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Biguanide metformin, which is widely used for the treatment of type 2 diabetes mellitus, improves carbohydrate and lipid metabolism and shows a pronounced cardio- and neuroprotective effects. It is assumed that an important role in these effects of metformin plays its ability to positively influence the activity of NO-synthase catalyzing the synthesis of NO, the most important vasodilator, and the activity of hormone-sensitive adenylyl cyclase signaling system (ACSS. To prove this, we have carried out a study whose purpose was to study the effect of long-term metformin treatment on the metabolic rates in obese rats, as well as on the activity of ACSS and NO-synthase in the myocardium and the brain of these animals. The metformin treatment of Wistar rats with obesity induced by high-fat diet was carried out for 2 months (daily dose of 200 mg/kg). The treatment with metformin led to a decrease in body weight and body fat, reduced glucose and insulin levels as well as reduced insulin resistance index HOMA-IR, improved glucose tolerance, and decreased the level of atherogenic forms of cholesterol. In the myocardium of obese rats, the attenuation of ACSS stimulation induced by the agonists of β1/β2-adrenergic receptors (AR) and the strengthening of β3-AR signaling has been found. At the same time, in the myocardium of animals treated with metformin, the regulation of ACSS by adrenergic agonists was restored, and the ratio of β-AR-signaling pathways returned to normal. In the brain of rats treated with metformin, adenylyl cyclase stimulating effects of serotonin and agonists of type 4 melanocortin receptors, which had been weakenend for obesity, were restored. Metformin treatment completely restored activity of total and endothelial NO-synthase in the myocardium decreased in obesity. It as also shown that metformin treatment induced hyperactivation of NO-synthase in the myocardium and brain of healthy animals. Thus, we conclude that the effects of metformin identified by us in rats with long-term treatment of obesity may explain cardio- and neuroprotective influence of this drug.

Using selective receptor's agonist and antagonists we show that mouse white fat cells express alpha1A-, alpha2-adrenergic receptors, which activation with noradrenaline is capable of causing calcium responses different by formation mechanism. Adipocyte's calcium responses to alpha1-adrenoreceptor agonists are caused by alpha1A-type adrenoreceptor and suppressed by inhibitors of PLC-dependent pathway. Calcium responses to alpha2-adrenoreceptors agonists are realized only in the presence of more than 200 microM of L-arginine and suppressed by inhibitors of NOS-PKG-RyR pathway. The incubation of cells with L-arginine creates conditions for switching on the signal pathway with participation of eNOS --> NO --> sGC --> cGMP --> PKG --> CD38 --> RyR --> Ca2+ and for switching of the PLC - IP3R-dependent pathway. Adipocyte's calcium response to L-arginine represents a sharp impulse of the big amplitude and is mediated by alpha2-adrenoreceptors. L-arginine activating alpha2-adrenoreceptors and being the substrate of eNOS, realizes two functions in this pathway.

Thermogenic capability of brown adipose tissue is controlled by norepinephrine. Interaction of norepinephrine with adipocyte at- and P3-adrenergic receptors results in the increase of Ca2+ and cAMP concentrations. The [Ca2+]i changes initiated by norepinephrine and selective agonists of alpha1- and beta-adrenergic receptors, cirazolin and isoproterenol, were recorded in single cells of primary culture on the 1st, 3rd and 6th days in vitro. On the first day, isoproterenol-induced [Ca2+]i changes as compared to cirazolin-induced ones were characterized by greater amplitude and lesser impulse duration over the entire range of physiological concentrations used. These differences were negligible after 3 days and kinetic differences were practically absent after 6 days of cultivation. The agonist-induced [Ca2+]i changes in proliferating and differentiated cells differed significantly: in the process of cell growth in culture, the amplitude of calcium response increased, the duration of impulse signal decreased and the sensitivity to adrenergic agonists increased. The Ca2+ store in endoplasmic reticulum increased during the cell growth and development in culture, according to thapsigargin-induced Ca2+ response amplitude increase in Ca2+ free medium. The rate of Ca2+ pumping out of cell characterizing PMCA-activity also increased.

It was studied the influence of 20 amino acids on beta-adreno- and M-cholinoreactivity of longitudinal strips (n = 268) of rat uterus horn (n = 46) with the help of adrenaline (10(-8) g/ml) and acetilcholine (10(-6) g/Ml) accordingly. It is shown, that 3 amino acids from 20, including L-histidine (3 x 10(-8) - 3 x 10(-5) g/ml), L-triptophan (10(-8) - 10(-5)) and D-, L-tyrosine (2 x 10(-8) - 2 x 10(-5)), not changing M-cholinoreactivity of uterus smooth muscles, everyone or complexly essentially raised their beta-adrenoreactivity, i.e. expressed their beta-adrenosensibilisatory activity. It allows to consider that this amino acids are possible components of endogenic sensibilisator of beta-adrenocepters. It is discussed the question about using this amino acids in a dietary meal and complex therapy at insufficiency of beta-adrenergic influences on visceral organs.

The paper reports the effects of alpha and beta-adrenergic substances on the cardiac rhythm and electrical activity of the brain under the hypoxic conditions. beta-adrenergic substances were shown to have a stronger influence on these parameters as compared with alpha-adrenergic. The neoepinephrine effects were pronounced before "lifting", while the propranolol effects increased "at the altitude". Neopinephrine was found to have a stimulating effect on the cerebral cortex under the conditions of hypoxia.

Formerly we showed that TRH had simulative effect on mesenteric bovine and rat lymphatic vessels (LV) in very low concentration--10(-12)-10(-18) M. In present paper, participation of LV alpha- and beta-receptors in realization of TRH activity on rat mesenteric lymphatic vessels was studied in situ. Propranolol increased the stimulative effect of TRH, isoproterenol exerted an opposite effect. Phentolamine, prazosin eliminated the simulative effect of TRH, yohimbine resulted in additional gain of effect, which seems to testify 1) presynaptic action of TRH or 2) increase of the output of norepinephrine, which is potentiated by alpha 2-adrenoceptor antagonists. Also the participation of adrenergic receptors in positive chronotropic effects of mesenteric rat LV was studied using the method of selective destruction of dopamine-containing neurons after 6-OHDA infusion. As it occurred, desympathization hindered development of stimulating action of TRH. Thus, the efficiency of TRH as a stimulator of LV is connected with activation of adrenergic mechanisms.

With the purpose of studying the mechanism of ozone action on uterus smooth muscles it was investigated the influence of ozone-content (approximately 0.50 mkg/ml) Krebs' solution or its 10- and 100-fold dissolution on contractile activity and beta-adrenoreactivity of 56 longitudinal strips of uterus horns of 17 nonpregnant rats. Ozone at concentration approximately 0.50 mkg/ml (but not in concentration of approximately 0.05 and approximately 0.005 mkg/ml) reversibly raised frequency, amplitude and total contractile activity of intact myometrium strips, and also fast and reversibly reducel its beta-adrenoreactivity, i.e. decreased of inhibitory action of adrenaline (10(-8), 10(-7), 10(-6) g/ml), but did not change uterostimulatory effect of acetylcholine (10(-6) g/ml) and oxiyocin (5 x 10(-4) ME/ml), what evident about specificity of ozone beta-adrenoblokate effect. Ozone (approximately 0.50 and 0.05 mkg/ml) did not change ov value of potassium contracture of myometrium strips which was depolarized by hyperpotassium (60 mM KCL) Krebs' solution, but reduced inhibitory action of adrenaline (10(-8) g/ml). The question is being discussed about mechanisms of ozone beta-adrenoblocade actions, about clinical role of this phenomenon, and the possibility of using beta-adrenoreceptor sensibilizators direct action (histidine, tryptophan, tyrosine, trimetazidin and mildronat) at ozonotherapy with the purpose reduction of its negative effects.

Changes in major paraments of alpha 1- and beta-adrenergic responses (EC50 and Pm) were studied in the intestine arterial blood vessels of rabbits adapted to cold for 1-30 days (daily cold exposures for 6 hours at -10 degrees C). It was shown that responses to phenylephrine, noradrenaline, adrenaline (alpha 1-agonists), isopropylnoradrenaline (beta-agonist) corresponded to the equation p = (Pm.An)/(EC50n + An) with n = 1 and n = 2, respectively. Adaptation to cold induced radically different changes in the major parameters of alpha- and beta-adrenergic responses. In the alpha-adrenergic responses, the parameters EC50 and Pm changed reciprocally. In the beta-adrenergic response, only Pm value changed while EC50 did not differ from the control over the entire period of adaptation to cold. The pronounced differences from the control gradually decreased within 1-30 days of adaptation.

The cholinergic, histaminergic and adrenergic features of regulation of the small muscles contractile activity in a vascular wall of a pulmonary artery in rabbits and involvement of an endothelium in these processes, were investigated. The cholinergic release phenomenon of small muscles of the rabbit pulmonary artery has a two-component character of dose dependence. The low-threshold components of Pilocarpinum relaxing effect has an endothelium-dependent nature. The important feature of histaminergic regulation of contractile activity of segments involves a direct contractile effect of histamine that is not inherent. The endothelium renders a suppressing effect on histaminergic contraction of small muscles of the rabbit pulmonary artery. A basic feature of adrenergic regulation of the pulmonary artery involves registered-beta-adrenergic contractile effects in small muscles of a vascular wall. The activation of the cAMP-dependent signal system in small muscles of a pulmonary artery is capable of rendering a contractile effect. The detected features of a regulation in the small circle can have an essential clinical-physiological value.

In alert normotensive and hypertensive (SHR) rats, effects of imidazoline receptor activating compounds of the central nervous system on the level of blood pressure, heart rate and value of arterial baroreceptor reflex at rest and in emotional tension, were investigated. It was shown, that the activation of the cerebral imidazoline receptors leads to an increase in the baroreceptor reflex value (both in resting and in emotional tension) and a decrease in the pressor reaction evoked by emotional affect. No data showing the role of imidazoline receptors in functioning of systems regulating of the initial level of blood pressure were obtained.

AL-275, a new antiarrhythmic agent, exhibits the properties typical of the class III antiarrhythmogen: (i) prolongs the ventricular repolarization; (ii) inhibits the sinus node automatism; (iii) increases the effective refractory periods in atrium and ventricles; and (iv) does not modify AV and intraventricular conduction. AL-275 produces a pronounced antiarrhythmic and antifibrillatory action. The effect of AL-275 is independent of the heart rate, which is an advantage over the other class III agents. Both character and intensity of the electrophysiological and antiarrhythmic activity of AL-275 were fully retained upon the preliminary infusion of isoproterenol. Independence of the drug action of both the heart rate and the isoproterenol-induced changes in refractoriness are related to the ability of AL-275 to block a slow component (IKs) of the potassium current.

The adrenoactivity of the mast cells (MC) in the albino rats mediastinal pleura was studied during the experiment with the use of the pharmacological preparations of adrenergic effect in vivo and in vitro. While injecting adrenolytics and adrenomimetics presence of heparin and biogenic monoamines (catecholamines and serotonin) was observed. Adrenomimetic substances in vivo and in vitro were observed to intensify the synthetic process, decrease degranulation, concentrate the density of heparin granules and increase the number of biogenic monoamines while adrenolytic substances were noticed to produce contrary effect.

In 12 anesthetized cats both hypoxia and hypothermia enhanced the shifts in arterial resistance against blood flow in response to noradrenaline and diminished the shifts in response to isoproterenol. Combination of both stress factors considerably weakened the adrenergic vasoconstriction and rather little affected the adrenergic vasodilatation. The findings suggest that protective effect of hypothermia against the background of a hypoxic stress might be a mechanism preventing disorders in the tissue metabolism.

NO synthase was studied in intact rats and in rats with bronchial asthma epitheliocytes after inhalation of phenotherol, propranolol, guanosine triphosphate (GTP) and combined inhalation of GTP with phenotherol. NO synthase mediator action on bronchial patency during adrenoagonists and GTP inhalation was demonstrated.

The chronic oral administration of epaden (a concentrate of n-3 polyunsaturated fatty acids, n-3 PUFA) to rabbits leads to a decrease in activity of the tissue type plasminogen activator (t-PA) in the blood plasma. In order to elucidate the mechanism of this phenomenon, the epinephrine (adrenaline) stimulated t-PA release in rabbits pretreated with epaden for 4 weeks was compared to that in the control (untreated) group. The epinephrine injections led to a reliable, albeit short-time, increase in the t-PA activity in both test and control groups. Although the base activity of t-PA in the epaden-treated group was lower than that in the control group, the t-PA release in the former group was more pronounced. In addition, the t-PA production was induced by the immobilization shock model in rabbits one month after beginning of the epaden administration (animals in the control group were subject to the shock without epaden pretreatment). In this test, the t-PA release was also more intense in the epaden-treated animals. These results indicate that the dietary epaden administration per os reduces the basal t-PA level, but increases the agonist-induced plasminogen activator production.

Following a stimulation with acetylcholine, the beta-adrenergic agonists adrenaline (A), noradrenaline (NA), isoproterenol (Iso) and salbutamol (Sal) induced a concentration-dependent decrease in the tone and (or) rate of amnion contraction with EC50 ISO < NA << A < Sal. Metaprolol, a specific beta 1-antagonist, induced a rightward shift in the dose-response curves of Iso, NA and A, whereas beta-antagonist butoxamine was ineffective. pA2 values for beta-antagonists were propranolol 8.3, metoprolol 7.0, butoxamine 5.6. EC50 values of alpha-adrenergic agonists form a sequence: clonidine < NA << methoxamine < phenylephrine. Specific alpha-antagonists yohimbine and idazoxan were found to antagonise competitively the effects of NA. The data obtained characterize the adrenergic receptors mediating stimulation of amniotic contractile activity as alpha 2-adrenergic receptors. Inhibition of contractile receptors in amnion is mainly mediated by beta 1-adrenergic receptor activation.

Two groups of coronary patients subjected to revascularization of the myocardium were examined in order to detect the negative hemodynamic effects of protamine sulfate (PS) and the possibility of their correction by simultaneous infusion of adrenaline microdoses. In group 1 (27 pts.) heparin was neutralized by infusion of PS alone (6 mg/kg) and in group 2 (27 pts.) by simultaneous infusion of PS and adrenaline (15 ng/kg/min). The functions of the right and left ventricles were evaluated by catheterization of the pulmonary artery by a Swan-Ganz catheter and transesophageal Doppler echocardiography. These methods provided volume and velocity characteristics of the right and left compartments of the heart. PS deteriorated the systolic function of the right ventricle, particularly in patients with initial dysfunction of the right heart. Infusion of adrenaline simultaneously with PS leveled its negative effects, thus preventing myocardial dysfunction.

Selective agonists of adenosine A1, GABAa, GABAb, and alpha 2-receptors (inhibitory neurotransmitter analogs) have a high neuroprotective effects (NPE) on two models of complete cerebral ischemia (CI). These NPEs are specific as they are inhibited by selective antagonists and, in addition, the selective alpha 1- and beta-receptor agonists have no NPE. The natural resistance to CI is also associated with A- and alpha 1-receptors. NPE does not result from improved cerebral blood flow. The receptor agonists protect the brain itself. They use a tolerance strategy and hypothermia is an important component, but not the only mechanism of NPE. Unlike most drugs, receptor neuroprotectors (RNP) guard not only a penumbra zone, but the core of ischemia as they are effective in complete global CI. Moreover, RNP-induced delay of irreversible lesions may increase a therapeutical window for using other drugs. RNPs are promising potential drugs in CI.

The authors studied the effect of m-cholino-, adreno-, and purinotropic agents on the development of postischemic reperfusion fibrillation of isolated rat hearts. Pilocarpine, norepinephrine, phenylephrine, and adenosine caused a proarrhythmogenic effect. Atropine, trimedoxim, prazosin, and chloroquine made fibrillation less expressed. A direct correlation was found between the arrhythmogenic effect of reperfusion and the size of the no-reflow zone, with the use of the drugs too. It is concluded that the phospholipid mechanism contributes to realization of the arrhythmogenic effect of reperfusion and vascular disorders, leading to the occurrence of the no-reflow phenomenon.

Administration of non-selective beta-blocker propranolol prevented the stress-activated action whereas the alpha-agonist isoprenaline enhanced the effect of immobilisation stress on the rat mast cells. beta-antagonists or agonists exerted no effect on the heparine secretion by the mast cells. ACTH activated the secretion in the absence of stress.

Effects of some drugs on different levels of phagocytic activity of polymorphonuclear leukocytes (PMNL) of human peripheral blood were studied in vitro. The drugs were found to regulate the phagocytic activity of PMNL. This effect depended on the initial level of PMNL phagocytic activity but not on the drug appurtenance to a certain pharmacological group.

The experiments on rats showed that high consumption of sodium chloride promotes the diuretic action of phenylephrine (mesaton), the alpha-adrenergic agonist, and prolong its pressor effect. In supplementation of diet with sanasol and hyposol, a new substitute of common salt, phenylephrine, causes the renal effects typical of beta-adrenoceptor stimulation. Both the sanasol and especially hyposol decrease the strength and duration of phenylephrine pressor action and increase the duration of isadrine depressor effect. Thus, the reactivity of alpha- and beta-adrenergic mechanisms depend on the mineral composition of diet, which is able to change the pharmacodynamics of cardiovascular agents.

Activation of different subtypes of adrenergic (AR) and dopamine receptors (DR) and its effect on the blood testosterone level, were studied. Intraventricular administration of selective agonists mesatone and clonedine as well as dobutamine increased the testosterone level in the blood, where as clenbuterol exerted no such effect. Activation of D1-DR by SKF 38393 in ZI and PVGM elevated the testosterone level as well. Activation of D2-DR by LY 171555 in ZI exerted no effect and in the PVGM even inhibited the testosterone level.

After chemical sympathectomy of mesenteric arteries and veins, different increase of responsiveness to noradrenaline, potassium chloride and ouabain was found. Stronger changes occurred in the vein which seems to be due to different adrenergic innervation of arteries and veins.

The portal vein was shown to possess two pools of alpha-adrenoreceptors and m-cholinoreceptors, and one beta-adrenoreceptor pool, with functional interrelationships among them. Increase in the temperature of the incubation medium to 40.5 and 41.0 degrees C induced characteristic changes of adrenergic response which were reversed or considerably attenuated by specific agonists and antagonists. The role of changes in the conformational membrane induced by adrenotropic substances in modulating specific responses to neurotransmitters and their agonists, is discussed.

The problem of nonopiate analgesia is briefly discussed in the historical aspect. The mechanism of the analgesic effect of adrenopositive compounds and its implementation through different populations of alpha-adrenoreceptors at supra- and segmental levels of the brain, the advantages of clopheline over traditional narcotic analgesics are grounded. The data confirming the clinical effectiveness of clopheline in pain syndromes are presented, the perspectives of the practical use of clopheline-like and other adrenopositive agents are discussed.

The effects of adrenaline, noradrenaline, isoproterenol, dopamine, histamine, acetylcholine, and serotonin on the wall tension in the isolated frog subclavian vein and modification of these effects by appropriate antagonists were examined. The existence of alpha- and beta-adreno-, M-choline- and H1-histamine receptors was demonstrated. Stimulation of alpha-adreno- and H1-histamine receptors augments and that of beta-adreno- and M-cholinoreceptors diminishes active wall tension in the vein.