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The neuroprotective effect of BGP-15 against peripheral sensory neuropathy was studied in rats that were exposed to short-term cisplatin or taxol administration. The changes of nerve conduction velocity were determined in situ after treating the Wistar rats with BGP-15 (50, 100, and 200 mg/kg po daily doses throughout the experiment), cisplatin (1.5 mg/kg ip daily dose for 5 days), or taxol (5.0 mg/kg ip daily dose every other day in a 10-day interval) alone or giving the test compound in combination with cisplatin or taxol. Electrophysiological recordings were carried out in vivo by stimulating the sciatic nerve at both sciatic notch and ankle site. Neither motor nor sensory nerve conduction velocity was altered by any dose level of BGP-15 tested. Both anticancer drugs decreased the sensory nerve conduction velocity (SNCV). BGP-15 treatment prevented the impairment of SNCV either in part or totally in the cisplatin- or taxol-treated groups. This neuroprotective potential of BGP-15 could be well correlated with its recently described poly(ADP-ribose) polymerase- inhibitory effect and its ability to protect against the damages induced by the increased level of reactive oxygen species in response to anticancer treatment.

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Pre-treatment with cisplatin (3 mg/kg) i.p. once a day over 6 days induced sensory neuropathy as confirmed by femoral nerve conduction velocity test and significantly decreased contractions induced by electrical field stimulation (100 stimuli, 20 V, 0.1 ms, 20 Hz) in isolated main bronchial rings from guinea-pigs. The field stimulation-induced non-adrenergic, non-cholinergic (NANC) relaxations, however, were amplified in rings from animals with cisplatin neuropathy. The NANC relaxation response was completely blocked by 30 microM N(G)-nitro-L-arginine methyl ester in preparations from both control and cisplatin-treated animals. Superoxide dismutase (40 units/ml) was without effect on NANC relaxation in control rings, however, it substantially decreased NANC relaxation in preparations from animals with cisplatin neuropathy. These results show that cisplatin-induced sensory neuropathy is accompanied by attenuation of neural bronchoconstriction and an enhanced NANC relaxation. The latter is in part attained by an increased peripheral superoxide production.

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[1,4]Benzodioxanylmethyl-, [1,4]benzodioxanylmethylaminopropyl- and phenoxyethylaminoethyl-substituted lactams were synthesised and their hypotensive activity was investigated. Some of these compounds show moderate to high hypotensive effect, but they had more toxic and/or side effects than GYKI-12 743.

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Restacorin is a recently developed effective antiarrhythmic agent with primarily class Ic properties. The present paper reviews the electrophysiologic and hemodynamic effects of this compound. The major electrophysiologic effects are a depression of Vmax and an increase in AH, HV and QRS duration. The administration of restacorin does not induce significant side effects. In subjects with a normal left ventricular function, restacorin does not show negative inotropic effects. However, in patients with a decreased left ventricular function, restocorin produces a moderate negative inotropic effect.

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Using the pithed rat preparation it has been proven that GYKI-12743 exerted its alpha-adrenergic blocking action only at the postsynaptic vascular level in the cardiovascular system. This new molecule failed to antagonize the presynaptic alpha 2-adrenoceptors of the cardiac sympathetic nerve endings. Thereby it was possible to demonstrate the first vasoselective postsynaptic adrenoceptor antagonist which potentially might be interesting in the cardiovascular therapy.

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The cellular electrophysiological effects of restacorin, a new antiarrhythmic agent were studied using conventional microelectrode techniques in isolated dog cardiac Purkinje fibres. Restacorin (1-30 mumol/l) decreased the maximum rate of rise of the action potential upstroke and action potential amplitude while action potential duration measured at 90% of repolarization was shortened in a concentration-dependent manner during pacing at a constant basic cycle length of 500 ms. The effect of 10 mumol/l restacorin on maximal rate of rise of the action potential upstroke and on action potential duration measured at 90% of repolarization were also studied while varying the constant pacing cycle length between 300 and 5000 ms. The results of these studies indicated a rate-dependent effect of restacorin on the action potential characteristics examined. After abrupt changes in cycle length, 10 mumol/l restacorin slowed the fast component of the relation for restitution of action potential duration from 155.3 +/- 5.2 ms (control, n = 6) to 217.1 +/- 17.8 ms (n = 6, P less than 0.05). In the presence of restacorin (10 mumol/l), a second slow component for recovery of maximal action potential upstroke rising velocity was expressed having a time constants of 8.5 +/- 1.2 s. The range of premature action potential durations was significantly decreased (by 57.1%, P less than 0.01) by 10 mumol/l restacorin. These results indicate that the cellular electrophysiological effects produced by restacorin in dog cardiac Purkinje fibres best resemble those produced by recognized class Ic antiarrhythmic drugs.

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To assess the participation of postjunctional coronary alpha 1-adrenoceptors in the dopamine-induced general circulatory stimulation, pentobarbital-anesthetized open chest dogs were infused with the agent (1-16 micrograms.kg-1.min-1 i.v.) before and after the administration of the alpha 1-selective adrenergic antagonist prazosin (0.15 mg.kg-1). Coronary responses were characterized by the changes of blood flow (electromagnetic flowmeter) and those of calculated vascular conductance. Left ventricular contractile force was measured with a strain gauge arch. In the control state, whereas coronary blood flow increased simultaneously with the dose-dependent hypertensive effect of dopamine, the calculated augmentation of coronary vascular conductance was relatively slight (maximum: greater than or equal to 50%) compared to the very great increase of cardiac inotropism (up to greater than or equal to 250%) and myocardial O2 consumption (up to greater than or equal to 250%). After blocking the alpha 1-adrenoceptors, in spite of the elimination of the hypertensive effect, the inotropic and blood flow actions of dopamine remained unaltered and the calculated value of vascular conductance indicated an enhanced vasodilation (up to 200%). The alpha 2-blocker yohimbine (0.5 mg.kg-1) failed to elicit actions of similar magnitude. It was concluded that postjunctional alpha-adrenoceptor-dependent coronary vasoconstrictor influences compete with metabolically coupled vasodilation during the cardiostimulatory action of dopamine.

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Open chest anesthetized dogs were given dopamine (DA) in intravenous (i.v., 2-16 micrograms.kg-1.min-1) and intracoronary (i.c., 10-40 micrograms.min-1) infusions. The drug effect was analyzed using the nonselective beta-adrenoceptor antagonist oxprenolol (0.5 mg.kg, i.v.) and the nonselective alpha-adrenoceptor antagonist phentolamine (1.0 mg.kg-1, i.v.). Coronary blood flow (CBF, electromagnetic flowmeter), arterial pressure and left ventricular contractile force (strain gauge) were measured. Coronary vascular responses were characterized by changes of CBF and calculated coronary vascular resistance (CVR). In the control state, DA-induced arterial hypertension (i.v. administration) and augmented inotropism (i.v. and i.c. administration) were accompanied by a dose-dependent coronary vasodilatation (increase of CBF and decrease of CVR). Oxprenolol converted coronary vasodilatation to vasoconstriction during DA infusions and blocked the inotropic action; the hypertensive DA effect remained unaffected. Similar alterations were observed after a transitory (45 min) regional myocardial ischemia, elicited by coronary occlusion. On the other hand, phentolamine-pretreatment potentiated the DA-induced coronary vasodilatation and converted hypertension to hypotension; the inotropic component of the DA action was not affected. After combined beta- and alpha-blockade, DA failed to increase CBF and decrease CVR during the infusion periods. Instead, the drug elicited a very slight coronary vasoconstriction. I.c. (but not i.v.) infusions of DA were regularly followed by a rebound-like, transient CBF increase, even after combined beta- and alpha-blockade. These results show that all of the multifactorial determinants of the direct, steady state coronary effects of DA can be ascribed to alpha- and beta-adrenoceptor stimulation, whereas the hypothetical dopaminergic coronary vascular receptors do not seem to play a decisive role in these responses. However, undefined after-effects provoked by i.c. DA, may be connected with specific dopaminergic effects.

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The frequency-dependent effect of 11 antiarrhythmic drugs on the impulse conduction time and excitability threshold was studied in isolated rabbit right ventricular muscle. Before drug application, conduction time and excitability threshold were independent of the stimulation cycle length (200-2000 msec). Quinidine, tocainide, lidocaine, disopyramide, procainamide, flecainide, lorcainide and mexiletine increased conduction time and excitability threshold in a frequency-dependent manner (use-dependency) while verapamil, clofilium and bretylium did not significantly alter conduction and excitability at any applied stimulation frequency. It was concluded that the use-dependent effect which was described earlier with most Class I antiarrhythmic drugs on the rate of rise of the action potential can be also demonstrated in extracellular electrophysiological experiments and this must be considered during routine pharmacological screenings.

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The cellular cardiac electrophysiological effects of GYKI-23 107 (1-/2,6-dimethylamino/-2-dimethylaminopropane dihydrochloride), a new investigational antiarrhythmic drug, were studied in rabbit and canine ventricular muscle and Purkinje fibers. For comparison, mexiletine was used. GYKI-23 107, like mexiletine, did not affect the resting membrane potential and slightly reduced the action potential amplitude in both fiber types. The time for repolarization was shortened, but the ratio of effective refractory period to action potential duration was increased by both drugs. The maximum rate of depolarization (Vmax) was depressed by the drugs in a frequency-dependent ("use-dependent") manner. GYKI-23 107 slowed the recovery kinetics of Vmax in the canine ventricular muscle (Tc = 229.9 +/- 5.6 ms; n = 7) and Purkinje fiber (Tc = 149.6 +/- 33.8 ms; n = 7) in the same way as mexiletine. The kinetics of restitution of action potential duration during premature and postmature stimulation were slowed to similar degrees in the presence of both GYKI-23 107 and mexiletine in canine Purkinje fibers. It is concluded that, on the basis of its cardiac cellular electrophysiological effects, GYKI-23 107 can be categorized as a class Ib antiarrhythmic agent.

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Cardiac electrophysiological properties of GYKI-23107, a new membrane stabilizing antiarrhythmic agent were studied in anaesthetized open-chest dogs. Epi- end endocardial electrograms (for sinus potential and for His bundle recording) were obtained during sinus rhythm and following atrial and ventricular pacing. The registration were performed under control conditions as well as five minutes after drug administration of 8 mg/kg slow i.v. or 20 minutes after 20 mg/kg intraduodenal administration respectively. GYKI-23107 did not influence significantly either the sinus cycles, PA-intervals, sinus node potentials, or the classical electrophysiological parameters of sinoatrial function as the corrected recovery time of the sinus node, sino-atrial conduction time or the secondary post-stimulation sinus cycles before and after vegetative blockade. Neither the AH intervals, anterograde Wenckebach period, nor ventriculo-atrial conduction time changed significantly. QRS duration, configuration and HV-intervals remained also unchanged after drug administration in doses which used in this study, and which seemed to be in therapeutic range. The agent did not influence significantly the effective refractory periods of the atrium and ventricle during sinus rhythm. This study suggest that the GYKI-23107 is not depressive on the anterograde (AV), retrograde (VA), intraventricular conduction and is slightly depressive on the intrinsic pacemaker properties.

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We tested GYKI-23107 a new agent with local anaesthetic activity, in experimentally induced life-threatening ventricular arrhythmias in pentobarbitone-anaesthetized dogs. By a cooling test and programmed stimulation ventricular fibrillation was induced before and after drug administration (8 mg/kg i.v., n = 14 and 20 mg/kg i.d., n = 12). Comparative experiments were carried out with lidocaine (10 mg/kg). In this lidocaine-treated group, ventricular fibrillation could be produced at 27.7 +/- 6.6 (S.D.) min, n = 12, while after GYKI-23107 ventricular fibrillation occurred at 46.6 +/- 10.7 min, n = 14. The new compound was well absorbed from the intestines; after i.d. administration it could prevent or reduce the onset of lethal arrhythmia for more than 40 min. Its i.d. efficacy correlated well with that of i.v. administration. GYKI-23107 appears to be a safe and potent long-acting agent against ventricular dysrhythmias. It may be a promising and valuable alternative to currently available antiarrhythmic agents. The strong antifibrillatory action observed in ischaemic canine heart (n = 5) both after i.v. or i.d. administration is of special importance.

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D-Phenylalanyl-L-prolyl-L-arginine aldehyde sulfate (RGH-2958), a directly acting synthetic thrombin inhibitor proved to be effective by experimental oral application. The rapid onset of its action has a special importance both from theoretical and practical point of view. Its antiplatelet effect relates to thrombin induced PA and runs parallel with the anticoagulant effect. RGH-2958 significantly reduced the thrombus weight in an experimental thrombosis model in rabbits. In the light of the therapeutic indices of the compound there is a real possibility to open a third way in the prevention and therapy of thrombosis.

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