Effects of ATP-dependent K+ channel modulators on an ischemia-reperfusion rabbit isolated heart model with programmed electrical stimulation.

The effects of glibenclamide and BRL-38227 were studied in isolated rabbit hearts subjected to ischemia and programmed electrical stimulation. Coronary artery occlusion over 24 min decreased the ventricular effective refractory period in the ischemic zone. BRL-38227 (0.1 microM) showed significant coronary vasodilator effects, but failed to modify the ventricular effective refractory period under these conditions. A higher concentration (5 microM) of BRL-38227 potentiated the ischemia induced ventricular effective refractory period shortening effects. Glibenclamide (0.1 and 1 microM) delayed the onset of the ischemia-induced ventricular effective refractory period shortening. Glibenclamide (1 microM) inhibited the potentiated ventricular effective refractory period shortening effects of BRL-38227 (5 microM) during ischemia, but failed to antagonise the coronary vasodilator effects of BRL-38227 (5 microM). A higher incidence of ventricular fibrillation was inducible when an extra beat was applied in the ischemic zone through programmed electrical stimulation. The incidence of programmed electrical stimulation induced ventricular fibrillation was increased by BRL-38227 (5 microM) and antagonised by glibenclamide (1 microM). The results suggest that high concentrations of KATP-activators can accentuate ischemia-induced decreases in refractory period and increase the susceptibility of hearts to ventricular fibrillation when an extra beat is applied to the ischemic myocardium. These effects did not occur at lower coronary vasodilating concentrations of BRL-38227.

An in vitro method for the evaluation of antiarrhythmic and antiischemic agents by using programmed electrical stimulation of rabbit heart.

A new model using isolated rabbit hearts perfused at constant flow in the Langendorff mode with the sinus node destroyed and under constant (2 Hz) pacing is described. Ventricular ischemia (24 min) was induced by ligation of the left ventricular branch of the coronary artery (LVB), followed by reperfusion (15 min). The programmed electrical stimulation (PES) technique was used to induce arrhythmias in the ischemic zone (IZ). Three agents with different mechanisms of action were tested to validate this model: dl-sotalol (10(-6) and 10(-5) M), oxfenicine (10(-6) M), and lidocaine (10(-5) M). These compounds were administered 15 min before the ligature and maintained until the end of the experiment. Ventricular effective refractory period (VERP), PES-induced ventricular fibrillation (VF), and coronary perfusion pressure (CPP) were monitored. PES-induced VF was only observed in ischemic tissue. Sotalol slightly reduced VF incidence only during reperfusion. Oxfenicine prevented PES-induced VF during the ischemia, but not during reperfusion, while lidocaine prevented VF during ischemia and throughout the reperfusion period. In conclusion, the rabbit heart model where PES is applied to normal and ischemic myocardium, appears useful to discern different mechanisms involved in ventricular arrhythmias. In addition, this model is considerably cheaper than equivalent dog models.

Animal pharmacology of the selective histamine H1-receptor antagonist tazifylline.

3,7-Dihydro-7-[2-hydroxy-3-[4-[3-(phenylthio) propyl]-1-piperazinyl]propyl]-1,3-dimethyl-1H-purine-2,6-dione dihydrochloride (tazifylline, RS-49014) potently inhibited contractions evoked by stimulation of histamine H1-receptors in isolated guinea pig ilea and exhibited high affinity for these receptors in radioligand binding studies in vitro. In rats, guinea pigs and dogs the antihistaminic effect of tazifylline was rapid in onset and long-lived. In anesthetized guinea pigs, tazifylline markedly inhibited histamine-induced bronchoconstriction and protected conscious animals from the lethal effect of large doses of the amine. In conscious rats, tazifylline was more potent in reducing the inflammatory effects of intradermal histamine than that evoked by anaphylactic reaction. In conscious dogs, orally administered tazifylline inhibited histamine-induced skin inflammation for long periods of time and in anesthetized animals attenuated that portion of the histamine-evoked hypotension attributable to stimulation of H1-receptors. Results obtained from a variety of in vitro and in vivo experimental preparations showed that tazifylline had much lower affinity for histamine H2-receptors, alpha- and beta-adrenoceptors, 5-hydroxytryptamine and muscarinic receptor subtypes. Tazifylline poorly inhibited the release of histamine from rat peritoneal mast cells. Large oral doses of tazifylline did not reduce spontaneous locomotor activity in mice, nor did they produce overt symptoms of behavioral depression in conscious rats. Therefore, tazifylline is a potent, selective and long-acting histamine H1-receptor antagonist that does not appear to produce central depression in animals.

New antihistaminic theophylline or theobromine derivatives.

A series of 3,4-dihydro-1,3-dimethyl-7-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones and 3,7-dihydro-3,7-dimethyl-1-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones was synthesized and evaluated for antihistaminic activity. Some of them displayed good inhibition of both histamine-induced bronchospasm in the anesthetized guinea pig at 10 micrograms/kg by the intravenous route and of passive cutaneous anaphylaxis in the rat at 10 mg/kg by the oral route. Comparison of the two most active compounds revealed a higher antihistaminic activity with the compounds containing a (phenylthio)propyl group (1 and 2) as compared with that containing a phenoxy group. Compound 2 [RS-49014, 3,4-dihydro-1,3-dimethyl-7-[3-[4-[3-(phenylthio)propyl]piperazin-1 -yl]- 2-hydroxypropyl]-1H-purine-2,6-dione] was selected for clinical trials on the basis of a comparative pharmacological study with chlorpheniramine, ketotifen, promethazine, and theophylline.

[Modification of the kinetics of healing after iterative exeresis in the rat. Action of a triterpenoid and its derivatives on the duration of healing]. / Modification de la cinétique de cicatrisation après exérèses itératives chez le rat. Action d'un triterpénoïde et de ses dérivés sur les délais de cicatrisation.

The authors have studied the action of Titrated Extract of Centella asiatica (TECA) on the duration off healing of iterative wounds in the Rat. After repeated exeresis, the planimetric quantification of the wounds, by episcopic projection, shows that the healing process involves an immediate phase of dilatation followed by another of contraction. A mathematical analysis has permitted determination of times of semi-healing and has shown that these are significantly lengthened after several exeresis in the control group. When administered by oral route, at a 100 mg/kg dosing, TECA shortens significantly this lengthening of time, acting more specifically on the immediate process of healing.

[Stomach ulcers in rats. New experimental model and protection by a triterpene healing agent]. / Ulcérations gastriques chez le rat. Nouveau modèle expérimental et essai de protection par un cicatrisant triterpénique.

An experimental model using restricted diet and exposure to cold for several weeks was devised. Following a two-week treatment with a triterpen healing agent, the rate of ulcerative lesion was significantly decreased.