Development of insulin resistance by nitrate tolerance in conscious rabbits.

Clinical evidence has been raised to suggest that transdermal nitroglycerin increases the sensitivity of peripheral tissues to the hypoglycemic effect of insulin. In this study we determined whether development of tolerance to the hypotensive effect of nitroglycerin also resulted in tolerance to the insulin-sensitizing effect in rabbits. Intravenous glucose disposal and hyperinsulinemic euglycemic glucose clamp studies were performed on naive and hemodynamic nitrate tolerant conscious New Zealand white rabbits.

BGP-15, a hydroximic acid derivative, protects against cisplatin- or taxol-induced peripheral neuropathy in rats.

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.

BGP-15 - a novel poly(ADP-ribose) polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor activity.

Nephrotoxicity is one of the major dose limiting side effects of cisplatin chemotherapy. The antitumor and toxic effects are mediated in part by different mechanisms, thus, permitting a selective inhibition of certain side effects. The influence of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) - a poly(ADP-ribose) polymerase (PARP) inhibitor - on the nephrotoxicity and antitumor efficacy of cisplatin has been evaluated in experimental models.

Reduction of acute photodamage in skin by topical application of a novel PARP inhibitor.

The ultraviolet (UV) components of sunlight induce damage to the DNA in skin cells, which is considered to be the initiating step in the harmful biological effects of UV radiation. Repair of DNA damage results in the formation of single-strand DNA breaks, which activate the nuclear poly(ADP-ribose) polymerase (PARP). Overactivation of PARP worsens the oxidative cell damage and impairs the energy metabolism, raising the possibility that moderation of PARP activation following DNA damage may protect skin cells from UV radiation.

Impaired bronchomotor responses to field stimulation in guinea-pigs with cisplatin-induced neuropathy.

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.

Synthesis and hypotensive activity of some heterocyclic analogues of GYKI-12 743.

[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.

Restacorin, a new antiarrhythmic drug: a review of its electrophysiologic and hemodynamic properties.

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.

GYKI-12743 a new postsynaptic vascular alpha-adrenoceptor antagonist.

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.

Concentration- and rate-dependent electrophysiological effects of restacorin on isolated canine Purkinje fibres.

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 role of coronary alpha 1-adrenoceptors of the dog heart in dopamine-induced cardiostimulation evidenced by treatment with prazosin.

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.

Dopamine-induced coronary effects in the dog heart attributed to beta- and alpha-adrenergic mechanisms.

Open chest anesthetized dogs were given dopamine (DA) in intravenous (i.v., 2-16 micrograms.

Frequency-dependent effects of class I, III and IV antiarrhythmic drugs on the conduction and excitability in rabbit ventricular muscle.

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.

Electrophysiological effects of GYKI-23 107, a new antiarrhythmic compound, in isolated rabbit and canine cardiac preparations.

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.

Antifibrillatory effect of GYKI-23107 in induced ventricular vulnerability by local cooling and programmed stimulation in canine models.

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.

Electrophysiological effects of the antiarrhythmic agent GYKI-23107 in dogs.

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.

Experimental oral anticoagulation by a directly acting thrombin inhibitor (RGH-2958).

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.

Use-dependent blockade of sodium channels induced by bencyclane in frog skeletal muscle and canine cardiac Purkinje fiber.

Applying conventional microelectrode technique, the effect of bencyclane was studied on the maximal rate of rise (Vmax) of the transmembrane action potential in frog skeletal muscle and canine cardiac Purkinje fiber. Bencyclane (10 microM) decreased the Vmax from 333.7 +/- 6.

Synthesis of thiazole derivatives with positive inotropic effect.

Thiazole derivatives with potential positive inotropic effect were synthesized. The highest activity (medium positive inotropic effect) was exhibited by ethyl 2-(2-hydroxyethylamino)-4-phenylthiazole-5-carboxylate (3b) of which several derivatives have been prepared. Among these derivatives only those which could presumably easily removed in the living organism to give 3b exhibited a medium positive inotropic effect (6, 8b).