[Proxodolol--a new beta- and alpha-adrenoblockader].

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.

[Atherogenic properties of phenothiazine drugs manifesting in cultured cells of the human aortic intima].

The effects of phenothiazine drugs on the levels of cholesterol in smooth cells of the human aortic intima. Two antiarrhythmics (ethacizin and ethmozine) and two neuroleptics (trifluoperazine and chlorpromazine) were evaluated. The three agents ethacizin, trifluoperazine, and chlorpromazine given in concentrations of 10(-7) to 10(-5) M were ascertained to cause intracellular cholesterol accumulation, whereas ethmozine produced no effects on the intracellular levels of cholesterol.

Effect of moracizine and ethacizine on receptors of potential-operated calcium channels and calcium-binding proteins.

The action of two antiarrhytmic drugs, moracizine (MOR, CAS 31883-05-3) and ethacizine (ETHA, CAS 33414-33-4) on receptors of potential-operated CA-channels has been investigated. ETHA binding to verapamil receptors was more effective than that of MOR (IC50 = 0.53 +/- 0.

[Antioxidants, lipid peroxidation, and receptor-dependent increase in Ca2+ concentration in human platelets].

Content of tocopherol and total antiradical activity of hydrophobic antioxidants were estimated in human blood platelets. Two hydrophobic antioxidants--tocopherol and ubiquinone were detected in hexane extracts of thrombocytes using thin-layer chromatography. After incubation of thrombocytes with N-ethyl maleimide content of malonyl dialdehyde was increased and of tocopherol--decreased, receptor-dependent increase of Ca2+ concentration in cytoplasm was potentiated, while the Ca(2+)-blocking effect of nitroglycerol was decreased.

[Increase of alpha 1-adrenoreactivity of the rat heart in adaptation to periodic hypoxia].

There is a possibility that the cardioprotective effect of adaptation to intermittent hypoxia is due to changes in receptors apparatus of the heart. In this connection the effect of preliminary adaptation to intermittent hypoxia (4 hours per day at the altitude of 4000 m during 40 days) on the state of beta-receptors-adenylate-cyclase system and same other receptors of the heart were studied. It was shown that at the end of the course of adaptation the number of beta-adrenoceptors in the heart was increased with simultaneous decrease in basal adenylate-cyclase activity, accompanied by the diminution of its response to beta-agonist.

[Alpha1 desensitization of the heart during adaptation to stress].

Results of the experiments evidence that a combination of three factors, limiting the Ca2+ concentration increase in myocardial cell, can play a role in the cardioprotective effect of adaptation of rats to short-term immobilization stress (every second day for a month) are presented. Those factors are as follows: desensitization of alpha 1-adrenoreceptors, M-cholinoreceptors up-regulation and reduced number of voltage-dependent Ca2+ channels in the myocardial membranes.

[Effects of beta adrenergic blocking agents and calcium antagonists on atherogenic properties of blood serum of patients with ischemic heart disease].

The beta-adrenoblockers anapriline and visken and the calcium antagonist corinfar were studied for effects on the atherogenic properties of the sera from patients with coronary heart disease who took the drugs. The study was performed by using cultured atherosclerotically altered human aortic smooth muscle cells. A single dose of anapriline, 80 mg, and that of visken, 20 mg, were found to give rise to or to enhance atherogenic properties of the patients' sera, while that of corinfar, 20 mg, yielded their antiatherosclerotic properties.

[Effects of cordarone on Ca2+-dependent cellular systems].

Cordarone was studied for effects on the pharmacological receptors of myocardial potential-dependent Ca channels, on the receptor-dependent increase in platelet Ca2+ content, on muscarinic cholinergic receptors of the M1- and M2-type, and on calmodulin regulation of cAMP phosphodiesterase (PDE). Without showing selectivity, cordarone is able to interact both with M1-, and M2-muscarinic choline receptors with Ki = 5.3-5.

[Membrane mechanisms of the effect of alkylating cytostatic agents].

The data bearing witness to realization of the cytostatic activity of alkylating agents by means of interaction with cell membrane receptors was obtained. Alkylating agents block receptors of the polyphosphoinositol system. It is shown that chloralkylamines inhibiting sites coincide with M-++cholinomimetics and alpha-adrenergic receptors, inhibitors of H-histamine receptors, cyclo- and lypoxigenase inhibitors.

[Interaction of calcium agonists and antagonists with Ca-binding proteins and their effect on cyclic nucleotide phosphodiesterase].

The effects of Ca2+ antagonists (nicardipine, felodipine, nitrenedipine, isradipine, niphedipine, darodipine and riodipine) and Ca2+ agonists (BAY K8644 and CGP 28392), 1.4-dihydropyridine derivatives (1.2-DHP), on the calmodulin (CM)-dependent activation of cyclic nuxleotide phosphodiesterase (PDE) were studied.

Antiatherosclerotic effects of calcium antagonists. Study in human aortic cell culture.

To investigate the effects of calcium antagonists on atherosclerotic cellular indices, [3H]thymidine incorporation and intracellular cholesterol content, primary culture of cells isolated from subendothelial intima of human atherosclerotic aorta was used. Among tested drugs were: verapamil, nifedipine, diltiazem, papaverin, nicardipine, D-600, cinnarizine, PN 200 110 and PY 108 068. Verapamil proved to be the most effective.

[Adenylate cyclase system of synaptosomes from the rat cerebral cortex during acute stress].

Synaptosomes and synaptic membranes were studied in brain cortex of rats after 6 hrs emotional-painful stress. No alterations were observed in beta-adrenoreceptors, adenylate and guanylate cyclases to the end of the second day after the acute stress action.

Relationship between the inhibition of receptor-induced increase in cytosolic free calcium concentration and the vasodilator effects of nitrates in patients with congestive heart failure.

Nitroglycerin, isosorbide dinitrate and sodium nitroprusside, like nifedipine, were found to inhibit the receptor-provoked increase of cytosolic free calcium concentration in human platelets loaded with 2-[(2-amino-5-methylphenoxy)methyl]-6-methoxy-8-aminoquinoline-N,N,N',N' - tetraacetate. Sodium nitroprusside and nitroglycerin induced elevation of cyclic guanosine 3',5'-monophosphate content in platelets which correlated with their calcium-blocking activity. Methylene blue and epinephrine decreased the calcium-blocking effect and the influence of nitroglycerin on cyclic guanosine 3'-5'-monophosphate content, but failed to suppress the inhibitory effect of sodium nitroprusside.

[Effect of cordarone on the cellular adrenergic systems].

Cordarone was examined for its effects on alpha- and beta-adrenergic receptors and adenylate cyclase (AC) of some tissues. Cordarone was shown to suppress the binding of [3H]-clonidine with alpha 2-receptors of the rabbit brain (Ki = 4 microM) and that of [3H]-prazosin with alpha 1-receptors of the rat liver (Ki = 22 microK), but not to displace [3H]-dihydroalprenolol from rabbit cardiac and pulmonary beta 1-receptors and from beta 2-receptors of rat reticulocytes and human lungs. Cordarone failed to affect the activity of rabbit heart and lung AC, as well as that of thrombocytes and human lungs, but showed a 80% inhibition of the activating effect of isoproterenol on reticulocyte AC.

Moracizine and ethacizine effects on membrane receptors.

Interaction of the antiarrhythmics moracizine (moricizine, ethmozine, ETHM) and ethacizine (ETHA), the ethyl ester hydrochlorides of 10-(3-R-propionyl)-phenothiazine-2-carbamic acid (where R is morpholine or diethylamine, respectively), with muscarinic cholinergic alpha- and beta-adrenergic systems and histamine H1 receptors (H1-R) has been studied. ETHA and ETHM displaced [3H]-quinuclidinyl benzilate ([3H]-QNB) from muscarinic receptors of M2 type (M2-R) of rabbit heart with Ki = 0.65 +/- 0.

[Atherogenic properties of beta adrenergic blockaders evident on vascular wall cells].

In cultured human cells, beta-adrenoblockers such as propranolol, alprenolol, metoprolol, atenolol, pindolol, and thymolol, as well as sera from patients with coronary heart disease were examined for atherogenic activity following a single administration of propranolol (80 mg) and pindolol (10 mg). Addition of the beta-adrenoblockers to the cell culture was demonstrated to enhance cellular total cholesterol levels and to stimulation their proliferation. Propranolol and pindolol given in a single dose was found to result in the appearance of atherogenic properties of the patients' sera.

[Biochemical features of platelet alpha2-adrenergic receptors and their connection with an increase in concentration of intracellular Ca2+].

Epinephrine (E) and norepinephrine (NE) alone did not increase free intracellular Ca2+ ([Ca2+]i) in human platelets loaded with Quin-2 or Fura-2; however, they did potentiate the effects of vasopressin (VP), serotonin (S) and platelet activating factor (PAF). The synergism in [Ca2+]i increase was also obtained in the presence of VP together with PAF, S with PAF as well as VP with S. The effect of E or NE was blocked by yohimbine and phentolamine.

The role of secondary messengers in the regulation of lipid peroxidation in rat liver microsomes.

The effect of phorbol-12-myristate-13-acetate (PMA), an activator of protein kinase C (PK-C) on lipid peroxidation (LPO) in rat liver homogenates and microsomes was studied. PMA (10(-10) to 10(-6) M) produced a concentration-dependent inhibition of LPO, which was greatly decreased by polymyxin B (PxB) (an inhibitor of PK-C). The non-active analogue of PMA, 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD) exerted no inhibitory effect.

Prostacyclin, thromboxane A2 and calcium antagonists: effects on atherosclerotic characteristics of vascular cells.

We investigated the effects of stable analogues of prostacyclin (carbacyclin) and thromboxane A2 (U46619) and various calcium antagonists on atherosclerotic cellular indices, intracellular cholesterol content and [3H]thymidine incorporation. Primary culture of human subendothelial cells derived from atherosclerotic plaques of aorta was used. Carbacyclin reduced cholesterol accumulation and cell proliferation.

Receptor binding potencies of chlorpromazine, trifluoperazine, fluphenazine and their 10-N-substituted analogues.

Receptor interactions of three pairs of phenothiazine derivatives, namely chlorpromazine, trifluoperazine, fluphenazine and their dialkylaminoacyl analogues were investigated. The data indicate that neuroleptic derivatives are less effective at dopamine (D2), alpha 1-adrenoceptors (AR) and histamine receptors (H1). No differences in affinity to alpha 2-AR were observed.

[New approaches to the study of the mechanism of action of nitrates].

The effects of nitrates on a Ca+2 increase and the content of cyclic nucleotides in human platelets were studied. Nitroglycerin (GTN), isosorbide dinitrate (ISDN) and sodium nitroprusside (NP) were found to inhibit dose-dependently the intracellular Ca+2 increase induced by the platelet activating factor (PAF). The inhibiting effect of NP was at lower concentrations than those of GTN and ISDN.

Cardiovascular drugs and atherosclerosis: effects of calcium antagonists, beta-blockers, and nitrates on atherosclerotic characteristics of human aortic cells.

Primary cell culture derived from atherosclerotic plaque of human aorta was used to assess direct effects of calcium antagonists, beta-blockers, and nitrates on vessel wall cells. Within 24 h, calcium antagonists (verapamil, nifedipine, darodipine, isradipine, diltiazem, etc.) reduced the cholesterol level in cultured cells.

[Effect of nonachlazine on the adenylate cyclase system of the rabbit heart].

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.

Metofenazate as a more selective calmodulin inhibitor than trifluoperazine.

The interaction of several phenothiazines, benzodiazepines, butyrophenones, polycyclic neuroleptics and tricyclic antidepressants with calmodulin and troponin C was investigated using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide. In the presence of Ca2+, trifluoperazine (2-trifluoromethyl-10-[3-(1-methylpiperazinyl-4)propyl]-phenothiaz ine dihydrochloride, TFP), which is commonly used as a selective calmodulin inhibitor, half maximally increased the fluorescence of the complex formed of the fluorescent dye with calmodulin at a concentration of 4 mumol/l, and with troponin C at 24 mumol/l. TFP completely inhibited the calmodulin dependent stimulation of cyclic nucleotide phosphodiesterase with a Ki of 4 mumol/l and decreased the maximum Ca2+ dependent troponin C mediated activation of actomyosin ATPase by 35% at a concentration of 100 mumol/l.