articles

High-affinity block of voltage-operated rat IIA neuronal sodium channels by 2,6 di-tert-butylphenol, a propofol analogue.

Propofol is a phenol derivative (2,6 di-isopropylphenol) with a unique effect profile including activating effects on GABA(A) and blocking effects on voltage-operated sodium channels. If the substituents in the 2- and the 6-positions are replaced by tert-butyl groups, the resulting phenol derivative, 2,6 di-tert-butylphenol, despite being a close structural propofol analogue, completely lacks GABA(A) receptor effects. The aim of this in vitro study was to investigate the effects of 2,6 di-tert-butylphenol on voltage-operated neuronal sodium channels in order to determine whether and, if so, how these structural changes alter the sodium channel-blocking effect seen with propofol. Whole-cell sodium inward currents through heterologously expressed rat type IIA sodium channels were recorded in the absence and presence of definite concentrations of 2,6 di-tert-butylphenol and propofol. When applied at concentrations > or = 30 micromol, 2,6 di-tert-butylphenol completely and irreversibly blocked sodium inward currents. The blockade equilibrium time was about 2 min. A partial washout was possible only if the application was stopped before the equilibrium of the blockade was achieved. 2,6 Di-tert-butylphenol exerts a high-affinity block of neuronal sodium channels. Apparently, the slight structural differences of 2,6 di-tert-butylphenol in comparison with propofol--which account for the lack of GABA(A) receptor effects--enhance its voltage-operated sodium channel-blocking effects. As 2,6 di-tert-butylphenol is much more potent than most sodium channel blockers in clinical use, it might be of interest in the development of local anaesthetics.

Intravenous Lidocaine Relieves Spinal Cord Injury Pain

Neuropathic pain in spinal cord injury is a common challenging therapeutic condition. The current study examines the analgesic effect of the sodium channel blocker lidocaine on neuropathic pain in patients with spinal cord injury and the predictive role of concomitant evoked pain on pain relief with lidocaine. Twenty-four spinal cord injury patients with neuropathic pain at or below the level of injury were randomized and completed a double-blind crossover trial of 5 mg/kg lidocaine and placebo infused over 30 min. Twelve patients reported evoked pain, and 12 patients had no evoked pain. Spontaneous and evoked pains were assessed using a visual analog scale and quantitative sensory testing. Lidocaine significantly reduced spontaneous pain in all patients (P < 0.01) and in each of the two groups with (P < 0.01) and without (P = 0.048) evoked pain, with no difference in number of responders (pain reduction > or = 33%) between the patients with (n = 6) and without (n = 5) evoked pain. Lidocaine significantly relieved both at-level and below-level neuropathic pain and decreased brush-evoked dysesthesia but not cold allodynia, pinprick hyperalgesia, or pain evoked by repetitive pinprick. Lidocaine reduced neuropathic pain at and below the level of injury irrespective of the presence or absence of evoked pain. Results are consistent with a central-acting effect of sodium channel blockers acting on neuronal hyperexcitability. Agents (such as anticonvulsants or antiarrhythmics) with sodium channel-blocking properties may be a treatment option for spinal cord injury pain.

Effect of sodium channel blocker (mexiletine) on pathological ectopic firing pattern in a rat chronic constriction nerve injury model

We studied the efficacy of mexiletine as a sodium channel blocker for neuropathic pain by investigating the effect of mexiletine on the pathological ectopic firing pattern in a chronic constriction nerve injury (CCI) model. The experiment was conducted with 60 male Wistar rats. The CCI model was created by loosely ligating the sciatic nerve. After breeding 7 days, the frequency and pattern of ectopic firing antidromically recorded from the sural nerve and the amplitude of antidromic sensory nerve-evoked potential were analyzed. The CCI rats were given an intravenous injection of normal saline and mexiletine (5 or 15 mg/kg). Mexiletine significantly suppressed spontaneous firing frequency, an on-off firing pattern that consisted of cyclic bursting spikes and ectopic firing generation under the hypoxic condition. Mexiletine did not influence the amplitude of Α-δ component in the antidromic sensory nerve-evoked potential. Mexiletine suppressed ectopic firing by blocking activity of the abnormal sodium channel at the nerve-injured site and dorsal root ganglion without blocking nerve conduction. This study suggests that mexiletine is useful for treating neuropathic pain in peripheral neuropathy.

Intrathecal tri-cyclic antidepressants produce spinal anesthesia

Tri-cyclic antidepressants (TCAs) have been widely used in treating major depressive disorders. Recent studies further demonstrated that TCAs have potent sodium channel blocking effect, and amitriptyline, one of the TCAs, has a potent spinal anesthetic effect. The aim of the study was to evaluate the spinal anesthetic effect of various TCAs and to see whether these TCAs could likewise act as local anesthetics after a single intrathecal injection. Bupivacaine, a potent and long-acting traditional local anesthetic, acted as control. The spinal anesthetic effect of nine TCAs (amitriptyline, doxepin, imipramine, trimipramine, clomipramine, protriptyline, desipramine, nortriptyline, and amoxapine) and three traditional local anesthetics (bupivacaine, lidocaine, and mepivacaine) was evaluated in rats and so were dose–response studies of amitriptyline, bupivacaine, and lidocaine. Under a given concentration of 5 mM, bupivacaine had the most potent spinal blockade of motor, propioception, and nociception ( P<0.001) and the longest duration of action of nociception ( P<0.01) among the three traditional local anesthetics. Under this concentration, amitriptyline had a similar potency but longer duration of spinal blockade of motor, propioception, and nociception ( P<0.001) than did bupivacaine, whereas several other TCAs had similar or less potencies of spinal blockade than did bupivacaine. In dose–response studies, amitriptyline had a more potent ( P<0.005) and longer duration ( P<0.001) of spinal blockade than did bupivacaine. We concluded that intrathecal amitriptyline had a more potent and longer duration of spinal anesthetic effect than did bupivacaine, whereas several other TCAs had similar or less potencies than did bupivacaine.

Characterization of the anticonvulsant profile of valpromide derivatives

The antiepileptic activity of nine derivatives of valpromide is discussed. They comply with a pharmacophore model that establishes the essential structural and electronic features responsible for the protection against the MES test. The model results from the comparison of 17 structures, using density functional methodologies combined with an active analog approach. The derivatives of valpromide have been tested for anticonvulsant activity in mice. These compounds displayed a phenytoin-like profile, being active in the MES test and inactive in the PTZ test. 4-(Valproylamido)benzenesulfonamide is the most active compound, with an ED 50 of 53 μmol/kg and no neurotoxicity at doses up to 1000 μmol/kg. The pharmacological behavior of the drugs points to a sodium channel blocking effect as one of the associated mechanisms. This mechanism was tested positive for N-ethylvalpromide through its competition with the binding of [ 3H]batrachotoxin-A-20α-benzoate to the voltage-dependent sodium channels from rat brain synaptosomes.

Nonopioid actions of U50,488 enantiomers contribute to their peripheral cutaneous antinociceptive effects.

The ability of arylacetamide kappa-opioid receptor agonists (kappa-ORAs) to block sodium channels by a nonopioid mechanism has been previously documented. The present experiments were undertaken to test whether two enantiomers of the arylacetamide kappa-ORA (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488), (+)-(1R,2R)-U50,488 and (-)-(1S,2S)-U50,488, are antinociceptive in the formalin model by a peripheral, nonopioid receptor-mediated mechanism. Although both enantiomers have been previously shown to block sodium channels with comparable potencies, only (-)-(1S,2S)-U50,488 has activity at the kappa-opioid receptor (KOR). In the formalin test, intrapaw administration of U50,488 enantiomers as well as lidocaine exhibited significant dose-related attenuation of formalin-induced flinching behavior. The rank order of potency of the drugs tested was (-)-(1S,2S)-U50,488 > (+)-(1R,2R)-U50,488 > lidocaine. The antinociception produced by lower doses of (-)-(1S,2S)-U50,488 was blocked by intrapaw nor-binaltorphimine as well as by antisense knockdown of the KOR. Such pretreatments, however, did not block the antinociception produced by (+)-(1R,2R) U50,488, lidocaine, or higher doses of (-)-(1S,2S)-U50,488. These data suggest that the sodium channel blocking effects of U50,488 and similar kappa-ORAs can contribute to their peripheral antinociceptive actions.

The pentapeptide QYNAD does not block voltage-gated sodium channels.

An endogenous pentapeptide (Gln-Tyr-Asn-Ala-Asp; QYNAD) that is present at elevated levels in human CSF from patients with demyelinating diseases has been reported to block voltage-gated sodium channels at low (10 micro M) concentrations. Objective : Because of the potential importance of sodium channel blocking activity in demyelinating disorders, this study attempted to determine the sensitivity to QYNAD of different sodium channel subtypes, including Na(v)1.6, the major sodium channel at nodes of Ranvier, and Na(v)1.2, which is expressed in axons with abnormal myelin. Sodium channel function was assayed using patch-clamp recordings, both in heterologous expression systems and in intact neurons. QYNAD synthesized in 10 different batches by four different facilities failed to block sodium currents, even at concentrations as high as 500 micro M (50-fold higher than the blocking concentration originally reported). QYNAD had no effect on the currents produced by recombinant Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.7 sodium channels or on the sodium currents that are produced by native channels in adult hippocampal or dorsal root ganglion neurons. QYNAD did not interfere with conduction in the optic nerve, a myelinated fiber tract that is often affected in MS. These experiments do not show any sodium channel blocking effect of QYNAD. The conclusion that QYNAD contributes to the pathophysiology of inflammatory neurologic disorders by blocking voltage-gated sodium channels should therefore be viewed with caution.

Transient Brugada-type electrocardiographic abnormalities in renal failure reversed by dialysis

The Brugada syndrome (BRS) is a hereditary cardiac condition (characteristically with a gene mutation affecting sodium channel function) identified by an elevated terminal portion of the QRS complex (prominent J wave) followed by a descending ST-segment elevation ending in a negative T wave in the right precordial leads, and malignant tachyarrhythmias in patients without demonstrable structural heart disease. We report a patient with a previous history of epilepsy treated with psychotropic drugs (with a sodium channel blocking effect) and chronic renal failure on haemodialysis who developed hyperkalaemia (6.6 mmol/l) and ECG findings resembling BRS. This condition was manifested by the prominent J wave, the coved-type ST-segment elevation and the negative T wave in the right precordial leads. These ECG changes disappeared after haemodialysis when the potassium became normal. Subsequently, a flecainide test did not reproduce ST-segment elevation. We conclude that hyperkalaemia associated with cardiac membrane active drugs may cause ECG changes mimicking the Brugada syndrome.

Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole.

Persistent activation of voltage-sensitive Na+ channels is associated with cellular toxicity and may contribute to the degeneration of neural tissue following traumatic brain and spinal cord injury (SCI). Pharmacological blockade of these channels can attenuate secondary pathophysiology and reduce functional deficits acutely. To determine the therapeutic effects of Na+ channel blockers on long-term tissue sparing and functional neurological recovery after traumatic SCI, the authors injected Wistar rats intraperitoneally with riluzole (5 mg/kg), phenytoin (30 mg/kg), CNS5546A, a novel Na+ channel blocker (15 mg/kg), or vehicle (2-HP3CD; 5 mg/kg) 15 minutes after induction of compressive SCI at C7-T1. Functional neurological recovery of coordinated hindlimb function and strength, assessed 1 week postinjury and weekly thereafter for 6 weeks, was significantly enhanced in animals treated with riluzole compared with the other treatment groups. Seven weeks postinjury the preservation of residual tissue and integrity of descending axons were determined with digital morphometrical and fluorescent histochemical analysis. All three Na+ channel blockers significantly enhanced residual tissue area at the injury epicenter compared with control. Riluzole significantly reduced tissue loss in rostrocaudal regions surrounding the epicenter, with overall sparing of gray matter and selective sparing of white matter. Also, counts of red nuclei neurons retrogradely labeled with fluorogold introduced caudal to the injury site were significantly increased in the riluzole group. Systemic Na+ channel blockers, in particular riluzole, can confer significant neuroprotection after in vivo SCI and result in behavioral recovery and sparing of both gray and white matter.

Anisotropic effects of sodium channel blockers on the wavelength for ventricular excitation in dogs.

The purpose of this study was to determine the anisotropic effects of sodium channel blockers on wavelength (WL) and proarrhythmia. In 18 anesthetized, open chest dogs, a 64-electrode array was placed on the left ventricle and the ventricle was constantly paced. Disopyramide, lidocaine or flecainide was intracoronarily administered. Conduction velocity (theta) and activation-recovery interval (ARI) were measured in the longitudinal (L) and transverse (T) directions. Flecainide markedly decreased thetaL, but did not alter thetaT or ARIs in either direction. As a result, the wavelength was significantly shortened only in the L direction. Disopyramide or lidocaine did not show direction-dependent effects on theta or WL. In 3 of 6 dogs with flecainide exposure, ventricular fibrillation (VF) developed. However, no VF occurred with disopyramide or lidocaine. Accordingly, the WL is dependent on the fiber orientation of myocardium. The anisotropic shortening of the WL may explain the character of the proarrhythmia observed with flecainide.

Re-examination of the anticonvulsant and sodium channel blocking effects of propranolol and its two enantiomers

Re-examination of the anticonvulsant and sodium channel blocking effects of propranolol and its two enantiomers

Overdrive prolongation of refractoriness and fatigue in the early stages of human bundle branch disease

Objectives. The aim of this study was to assess the response of refractoriness in normal and diseased human bundle branches to changes in cycle length, as well as during a long period of continuous overdrive pacing.Background. The anterograde refractory period of the bundle branches in patients with functional bundle branch block shortens as the rate is increased. The rate-dependent response of refractoriness in diseased bundle branches is quite different. However, this difference has not been precisely delineated, and its physiologic meaning is uncertain.Methods. Refractoriness of the bundle branches was measured by the extrastimulus technique in 16 patients with tachycardia-dependent bundle branch block and 10 patients with functional bundle branch block, both after basic trains of 8 atrial-paced impulses at different cycle lengths and during a 10-min period of continuous overdrive pacing.Results. The baseline refractory period in the bundle branches of patients with functional bundle branch block measured 430 ±32 ms (mean ± SD) and shortened to 368 ± 30 ms at the shortest cycle length. The maximal effect was reached within the 1st min of overdrive pacing. The baseline refractory period of the bundle branches was significantly longer in patients with tachycardia-dependent bundle branch block (611 ± 184 ms) and demonstrated a cumulative overdrive prolongation in 15 (83%) of 18 studies with typical manifestations of fatigue. In two other studies, this occurred only after ajmaline administration.Conclusions. A rate- and time-dependent prolongation of refractoriness frequently occurs in diseased human bundle branches. When absent, this response may be induced under the effects of sodium channel blockers. This would suggest that an abnormality in the recovery from inactivavion of the sodium channel might underlie the early stages of bundle branch disease.

New antiarrhythmic drugs in pediatric use: propafenone.

Propafenone hydrochloride, a class 1C antiarrhythmic agent, combines sodium channel-blocking effects with beta-blocking capacities and a weak calcium antagonism. The drug exerts marked electrophysiologic effects on accessory atrioventricular pathways. In patients with atrioventricular nodal reentry tachycardia, propafenone is able to block conduction in the fast conducting pathway. In addition, propafenone is very effective in young patients with supraventricular tachycardia based on enhanced abnormal automaticity. In pediatric patients, left ventricular performance remains unimpaired. Proarrhythmic events have been noted in children only occasionally. In accordance with the electrophysiologic profile, intravenous and oral propafenone is an effective agent for treatment of supraventricular tachycardia based on a reentry mechanism and due to abnormal automaticity (i.e., supraventricular tachycardia based on an accessory atrioventricular pathway, atrioventricular nodal reentry tachycardia, junctional ectopic tachycardia, and atrial ectopic tachycardia). In children with ventricular dysrhythmias, efficacy seems to be related to the underlying cardiac diagnosis. Propafenone is well tolerated in the majority of young patients. Incidence of proarrhythmic events seems to be lower with propafenone than with other class 1C agents. However, the risk of these serious adverse events should be taken into account when therapy with propafenone is considered, particularly in patients with structural heart disease.

Propafenone and disopyramide enhance post-ischemic contractile and metabolic recovery of perfused hearts

The effects of sodium channel blockers, propafenone and disopyramide, on post-ischemic contractile dysfunction of perfused rat hearts were examined. Isolated hearts were subjected to 35 min ischemia, followed by 60 min reperfusion with and without administration of either drug during 3 min of pre-ischemia. Ischemia/reperfusion induced complete cardiac dysfunction, rise in left ventricular end-diastolic pressure, increase in perfusion pressure, accumulation of Na + and Ca 2+ and loss of K + and Mg 2+, and release of creatine kinase and purine nucleosides and bases from the heart. These observations suggest that ischemia/reperfusion in the current study induces cardiac cell necrosis or an increase in cell membrane permeability to ions, substrates and macromolecules. Treatment of perfused hearts with either propafenone at concentrations ranging from 5 to 70 μM, or disopyramide at concentrations of 100 μM or higher resulted in a pronounced contractile recovery of the heart, associated with suppression of reperfusion-induced tissue ion alteration and inhibition of reperfusion-induced release of creatine kinase and purine nucleosides and bases. Ischemic insult itself caused tissue Na + accumulation and K + loss without any change in tissue Ca 2+ and Mg 2+. The alterations in the electrolytes were attenuated by treatment with either agent. The results suggest that prevention of ischemia- and reperfusion-induced ionic disturbance of cardiac cells by propafenone and disopyramide plays a role in the improvement of post-ischemic contractile dysfunction.

Reversal of lidocaine effects on sodium currents by isoproterenol in rabbit hearts and heart cells.

We demonstrated recently that isoproterenol enhanced the cardiac voltage-dependent sodium currents (INa) in rabbit ventricular myocytes through dual G-protein regulatory pathways. In this study, we tested the hypothesis that isoproterenol reverses the sodium channel blocking effects of class I antiarrhythmic drugs through modulation of INa. The experiments were performed in rabbit ventricular myocytes using whole-cell patch-clamp techniques. Reversal of lidocaine suppression of INa by isoproterenol (1 microM) was significant at various concentrations of lidocaine (20, 65, and 100 microM, P < 0.05). The effects of isoproterenol were voltage dependent, showing reversal of INa suppression by lidocaine at normal and hyperpolarized potentials (negative to -80 mV) but not at depolarized potentials. Isoproterenol enhanced sodium channel availability but did not alter the steady state activation or inactivation of INa nor did it improve sodium channel recovery in the presence of lidocaine. The physiological significance of the single cell INa findings were corroborated by measurements of conduction velocities using an epicardial mapping system in isolated rabbit hearts. Lidocaine (10 microM) significantly suppressed epicardial impulse conduction in both longitudinal (theta L, 0.430 +/- 0.024 vs. 0.585 +/- 0.001 m/s at baseline, n = 7, P < 0.001) and transverse (theta T, 0.206 +/- 0.012 vs. 0.257 +/- 0.014 m/s at baseline, n = 8, P < 0.001) directions. Isoproterenol (0.05 microM) significantly reversed the lidocaine effects with theta L of 0.503 +/- 0.027 m/s and theta T of 0.234 +/- 0.015 m/s (P = 0.014 and 0.004 compared with the respective lidocaine measurements). These results suggest that enhancement of INa is an important mechanism by which isoproterenol reverses the effects of class I antiarrhythmic drugs.

Anticonvulsant and sodium channel blocking effects of ralitoline in different screening models.

Ralitoline, a thiazolidinone derivative chemically distinct from known antiepileptic drugs, possesses remarkable anticonvulsant properties as demonstrated in various animal models of epilepsy. The efficacy of this compound seems to be comparable or even better than that of conventional antiepileptics. In the present study, the activity of ralitoline was investigated in four seizure models in rodents in order to characterize the anticonvulsant profile of action further. In the maximal electroshock seizure test (mice), this compound showed marked anticonvulsant effects (ED50 2.8 mg/kg i.p.). The efficacy of clinically established anti-epileptics was significantly increased when ralitoline was given as co-medication. In the strychnine seizure test (mice), ralitoline (5 and 10 mg/kg) prolonged the latency of tonic seizures as well as the survival time. On the other hand, in the subcutaneous pentylenetetrazol seizure threshold test (mice), this drug revealed limited protective actions at higher doses and increased the effectiveness of ethosuximide. In unrestrained rats with chronically implanted electrodes, ralitoline (5 mg/kg) significantly reduced the duration of electrically-evoked hippocampal discharges and raised the focal stimulation threshold (10 mg/kg). In the rotorod ataxia test (mice), a TD50 value of 14.5 mg/kg i.p. was determined for ralitoline (protective index TD50/MES-ED50 5.2). With regard to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that ralitoline may act specifically on voltage-sensitive sodium channels. The compound inhibited the fast sodium inward current in a frequency- and voltage-dependent manner. In conclusion, the findings confirm the potent anticonvulsant effects of ralitoline, especially against generalized tonic-clonic and complex partial seizures. Moreover, in combination with antiepileptics, an additive synergism can be found at lower concentrations. Regarding the mode of action, this drug was capable of depressing the fast sodium inward current in cultured heart ventricular cells, suggesting that the local anesthetic properties may be important for the anticonvulsant activity of ralitoline.

Rate-dependent effects of diltiazem on human atrioventricular nodal properties.

Tachycardia enhances the channel-blocking effects of antiarrhythmic drugs. In contrast to the extensive data regarding the rate-dependent effects of sodium channel blockers in humans, little is known about the frequency-dependent effects of calcium channel blockers on human atrioventricular (AV) nodal properties. Accordingly, the purpose of this study was to evaluate the importance of heart rate in modulating the electrophysiological effects of diltiazem in humans. Electrophysiological studies were performed in 25 patients. Sinus node, atrial, and AV nodal function were evaluated at multiple atrial rates under control conditions and after administration of one of three intravenous doses of diltiazem designed to produce low, intermediate, and high stable plasma concentrations (designated doses 1, 2, and 3, respectively). Results were analyzed in terms of the longest and shortest cycle lengths obtainable in each patient under control and drug conditions. Plasma concentrations of diltiazem were stable and averaged 43 +/- 4, 73 +/- 6, and 136 +/- 11 ng/ml for doses 1, 2, and 3, respectively. Sinus node recovery time, intra-atrial conduction time, atrial effective refractory period, and HV interval were unaffected by diltiazem infusion. Effects of diltiazem were limited to changes in AV nodal parameters. Stable, dose-dependent increases in Wenckebach cycle length were observed after all three doses of diltiazem (increases of 54 +/- 13, 84 +/- 18, and 174 +/- 33 msec for doses 1, 2, and 3, respectively). Small nonsignificant increases in AH interval and atrioventricular effective refractory period (AVERP) were observed after dose 1 of diltiazem. At long cycle lengths, diltiazem caused modest increases in AH interval (3 +/- 4 and 25 +/- 8 msec for doses 2 and 3, respectively) and AVERP (36 +/- 12 and 70 +/- 25 msec). Drug effects were far greater at short cycle lengths (45 +/- 17 msec, 58 +/- 12 msec for AH interval and 80 +/- 24 msec, 163 +/- 41 msec for AVERP; p less than 0.05 versus values at long cycle lengths). At rapid rates, effects of diltiazem on AVERP substantially exceeded those on AV conduction, a result that could account for the beneficial effects of diltiazem during paroxysmal AV reentrant tachycardia by decreasing the excitable gap. Depressant effects of diltiazem on human AV nodal function are highly dependent on atrial rate; the rate-dependent actions on AV nodal refractoriness probably contribute to beneficial effects of diltiazem in patients with supraventricular arrhythmias.

Actions of 6- epitetrodotoxin and 11-deoxytetrodotoxin on the frog skeletal muscle fiber

Epitetrodotoxin (6- epiTTX) and 11-deoxytetrodotoxin (11-deoxyTTX), isolated from an Okinawan newt, Cynops ensicauda, were tested for sodium-channel blocking effects on the voltage-clamped frog skeletal muscle fiber. In 6- epiTTX, the C-6 -OH is in an epimeric position; in 11-deoxyTTX, C-11 has a methyl in place of a hydroxymethyl group. At pH 7.25, the ed 50s for reducing I Na are: 4.1 nM (TTX), 96 nM (6- epiTTX), and 445 nM (11-deoxyTTX). In each analogue, the lowered potency can be attributed energetically to the loss of a hydrogen bond. By complementarity, in the sodium-channel receptor for TTX, there must be a hydrogen-acceptor group for the C-6 -OH, and another for the C-11 -OH. Therefore, the TTX molecule is bound to the receptor through an ion-pair (for the guanidinium), and five hydrogen bonds, one each for the -OH on C-9, C-10, C-4, and, as now identified, for C-6 and C-11. Considering the three-dimensional structure of the toxin molecules, these binding sites must be located in a fold or a crevice of the channel protein. If glutamate 387 of rat brain sodium channel II is the ion-pairing site for the guanidinium group, then the carbonyl oxygen of asparagine 388 is the hydrogen acceptor for the C-9 and C-10 -OHs.

Sodium channel blockers in the treatment of ventricular arrhythmias: different effects in the normal, ischaemic or failing heart?

In past decades, numerous experimental and clinical studies have improved our knowledge of the electrophysiological effects of sodium channel blockers, as well as of the mechanisms of arrhythmogenesis. However, the mechanisms of antiarrhythmic as well as potentially proarrhythmic drug action have been less well clarified. Sodium channel blocker agents have different effects on the normal, ischaemic, and failing heart since their antiarrhythmic actions depend on the substrate and the mechanisms of arrhythmogenesis, as well as other mostly interrelated cardiac and non-cardiac factors. Strict criteria of efficacy and safety have to be applied when sodium channel blockers are used for the treatment of ventricular arrhythmias.

Tocainide and Mexiletine

Because currently available antiarrhythmic agents frequently produce side effects and are only moderately effective, a number of new drugs are currently in the late stages of premarketing development and should be available to'the practicing physician within the next year or two. Among these agents are tocainide (released for marketing in November 1984) and mexiletine (soon to be released), both close structural analogues of lidocaine that can be used orally. In fact, the tocainide molecule emerged from a systematic search of lidocaine analogues that might be useful for oral therapy. 1 Mexiletine was originally developed as an anticonvulsant and anorexiant, and when its close structural resemblance to lidocaine was noted, antiarrhythmic studies were performed that showed its activity. 2 In basic electrophysiologic terms, both agents produce local anesthetic (sodium-channel blocking) effects similar to those of lidocaine, 3,4 although subtle differences in the time course of the drug-sodium channel interaction have been reported. 5 Like lidocaine,