The influence of adrenoreactive preparations on clinical and haemodynamic parameters in patients with ischaemic heart disease.

The influence of anaprilin, oxprenolol, nonachlazine, prazosin and levodopa on the clinical course and haemodynamics was investigated in 138 patients with ischaemic heart disease in whom selective coronary angiography had revealed an up to 50 percent stenosis of one of coronary arteries. The clinical picture of IHD patients with a high tolerance of physical exercise was characterized by a preponderance of spontaneous angina pectoris accompanied by painless myocardial ischaemia. A certain role in the genesis of these disturbances is played by the relative increase in the activity of alpha 1-adrenoreceptors and decrease in beta-adrenoreceptor activity. Prazosin and nonachlazine in monotherapy reduced the number of anginal attacks and episodes of painless myocardial ischaemia.

[Effect of nonachlazine on the adenylate cyclase system of the rabbit heart]. / Vliianie nonakhlazina na adenilattsiklaznuiu sistemy serdtsa krolikov.

The influence of nonachlazine on the adenylate cyclase system of the rabbit heart was investigated. The faint beta-blocking activity (displacement of up to 20% of [3H]-dihydroalprenolol and inhibition of isoproterenol-stimulated activity) as well as the ability to stimulate basal activity in micromolar concentrations has been observed. Such combination of properties may be important in the realization of some positive effects of nonachlazine pharmacological activity.

[Mechanisms of the hemodynamic effects of nonachlazine in ischemic heart disease patients]. / K voprosu o mekhanizmakh gemodinamicheskikh éffektov nonakhlazina u bol'nykh ishemicheskoi bolezn'iu serdtsa.

During course therapy with nonachlazine of patients with ischemic heart disease, stable angina pectoris a negative inotropic effect of the drug in persons with eukinetic and in particular hyperkinetic type of hemodynamics was revealed. Enhancement of beta-adrenoblocking effect of nonachlazine with an increase of its daily dose was found. Nonachlazine effect on hemodynamic parameters was shown to be mediated through adrenoreactive structures.

[Effect of nonachlazine on the temperature sensitivity of the lysosomal membranes of the heart muscle in rats in vitro]. / Vliianie nonakhlazina na temperaturnuiu chuvstvitel'nosti lizosomal'nykh membran serdechnoi myshtsy krys in vitro.

It has been shown in vitro that nonachlazine stabilizes rat myocardial lysosomal membranes and activates total acid phosphatase in homogenates of rat myocardium. Preliminary addition of nonachlazine to homogenates in two different final concentrations produces unequal changes in total and free activity of acid phosphatase and cathepsin D during 2.5-hour incubation of homogenates at 37 degrees C.

[Mechanisms of the inotropic action of nonachlazine]. / O mekhanizmakh inotropnogo deistviia nonakhlazina.

It has been demonstrated clinically and experimentally that administration of nonachlazine enhances myocardial contractility because of the stimulation of beta-adrenostructures and that the initial status of the latter ones determines in many respects the drug action intensity.

[Various aspects of the effects of beta adrenergic receptor blockaders, stimulants and calcium antagonists on the cardiovascular system]. / Izuchenie nekotorykh aspektov vliianiia na serdechno-sosudistuiu sistemu blokatorov i stimuliatorov beta-adrenoretseptorov i antagonistov kal'tsiia.

Experiments with isolated animal hearts showed that intracoronarily injected propranolol (beta-adrenoblocker) and nonachlasine (beta-adrenostimulator) lead to coronary dilatation changing into coronary constriction. Unlike propranolol, nonachlasine reduced the venous bed capacity. The use of nonachlasine resulted in primary reduction and consequent increase of myocardial contractility, propranolol leading to negative inotropic effect. The character and degree of the drug effect in hemodynamics depend on the initial activity of the sympathoadrenal system. The therapeutic effectiveness of the drugs also depends on the initial hemodynamic state and on the sympathoadrenal system activity. A comparative study of Ca2+ antagonists demonstrated corinfar to have positive ino- and chronotropic effect. Isoptine was shown to produce negative ino- and chronotropic action, with hemodynamics remaining indifferent to sensite. Ca2+ antagonists examined in the study are characterized by a diverse therapeutic effect and considerably differ in their influence on the circulatory system.

[Biochemical basis for the spasmolytic effect of isoquinoline and phenothiazine derivatives]. / Biokhimicheskaia osnova spazmoliticheskogo éffekta proizvodnykh izokhinolina i fenotiazina.

Experiments with isolated ring-like strips of pig heart veins and arteries and those with rat small intestinal strips made in the presence of hyperpotassium contracture have demonstrated that spasmolytic activity of papaverine, nospa, nonachlazine, and ethmozine is a consequence of the reduced respiratory intensity and phosphorylation in smooth muscle mitochondria. No changes in the anaerobic glycolysis rate have been found after drug administrations.

[Effect of nonachlazine on transmembrane ionic currents in the frog atrial trabeculae]. / Vliianie nonakhlazina na transmembrannye ionnye toki trabekul predserdiia liagushki.

The effect of the antianginal drug nonachlazine displaying antiarrhythmic properties on transmembrane ionic currents in the frog atrial fibers was studied in experiments on isolated trabeculae of the frog atria. The transmembrane ionic currents were measured by a voltage clamp technique based on a double sucrose gap arrangement. Nonachlazine (1.03 X 10(-5) mol/l) decreased the amplitude of the fast inward current whatever the magnitude of membrane potential. The drug inhibited the slow inward current and prevented the adrenaline-increased permeability of the slow sodium-calcium channel if external sodium ions were replaced by choline chloride. Nonachlazine (1.03 X 10(-5) mol/l) diminished the amplitude of the inward ionic current in a calcium-free medium as well. The stimulatory effect of prostacycline (2 X 10(-7) mol/l) on the fast inward ionic current was inhibited by nonachlazine. The data obtained suggest that the antiarrhythmic effect of nonachlazine might be linked with the inhibition of the fast sodium inward current and the slow calcium inward current.

On the mechanism of action of the antianginal drug nonachlazine on ischemic myocardium.

The activity of a new antianginal drug, nonachlazine, synthetized in the Institute of Pharmacology, Academy of Medical Sciences of the USSR, has been demonstrated using model myocardial ischemias on anesthetized dogs and conscious cats. Antianginal activity was evaluated by ECG, epicardial electrogram, lactate level, and lactate/pyruvate ratio in the venous blood flowing from the ischemic myocardial area. The study of the cardiotropic effect of nonachlazine provided the following findings: (1) nonachlazine enhances ino- and chronotropic functions of the heart via stimulation of its beta-adrenergic receptors; (2) nonachlazine's positive chronotropic effect is substantially less marked than the inotropic one; (3) nonachlazine decreases the intensity of chronotropic reactions of the heart induced by isopreterenol. Biochemical analysis showed that in addition to its activation of oxidative phosphorylation, the ability of nonachlazine to stimulate glycogenolysis is also of importance in the development of its antianginal effect. This conclusion has been suggested by the following: (1) in acute myocardial ischemia, nonachlazine decreased lactate level and increased ATP level up to the norm; (2) at day 3 after ligation of the coronary artery, nonachlazine did not change lactate content, increased ATP and NAD, and decreased NADH2; (3) in experiments on rabbit myocardial mitochondria in vivo and in vitro nonachlazine was found to stimulate oxidative phosphorylation; (4) nonachlazine was found capable of increasing the norepinephrine level and of increasing phosphorylase a activity and the rate of glycogenolysis.

Influence of cardiovascular drugs on platelet aggregation.

All vasodilatory drugs reported in this chapter possess an antiaggregatory effect on platelets, some of them with a synergistic effect on prostacyclin-induced inhibition of aggregation. Thus, the question seems valid whether the antiaggregatory effect represents one part of their antianginal and antihypertensive action. Some vasodilators stimulate the biosynthesis of prostacyclin and/or other vasodilating prostaglandins. This stimulation could be linked not only to the antiaggregatory but also to the vasodilating action. The influence on prostaglandin biosynthesis, however, is not obligatory for all vasodilators, as nitroglycerin proves. Trapidil inhibits the biosynthesis and the effect of thromboxane A2, as our own experiments and those by Ohnishi et al. (7) have shown. This effect could be favorable in patients with heart infarction. Lefer et al. (5) have demonstrated a fivefold increase in thromboxane release after experimental ligation of the coronary artery in the cat. Pinane thromboxane, a thromboxane antagonist, almost completely abolished all deleterious consequences of ischemia. Whether trapidil is also able to inhibit thromboxane biosynthesis and activity under clinical conditions of heart infarction will be the topic of further investigations.

[Mechanisms of action of nonachlazine]. / O nekotorykh mekhanizmakh deistviia nonakhlazina.

In animals with a ligated anterior descending left coronary artery, a single administration of nonaclazine (5 mg/kg bw) leads to a marked increase in the coronary blood flow and to an improvement in cardiovascular system function. Administration of nonachlazin for 7 days helps normalize the electrophysiological and hemodynamic characteristics and produces a beneficial effect on the myocardial blood flow and contractility. Interaction of nonaclazine with adrenergic receptors does not appear to have any decisive significance in the drug action mode.

[Effect of indomethacin and nonachlazine on myocardial and cerebral tyrosine hydroxylase activity in rats]. / Vliianie indometatsina i nonakhlazina na aktivnost' tirozingidroksilazy v miokarde i golovnom mozge krys.

Nonachlazin (6 mg/kg) and indomethacin (10 mg/kg) intraperitoneally have a unidirectional effect on the activity of tyrosin hydroxylase, reducing it in the hypothalamus and in the brain stem and increasing it in the heart septum. In the brain, the effects of nonachlazin and indomethacin are not summarized whereas in the heart their effects are summarized. Unlike indomethacin, nonachlazin exerts a direct effect on the rate of tyrosin hydroxylase reaction but has no effect on the activity of cyclooxygenase and on synthetase of prostaglandins. It is concluded that prostaglandins produce a modulating action on the activity of brain and heart tyrosine hydroxylase and participate in the mechanism of action of nonachlazin.

[Protection of myocardial mitochondria from penetration by calcium ions using isoquinoline and phenothiazine derivatives]. / Zashchita proizvodnymi izokhinolina i fenotiazina mitokhondrii miokarda ot proniknoveniia v nikh ionov kal'tsiia.

It has been established that malonate-like action of isoquinoline derivatives (papaverine and nospan) on respiratory function of myocardial mitochondria leads to inhibition of the accumulation rate of Ca2+ by these organelles on the use of glutamate and alpha-ketoglutarate as substrates. A greater inhibition of Ca2+ transport rate in the mitochondria is observed in the presence of glutamate. It has been validated theoretically that the decreased intensity of Ca2+ accumulation is aimed at protecting the mitochondria from irreversible lesions in ischemia. Nitroglycerin and sodium nitrite do not affect Ca2+ exchange in the mitochondria.

[Effect of nonachlazine on ino- and chronotropic function]. / Vliianie nonakhlazina na ino- i khronotropnuiu funktsiiu.

As a result of the stimulation of beta-adrenostructures of the myocardium nonachlazin intensifies ino- and chronotropic functions of the heart. This effect does not manifest after administration of practolol and is less pronounced in animals anesthesized with urethane and alpha-chloralose since the sensitivity of the beta-adrenostructures of the myocardium decreases under the influence of the anesthetics. Apart from the stimulation of ino- and chronotropic function of the heart nonachlazin reduces concurrently the intensity of positive chronotropic effect of isoproterenol. Such a combination of the efects called a "partial" beta-adrenoblockade seems likely to play an important role in the manifestation of the antianginal action of nonachlazin.

[Effect of nonachlazine on the cardiac component of baroreceptor reflexes in unanesthetized cats]. / Vliianie nonakhlazina na serdechnyi komponent baroretseptivnogo refleksa u nenarkotizirovannykh koshek.

Nonachlazin in doses of 1 and 6 mg/kg provoked a rise in the arterial pressure of cats by 7--20 mm Hg. Administration of 1 mg nonaclazin into the IV ventricle induced a similar elevation of arterial pressure. Premedication with propranolol (1--3 mg/kg) did not prevent the pressor reaction. In half of the experiments, nonachlazin (6 mg/kg) produced an appearance of Meyer's waves and inhibition of the cardiac component of the barorecptor reflex that is not related to the potentiation of the sympathetic effects on the heart.

[Influence of nonachlazin, riboxin and isoptin on the blood coagulation system and the anticoagulant effect of heparin]. / Vliianie nonakhlazina, riboksina i izoptina na sistemu svertyvaniia krovi i antikoaguliantnyi éffekt geparina.

Nonachlazin binds in vitro heparin in blood plasma and aqueous medium. This interaction complies with logarithmic dependence. Isoptin increases in vitro plasma susceptibility to heparin, reduces the period of whole blood coagulation and thrombin time. Riboxin does not produce in vitro any effect on the blood coagulation parameters and heparin susceptibility. Single and chronic adminstration of the drugs exerts no effect on blood coagulation. Prolonged use of riboxin promotes the increased level of endogenous heparin. Both single and chronic administration of the drugs potentiates the anticoagulant action of heparin.

[Effect of nonachlazine and oxyfedrine on central processes regulating vasomotor tone]. / Vliianie nonakhlazina i oksifedrina na protsessy tsentral'noi reguliatsii vazomotornogo tonusa.

Effect of the antianginal drugs nonachlazin and oxyfedrin on tonic and evoked activity in sympathetic renal nerves and on vasomotor reflexes induced by stimulation of the tibial nerve was studied and compared in anesthetized cats with intact brain. Low doses of nonachlizin facilitated somatosympathetic reflexes. High doses of the drug induced a selective inhibition of somatosympathetic reflexes evoked by stimulation of high-threshold afferent A-fibers. The inhibition of somatosympathetic reflexes induced by oxyfedrin had no such a selectivity and was less prolonged. The effects of nonachlazin and oxyfedrin attained after the administration of reserpine and propranolol allow a conclusion that the central effects of nonachlazin and oxyfedrin are related to the fact that they modulate the adrenergic brain structures.