[Studying the effect of the new beta-adrenoreceptor blocker proxodolol on the ischemic model of cardiac insufficiency].

The effects of proxodolol--new beta-blocker with alpha-blocking activity--on system hemodynamics, heart function and morphology of rats with ischemia-induced congestive heart failure were studied and compared with those of carvedilol. It was shown that both drugs administered during 3 weeks after ligation of coronary artery inhibit heart remodeling and development of myocardial hypertrophy. Proxodolol was more effective than carvedilol in prevention of heart dysfunctions typical for congestive heart failure, that was especially evident during the pharmacological overload tests.

[The creation of original Russian beta-adrenoblockers]. / Sozdanie otechestvennykh original'nykh beta-adrenoblokatorov.

Results of search for new beta-adrenoreceptor blocking agents of different effects are summarized. Derivatives of 4-hydroxyindolyl-3-acetic acid are characterized by a prolonged beta-adrenoblocking effect, cardioselective beta-adrenoblockers were found among derivatives of N,N-bis(2-hydroxy-3-phenoxypropanol)amine, and highly effective "hybrid" beta-,a-adrenoblockers were detected among derivatives of 3(5)-phenoxymethylisoxazolines and 5-phenoxymethyl-1,2,4,-oxadiasoles. Clinical studies of one of the most promising compounds of the latter series named proxodolol showed it to be a highly effective antihypertensive, antianginal, and antiglaucoma drug. Proxodolol is permitted for clinical application. At present it is manufactured as eye drops for decreasing intraocular pressure in glaucoma; its production as a solution for injections for arresting hypertensive crises is starting.

[The first original Russian class-III antiarrhythmic nibentan]. / Pervyi original'nyi otechestvennyi antiaritmik III klassa nibentan.

The paper presents experimental and clinical findings of the new antiarrhythmic drug nibentan. The agent was found to be a class-III antiarrhythmic agent in terms of its electrophysiological effects and an inhibitor of the delayed rectifier potassium current in terms of its effects on the ionic channels of cardiomyocytes. The clinical trial of nibentan shows that the drug is highly effective (in 70-100% of cases) in patients with atrial flutter and fibrillation and in those with supraventricular tachycardia and it is less effective in suppressing ventricular premature contractions and tachycardia. The rate of arrhythmogenic effects produced by the drug was inversely related to its antiarrhythmic action. Nibentan has been approved for clinical use.

[Proxodolol, a new domestic preparation for lowering intraocular pressure in glaucoma]. / Proksodolol--novyi otechestvennyi preparat dlia snizheniia vnutriglaznogo davleniia pri glaukome.

Effects of a Russian b-a-adrenoblocker proxodolol on the intraocular pressure, ocular hemodynamics, pupil diameter, ocular functions, arterial pressure, and heart rate were studied in 105 patients (163 eyes) with primary open-angle glaucoma. A manifest hypotensive effect of proxodolol was due to depression of aqueous humor production and improvement of its outflow. Comparative study of the efficacies of proxodolol and timolol maleate by the blind test and randomization demonstrated the identity of these drugs. A synergic effect on intraocular pressure was observed when proxodolol was combined with pilocarpine and/or klofelin.

[A search for new beta-adrenoblockaders in the series of 5-phenoxymethyl-1,2,4-oxadiazole derivatives]. / Poisk novykh beta-adrenoblokatorov v riade proizvodnykh 5-fenoksimetil-1,2,4-oksadiazola.

The experiments on anesthesized rats have revealed that some derivatives of (3-amino-2-hydroxypropoxy)phenomethyl-1,2,4-oxadiazole with the oxadiazole cycle at the o-position of the aromatic ring possess a significant beta-adrenoceptor blocking activity associated with alpha-adrenoceptor blocking properties. The most potent compound is 3-methyl-5-[2-(3-tret.butylamino-2-hydroxypropoxy) phenoxymethyl]-1,2,4-oxadiazole (Compound 1, prodolol) which is superior to propranolol, oxprenolol, and particularly labetalol in its beta-adrenoceptor blocking activity. The agent does not greatly differ from labetalol in its alpha-adrenoblocking activity. Proxodolol has been chosen for preclinical and clinical studies.

[The effect of proxodolol on systemic and regional hemodynamics]. / Vliianie proksodolola na sistemnuiu i regionarnuiu gemodinamiku.

The effect of the new hybrid (beta-, alpha-) adrenoceptor blocking drug proxodolol on cardiac output and its distribution between 16 vascular regions, by using the microsphere method on anesthesized normotensive rats and rats with persistent renovascular hypertension. Proxodolol given in beta-adreno-blocking doses similar to those of labetalol was shown to exert vasodilating effects in normotensive rats. Renal, adrenal, splenic, and skeletal muscle vessels were most sensitive to labetalol, whereas cardiac and pulmonary vessels were responsive to proxodolol. In rats with persistent renovascular hypertension, proxodolol had a vasodilating effect only when it was used in doses inducing alpha-adrenoceptor blockade.

[Proxodolol--a new beta- and alpha-adrenoblockader]. / Proksodolol--novyi (beta-, al'fa-)adrenoblokator.

The beta- and alpha-adrenoceptor blocking activity, the specificity of its beta-adrenoceptor blocking action, partial agonistic and membrane-stabilizing properties, as well as antihypertensive, antiarrhythmic, and anti-ischemic effects were studied. Proxodolol was shown to be superior to labetalol in its beta-adrenoceptor blocking action and similar to it in its alpha-adrenoceptor blocking agent. The drug has no a partial agonistic activity and produces a moderate membrane-stabilizing action. Proxodolol proved to be effective in treating experimental hypertension and arrhythmias. It exhibits anti-ischemic activity.

[Search for new beta-adrenoblockaders among derivatives of (3-amino-2-hydroxypropoxy) phenoxymethyl isoxazole]. / Poiski novykh beta-adrenoblokatorov v riadu proizvodnykh (3-amino-2-oksipropoksi) fenoksimetilizoksazola.

In experiments on anesthetized rats it was found that some derivatives of 2-(3-isopropylamino-2-hydroxypropoxy) phenoxymethyl isoxazole possess marked beta-adrenoblocking activity associated with alpha-adrenoblocking properties. The most active compound is 3-methyl-4-chloro-5-(3-isopropylamino-2-hydroxypropoxy) phenoxymethyl isoxazole hydrochloride (compound II) which by its beta-adrenoblocking activity is superior to propranolol, oxprenolol and especially labetalol. By its alpha-adrenoblocking activity the compound does not differ significantly from labetalol but it is inferior to phentolamine. Compound II has partial agonistic activity, exerts nonspecific membrane-stabilizing action and exhibits antifibrillatory and antiarrhythmic activity.

[Beta-adrenoblocking activity and other pharmacological properties of 2-(3-amino-2-hydroxypropoxy)phenyoxymethyl isoxazole derivatives]. / Beta-adrenoblokiruiushchaia aktivnost' i drugie farmakologicheskie svoistva proizvodnykh 2-(3-amino-2-oksipropoksi)fenoksimetilizoksazola.

Some derivatives of 2-(3-amino-2-hydroxypropoxy)phenoxymethyl isoxazole possess beta- and alpha-adrenoblocking activity. 3-Methyl-4-chlor-5-(3-isopropylamino-2-hydroxypropoxy)phenoxymethyl isoxazole hydrochloride (compound OF-4452) is the most active of the compounds studied. As to the beta-adrenoblocking activity, this compound given in vivo and in vitro compares very favourably with propranolol, oxprenolol and labetalol, in particular; as regards the alpha-adrenoblocking action, it is not inferior to the latter drug. Compound OF-4452 has a partial agonist activity and nonspecific membrane-stabilizing action. It displays antifibrillatory and antiarrhythmic activity as well.

[Role of transmembrane ion currents in the mechanism of action of beta-adrenoblockers]. / Issledovanie roli transmembrannykh ionnykh tokov v mekhanizme deistviia beta-adrenoblokatorov.

The effects of propranolol, oxprenolol, pindolol, labetalol, and atenolol on the isoproterenol-stimulated slow calcium current as well as on spontaneous slow calcium and fast sodium currents were studied in frog trabeculae by the double sucrose bridge technique. Administration of beta-adrenoblockers in low doses (10(-7)-10(-6)M) antagonized the stimulatory effect of isoproterenol on the slow calcium current (pindolol greater than oxprenolol greater than or equal to propranolol = labetalol greater than atenolol). When administered in high doses (2 X 10(-6)-10(-4)M) the beta-adrenoblockers reduced the slow calcium current. Meanwhile, some of them (propranolol, oxprenolol, labetalol) suppressed the fast sodium current.

[Effect of the beta-adrenoblockader atenolol on the extent of myocardial necrosis in transient and permanent coronary occlusion]. / Vliianie beta-adrenoblokatora atenolola na razmery nekroza miokarda pri tranzitornoi i postoiannoi koronarnoi okkliuzii.

It has been demonstrated in experiments on rats that atenolol in a dose of 10 mg/kg exerts an antiischemic action in transitory coronary occlusion lasting 30 minutes followed by reperfusion for 23h and 30 min. The effect manifested in the diminution of the relative area and mass of myocardial necrosis zone and in the dilatation of the left ventricle. Atenolol also produced an antiischemic action in permanent coronary occlusion for 24 h. However, the effect in the latter case was less marked than in transitory occlusion. When injected for permanent occlusion, atenolol (10 mg/kg i. v.) led to a 1.59-fold decrease in the necrosis area and a 2.1-fold decrease (p less than 0.001) when administered for transitory occlusion. The mass of the myocardial necrosis zone also dropped (by 1.65-fold and 2.3-fold, respectively), whereas the degree of dilatation by 2.1- and 2.3-fold, respectively.

[Effect of atenolol and propranolol on systemic and regional hemodynamics]. / Vliianie atenolola i propranolola na sistemnuiu i regionarnuiu gemodinamiku.

Experiments on anesthetized rats were made to study the effects of atenolol and propranolol on cardiac output and distribution of the drugs in the heart, lungs, brain, kidneys, large and small intestines, stomach, liver and skeletal muscles with the use of radioactive carbonized microspheres techniques. Atenolol and propranolol provoked a decrease in cardiac output and raised the total peripheral resistance without a detectable effect on blood pressure. Administration of atenolol brought about a decrease in the renal blood flow whereas that of propranolol in the myocardial blood flow.

[Effect of beta-adrenoblockaders on the smooth muscles of the trachea and bronchi]. / Vliianie beta-adrenoblokatorov na gladkie myshtsy trakhei i bronkhov.

It has been shown in experiments on anesthetized guinea-pigs that (+/-) and (+) propranolol produced a dose-dependent increase in the resistance of the air ways. Meanwhile oxprenolol, trimepranol and atenolol had a poor bronchoconstrictor effect, and labetalol evoked no changes in the tone of the bronchi. On an isolated trachea of the guinea-pig both forms of propranolol, as well as trimepranol and oxprenolol produced contractions, atenolol did not cause any changes in the tone of the smooth muscles, while labetalol made the smooth muscles relax. It has been also demonstrated on an isolated trachea that pretreatment with atropine, diphenhydramine, and diethylamide of lysergic acid did not lead to any noticeable changes in the bronchoconstrictive action of propranolol. At the same time verapamil and Ca2+-free Krebs solution reversed the propranolol effect.

[Effect of reserpine, octadine and methyldopa on the distribution of cardiac output in hypertension]. / O vliianii rezerpina, oktadina i metil-dofa na raspredelenie serdechnogo vybrosa v usloviiakh gipertonii.

Tests conducted on anesthetized rats with experimental renal hypertension demonstrated that octadine, reserpine and methyl-DOPA with their one-time administration produce at the onset of the maximal hypotensine effect of fall of the arterial pressure at the expense of the lowered total peripheral resistance. Most characteristic of the action exercised by these drugs is an increased fraction of the cardiac ejection going to the gestro-intestinal tract. In hypertension all the substances under study reduce the coronary and splenic fractions of the cardiac ejection. Reserpine and methyl-DOPA do not change, while octadine reduces the fraction of the cardiac ejection that goes to the kidney.

[Influence of octadine, reserpine and methyl-dopa on the hemodynamic system]. / O vliianii oktadina, rezerpina i metil dofa na sistemnuiu gemodinamiku

In experiments set up on rats the influence of octadine (sanotensin), reserpine and methyl-dopa on the basic characteristics of the systemic hemodynamics in persistent renovascular hypertension was studied. The nature of the influence exerted by the above drugs on the systemic hemodynamics of hypertensive rats is shown to depend upon the duration of their action on the organism. The hypotensive effect manifests itself first by reduced cardiac ejection and then by a fall of the total peripheral resistance. It is presumed that the disappearance of the inhibitory action of octadine, reserpine and methyl-dopa on the cardiac ejection is related to the development of a compensatory reaction aimed at maintaining the needed level of the blood supply to the organs and tissues--i. e. at "systemic autoregulation".