[Fibrinolytics: from the thrombolysis to the processes of blood vessels growth and remodeling, neurogenesis, carcinogenesis and fibrosis].

One of the most outstanding scientific achievements in the thrombolysis is the development and administration of fibrinolysin - the first Soviet drug that lyses blood clots. Intracoronary administration of fibrinolysin reduced the mortality of patients with myocardial infarction by almost 20%. For his work in this field Yevgeny Chazov was awarded the Lenin Prize in 1982. Over the next decades, under his leadership, the Cardiology Center established scientific and clinical laboratories that created new generations of drugs based on fibrinolytics for treating patients with myocardial infarction, restoration of blood flow in ischemic tissue, and also studying the mechanisms of remodeling of blood vessels involving the fibrinolysis system. It have been found new mechanisms of regulation of the navigation of blood vessels and nerves growth, tumor growth and its metastasis with the participation of the fibrinolysis system proteins. The review reports the role of the fibrinolysis system in the thrombolysis, blood vessels growth and remodeling, neurogenesis, carcinogenesis and fibrosis. The article is dedicated to the 90th anniversary of academician E.I. Chazov.

[Hemodynamic effects of the synthetic analogue of endogenous nitric oxide (II) donors a dinitrosyl iron complex in hypertensive patients with uncomplicated hypertensive crisis].

AIM: To examine the antihypertensive effect of the synthetic analogue of the endogenous nitric oxide donors in patients with grades 2-3 hypertension and uncomplicated hypertensive crisis (HC). SUBJECTS AND METHODS: The study included 30 male patients aged 35 to 73 years (mean age 55.5 ± 10.8 years). All the patients had grades 2-3 essential or secondary hypertension. Thirteen (43.3%) patients were observed to have signs of HC; 17 (56.7%) patients had persistent blood pressure (BP) elevation. A dinitrosyl iron complex was injected in a dose of 1.5 or 3 mg per kg of body weight. The purpose of its administration was to lower BP by at least 20% of its baseline level. RESULTS: No significant side effects associated with the administration of the test drug were recorded when the clinical trial protocol was implemented. All the patients reported fever and facial hyperemia during and 10-20 minutes after injection. They all (100%) showed efficient blood pressure reduction of at least 20% of the baseline level. Blood pressure changes were similar when the agent was administered in doses of 1.5 or 3 mg/kg. At 6-8 minutes after the drug was injected, there was a maximal decrease in blood pressure, then its gradual rise and stabilization at a lower level than the baseline one within the following 8 hours. There were no significant differences in the magnitude of a blood pressure reduction after administration of 1.5 and 3 mg/kg. CONCLUSION: The findings suggest that the dinitrosyl iron complex is highly effective in treating uncomplicated HC. The antihypertensive effect of the drug persists for 8 hours after its injection, which is very important during prehospital therapy. The drug is well tolerated by patients and causes an insignificant number of side effects.

[The study of hypotensive action of dinitrosyl-iron complex with glutathione containing drug oxacom in healthy volunteers].

On the basis of earlier executed studies of hypotensive effect of dinitrosyl iron complexes (DNIC) with glutathione, the drug has been created in industrial conditions named oxacom. Preliminary pharmacological studies of oxacom have not revealed negative qualities. The drug has been now tested in 14 healthy men in whom at single intravenous introduction it caused typical response - a decrease of diastolic as well as systolic arterial pressure on 24-27 mmHg through 3-4 min with subsequent very slow restoration in 8-10 hours. The heart rate after initial rise was quickly normalized. Echocardiography revealed unaltered cardiac output in spite of reduced cardiac filling by 28%. The multilateral analysis of clinical and biochemical data has revealed an absence of essential alterations which could lead to pathological consequences. The drug is recommended for carrying out of the second phase of clinical trial. The comparative study of the efficiency of hypotensive action of oxacom, S-nitrosoglutathione (GS-NO) and sodium nitrite (NO2) in rats has shown that the duration of effect was the greatest at oxacom action.

[Prospects of designing the medicines with diverse therapeutic activity on the basis of dinitrosyl iron complexes with thiol-containing ligands].

A stable hypotensive preparation (Oxacom) based on dinitrosyl iron complexes (DNIC) with glutathione has been developed. The preparation has successfully passed through pharmacological trials. The tests on volunteers have shown a high hypotensive activity of the preparation: a single intravenous infusion of its aqueous solution at a dose of 0.2 microM per kg of body weight led to a 20-30% decrease in arterial pressure, which persisted for a period of 15-20 h. Similar experiments on the animals demonstrated that aqueous solutions of DNIC with cysteine or glutathione exert also the hypotensive action due to their vasodilatory activity. Besides, these complexes accelerate wound healing and produce a potent erective action. There is reason to suggest that DNIC with thiol-containing ligands as NO donors can produce the cytotoxic action on the pathogenic mycobacteria Mycobacterium tuberculosis and, after respective treatment, inhibit cancer cell proliferation. These complexes can be used as analgetics, for inhibiting the adhesion process, in the therapy of preexplampsia, spermatogenesis pathologies, and in cosmetology for the treatment of skin injury.

[Action of a nitric oxide donor dinitrosyl complex of iron with glutathione on hemodynamics in rats and monkeys].

We studied action of a nitric oxide donor, dinitrosyl complex of iron (DNIC) with glutathione as a ligand on the hemodynamics of normotensive Wistar rats, spontaneously hypertensive rats (SHR), and monkeys. Intravenous DNIC introduction (2-120 mg/kg) rendered fast (1-2 min) hypotensive effect combined with increased heart rate by 10-25%. Second phase of the effect in Wistar rats was characterized by slowed recovery of arterial pressure and heart rate up to initial level. A gradual DNIC breakdown in blood occurred during this period associated with increased NO accumulation in organs with intensive oxidative metabolism (liver, heart, and kidney). Duration of hypotensive effect in all animals depended on dose, this dependence was most expressed in SHR.

[Cardioprotective efficacy of dinitrosyl iron complex with L-cysteine in rats in vivo].

The effect ofdinitrosyl iron complex (DNIC) with L-cysteine on the hemodynamic indices and the size of myocardial infarction, which was induced by 40-min regional ischemia and subsequent 60-min reperfusion, have been studied in rats in vivo. Intravenous bolus injection of DNIC (3.1 micromol/kg body weight in 0.5 ml saline) was performed before regional ischemia; the control group was administered the same volume of saline. DNIC administration significantly decreased the mean blood pressure throughout the experiment. DNIC reduced the duration of cardiac arrhythmias to 170 +/- 10 s as against 445 +/- 30 s in control. The myocardial infraction size significantly decreased in the DNIC group compared to control (38.0 +/- 1.4 and 48.0 +/- 3.9% of the area at risk, respectively; p < 0.05). A combination of the vasodilatory effect of DNIC with the reduction of the damaging effect of cardiac ischemia and reperfusion encourage the development of hypotensive and antiischemic drugs on this class of NO donors.

[Clinico-epidemiological program of the study of depression in cardiological practice in patients with arterial hypertension and ischemic heart disease (COORDINATA)].

UNLABELLED: COORDINATA - first Russian multicenter prospective (3 year long) study having the aim to elucidate prevalence of symptoms of anxiety and depression among patients with arterial hypertension (AH) and ischemic heart disease (IHD) and their influence on cardiovascular (CV) prognosis. Results of baseline epidemiological part of the study are presented. Results of prospective phase will be published in 2008. MATERIAL AND METHODS: Symptoms of depression and anxiety were assessed by validated in Russia Hospital Anxiety and Depression Scale (HDS) in 5038 patients with AH and/or IHD aged 55 years and older. Prevalence of CV risk factors was also studied and their association with anxiety/depressive symptoms were evaluated in a framework of multivariate regression analysis. RESULTS: Clinically significant symptoms of anxiety (HADS score >or=11) took place in 33 and 38%, symptoms of depression - in 30 and 38% of patients with AH and IHD, respectively. Relationship of symptoms of anxiety and depression was established with a number of psychosocial and biological risk factors of CV diseases (D) specifically low levels of education and income, insufficient level of physical activity, high level of chronic psychoemotional stress, exposition to acute stresses of great power, lack of social support, social isolation, elevated blood pressure level. It was shown that CVD comorbid anxiety and depressive states might cause excessive use of health care resources by patients.

[Depressive symptoms worsen prognosis in patients with arterial hypertension and ischemic heart disease: first results of prospective phase of Russian multicenter study COORDINATA].

COORDINATA - Russian multicenter prospective (3 year long) study having the aim to elucidate influence of symptoms of anxiety and depression on cardiovascular (CV) prognosis in patients with arterial hypertension (AH) and ischemic heart disease (IHD). Results of 1.5 years of prospective phase of the study are presented. Material and methods. Symptoms of depression and anxiety were assessed by Hospital Anxiety and Depression Scale (HDS) in 5038 patients with AH and/or IHD aged 55 years and older. By the end of 1.5 years follow up telephonic interview was carried out with 4449 patients or their relatives in the course of which occurrence of soft and hard end points (cardiovascular complications and deaths of IHD, cardiovascular and other causes) were established. There were 142 deaths (60.6% cardiovascular), 85 strokes, and 42 dynamic disturbances of cerebral circulation. Total number of hard and soft end points was 356 (8.0%). Presence of depressive, anxious, and combined anxious-depressive symptoms in patients with AH/IHD at initial examination increased 1.5 - 2 fold risk of development of cardiovascular catastrophes and death (due to IHD, CV and all causes). Besides psychological factors clear-cut influence on prognosis exerted sex, age, level of education and income of patients, smoking (both in the past and at inclusion in the study), low level of daily physical activity, elevated levels of blood pressure and heart rate, as well as a row of social characteristics of patients.

[Platelet activation and inflammation markers in patients with coronary heart disease and depression].

AIM: To study morphological features and functional activity of platelets, their relations with the level of inflammation markers in coronary heart disease (CHD) patients with depression. MATERIAL AND METHODS: The study group consisted of 33 CHD patients with stable effort angina (NY-HA FC I-III), 14 had depression, 19 were free of depression. Sixteen healthy volunteers comprised the control group. Platelet aggregation was registered by a mean size of aggregates and turbidometrically. Platelets shape, leukocytic-thrombocytic and erythrocytic-thrombocytic aggregates (LTA, ETA) in the whole blood were studied electron-microscopically. The levels of IL-2, IL-6, TNF-alpha, sVCAM, hsCRP were measured in the blood, serotonin--in platelets. RESULTS: Spontaneous aggregation enhanced in 52.6% CHD patients (p < 0.05). The blood contained reticular platelets, high number of prothrombocytes (p < 0.05), mean volume of thrombocytes was greater (p < 0.05). This reflected changes in megakaryocytopoiesis. Some of the patients had LTA and ETA. Out of inflammation markers, only IL-6 and sVCAM were elevated (p < 0.01), hsCRP concentration rose, but not above normal range. Serotonin in platelets was the same in the patients and controls. Depression aggravated the disorders and elevated other indices. Spontaneous aggregation was high in 71.4% of depressive CHD patients. The count of reticular platelets, prothrombocytes, mean volume platelets were also elevated. LTA and ETA were high in all the depressive patients. Elevated were also concentrations of IL-6, sVCAM, IL-2, hsCRP. Serotonin in platelets was low (p < 0.05). CONCLUSION: Depression stimulates functional activity of platelets, is a factor of risk of intravascular inflammation and contributes to development of thrombotic complications in CHD patients.

[New approaches to the study of central nervous system regulation mechanisms]. / Novye podkhody k izucheniiu mekhanizmov tsentralnoi nervnoi reguliatsii.

The paper discusses whether microdialysis can be used for follow-ups of the biochemical bases of human and animal brain functions. This technique provided evidence for varying norepinephrine levels in various brain regions when the appetite-regulating centers are artificially stimulated, as well as for nicotine-induced changes of serotonin. The paper also demonstrates this technique in monkeys while studying stress in particular. Evidence is also given for the possibility of using the technique to follow-up the biochemical processes occurring in the human brain in case of studying the levels of dopamine, serotonin, and purines in parkinsonian patients. The formation of the new direction in neurobiology--functional biochemistry of the brain--is stated in the paper.

Energy metabolism and ion fluxes across cardiac membranes.

The possible role of the intracellular creatine kinase system in energy transport and in the metabolic control of ion fluxes across the cardiac cell membranes has been studied. The experimental data reported indicate that creatine kinases bound to the sarcolemmal membrane and to the membrane of sarcoplasmic reticulum are coupled to Na+, K+-ATPase and Ca2+-ATPase, respectively, and ensure rapid rephosphorylation of ADP produced in the ATPase reactions, maintaining a high and constant ATP:ADP ratio near the active centers of ATPases. The ability of creatine phosphate to increase the rate of activator calcium entry across the surface membrane into cardiac cells has been experimentally demonstrated. It is concluded that the intracellular creatine kinase system can exert metabolic control of heart muscle contraction.