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The data relating to the pathogenesis of cerebral stroke, and the role of nitric oxide in the mechanism of its development is presented. Information on the changes of the expression levels of enzymes NOS, concentrations of nitric oxide and its metabolites in the ischemic regions of the brain is analyzed. The data on the connection between the NOS with other enzyme systems is shown. The possibilities of the use of nitric oxide in cerebral stroke are discussed.

The data, concerning anatomy of brain vessels and the main parameters of cerebral blood flow, including vascular dilation (nitric oxide, prostacyclin, endothelial hyperpolarising factor, estrogen, calcitonin) and vascular contracting (thomboxan A2, endotolin) agents, as well the interaction between them have been scrutinized. Emphasized the leeding role of vascular endothelium and nitric oxide in the regulation of cerebral circulation. Analysis have been done of mechanisms of neuron/vascular conjugent, autoregulation of the brain blood flow, effects of functional loading (hyperoxia, hypoxia, hypercapnia, hypocapnia, acidosis) on the cerebral circulation, the different reactions between them in central and peripheral circulations, oxidant stress, inflammantion. Pointed the significance of these data for the pathogenic mechanisms and therapy of cerebral insult, others physiological and pathophysiologic process in the brain.

The NO system plays an important role in pathogenesis of coronary heart disease. Disturbances of reperfusion associated with myocardial infarction and post-infarction heart failure are shown to be related to reduced synthesis and biological availability of NO. Variations of activity of three NOS isoforms (eNOS, nNOS, and iNOS) in patients with ischemic heart disease are linked to altered expression of the respective genes. They correlate with the character and severity of myocardial dysfunction. Cardiotropic effects of the above isoenzymes depend on their subcellular localization, interaction between themselves and between NO and reactive oxygen species, disturbed NO/redox balance, and other factors. Enhanced NOS activity and NO level at the premorbid stage of coronary heart disease have important implications for the prevention and treatment of this condition.

The effect of sodium nitroprusside, possible nitric oxide donor, on the activities of Ca2+, Mg(2+)- and Na+, K(+)-ATPases and lipid peroxidation was investigated in erythrocytes in vitro. Sodium nitroprusside caused 3-fold increase of mechanical and peroxidative erythrocyte hemolysis and also increase of bound malonic dialdehyde. Sodium nitroprusside-treated erythrocytes were also characterized by increased Na+, K(+)-ATPase activity.

It is shown that intracoronary infusion of L-arginine and sodium nitroprusside induces an increase in coronary flow (CF), myocardial contractility (MC) and heart rate (HR) in the isolated perfused heart of the rat. Three combinations of these effects have been observed in different experiments: generalized effect (increase of CF + MC + HR), a double effect in three variants (increase of CF + MC, CF + HR, MC + HR) and isolated effect (increase of CF or MC or HR). The data obtained suggest that an increase of CF is the main change induced by L-arginine in the isolated perfused heart, an increase of MC being secondary in relation to a CF increase, i.e. an increase of CF mediates an increase of MC (Gregg's phenomenon). A positive inotropic effect of sodium nitroprusside is the result mainly of its direct action on the myocardium and to a lesser extent due to a CF increase.

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. Adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5-6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate a significant role of correction of endothelial NO deficiency in the antihypertensive effect of adaptation to hypoxia.

Brief description of the system L-arginine--nitrogen oxide (NO), of mechanisms of NO production and secretion by vessels endogelium. Discussion of the generalised regional NO effects on the cardio-vascular system role of NO in regulation of vessels tone and of blood circulation in different sections of the vascular flow, including microcirculation. Data on NO impact on endogelium-dependent vasodilatators, on the effect of activation of vessels ventilation, on the "heterogenic" nature of this function in different sections of the vascular system, in vessels of different diameter. Detailed discussion of the issue of acute and chronic increase of the systemic arterial blood pressure in response to NO inhibitors effect on NO-synthetase. Description of the specific features of "NO-deficit hypertension", role of low NO production as a major pathogenic factor of other forms of arterial hypertension, analysis of mechanisms of the relevant effects at the systemic, organic, cellular levels. Special emphasis on the role of NO in regulation of the coronary blood circulation in lungs and on other issues. Comparisons of the experimental and clinical observations on some aspects of the problem under discussion. Justification of the need for further research of the NO system in physiology and pathophysiology of the cardio-vascular system.

Recent data concerning the physiological, biochemical and pathological aspects of NO and CO in the brain are reviewed. Among them: biosynthesis, regulation and localization of corresponding enzymes (NOS, GO-2) and also cGMP in discrete populations of neurons; interrelationship between glutamate, NMDA-receptors, NO and CO; the role of NO and CO in different physiological and pathological processes in the nervous system, etc. On the basis of data obtained during the last several years, a conception of NO and CO as a novel class of signal molecules operating as neuromediators and/or retrograde transsynaptic messengers is discussed.

Participation of renal prostanoids in development of diabetes-induced nephropathy was studied in rats with streptozotocin diabetes. Development of diabetic nephropathy occurred with simultaneous decreases in production of intrarenal natriuretic, depressor prostaglandin and prostacyclin as well as with increases in content of antinatriuretic, pressor, prothrombogenic TxA2. The imbalance observed in the production of renal prostanoids contributed slightly to impairments of hemodynamics, osmo- and ion regulating functions of kidney, i.e. to formation of diabetic nephropathy in the experimental animals.

The immobilization- and sound stimulus-induced changes in cerebral circulation were studied in spontaneously hypertensive rats. It was found that there was a stress-induced increase in the levels of epinephrine and norepinephrine in brain tissue, which was associated with lower levels of vasoactive prostaglandins E and F2 and with their imbalance with vasodilator prostaglandins E being prevalent. The change in the cerebral ratio of biologically active substances results in cerebral blood flow autoregulation failure and development of large cerebral hemorrhages.

A study was made of renin-angiotensin-aldosterone system activity and plasmic concentrations of atrial natriuretic peptide (NUP) as well as antidiuretic hormone in children with primary glomerulonephritis. A close relationship was established of these parameters in regulation of water-salt homeostasis. The above systems are involved in pathogenesis of childhood glomerulonephritis. This finding should be considered in development of pathogenetically validated therapy of glomerulonephritis, including introduction of synthetic NUP.

The experiments performed in endothelin-denuded preparations (the strips of thoracic aorta and perfused tail arteries) showed that: 1) ET-1 exerts dose-dependent and slowly developing contractions and in subthreshold doses it potentiates vasoconstriction reactions to stimulate sympathetic nerve endings or phenylephrine exposure. 2) ion F(-), that activates G-proteins in the cell membranes, at a dose of 2 microM increased about two times the ET-1-induced vasoconstriction. 3) the aortic strip incubation with the protein kinase C inhibitor staurosporin led to a 50% decrease in the contraction amplitude. Results suggest that G proteins and protein kinase C may participate in the development of ET-1 induced vascular smooth muscle contraction.

Under study were effects of intravenous infusions of a new emulsion, alpha-tocopherol, on the development of diabetic microangiopathy, platelet alpha-tocopherol level, ADP-induced platelet aggregation level, exogenic (from 14C-arachidonic acid) thromboxane (TxA2) biosynthesis in suspension of washed platelets and of prostacyclin (PgI2) one in isolated aortic rings of rats with streptozotocin-induced diabetes. Six-week injections of alpha-tocopherol in a dose 100 mg/100 g b. w. with 48 h intervals immediately after development of streptozotocin-induced diabetes prevented the development of diabetic angiopathy but did not normalize platelet functional activity and PgI2/TxA2 balance in vessels and platelets. Similar injections of alpha-tocopherol in the presence of developed angiopathy resulted in its regressive development and normalization of the before-said prostanoid balance and platelet characteristics.

Some mechanisms responsible for extracellular Ca++ entry into rat aortic smooth muscle cells were studied in response to endothelin-1 (ET-1). Isometric tension of de-endothelialized aortic strips was recorded. It was shown that the calcium-free medium or nifedipine blockade of calcium entry diminished responses to ET-1 to 20-30% of the control levels. Depolarization of the specimens with hyperpotassium solution also reduced constriction almost by 50%. When sodium ions were replaced by NMDG in the medium, a response to ET-1 showed a 50% reduction. The findings suggest that the potential-dependent calcium channels of the L-type are involved in cellular calcium entry, the opening of the channels depending upon the entry of Na+.

The angiotensin-converting enzyme inhibiting agent captopryl suppressed a moderate hypertension in rats with pyelonephritis and with ureteral obstruction, but not in rats with ureteral obstruction combined with the renal artery constriction. The suppression of the hypertension was accompanied by a reversion of structural alterations in the blood vessels.

The effects of endothelin on intracellular pH (pHi) were examined in cultured rat vascular smooth muscle cells (VSMC) using the fluorescent probe BCECF. Endothelin induced biphasic changes in pHi: initial decrease followed by a subsequent increase above the basal level due to activation of the Na+/H+ exchange. The elevation of pHi was slow and sustained, but depended on the dose of endothelin: IC50 was about 3 x 10(-8) M. Na+/H+ exchange inhibition by EIPA (10(-7) M) or by equimolar replacement of external Na+ by choline abolished the pHi increase by enhancing the first phase of cytoplasm acidification. Effects of endothelin were compared with the action of protein kinase C (PK-C) activator phorbol 12-13 myristate ester (PMA). PMA induced a monophasic slow and sustained increase in pHi. The treatments of VSMC with H-7 and staurosporine (PK-C) inhibitors prevented the pHi response to endothelin and PMA. These results suggest that protein kinase C may play an important role in mediating the effects of endothelin on Na+/H+ exchange in VSMC.

Using the fluorescent probe, BCECF, the changes in intracellular pH (pHi) in rat peritoneal mast cells were studied. alpha-Thrombin (0.1 nM) induced biphasic changes in pHi which consisted in a temporary decrease in pH with its subsequent steady increase due to the Na/H exchange activation which was inhibited by EIPA and controlled by extracellular Na+. The biphasic changes in pHi induced by DIP-alpha-thrombin (0.1 pM-1 nM), a catalytically inactive form with an intact recognition site, were similar to those of alpha-thrombin, whereas beta/gamma-thrombin (10-1000 pM), a catalytically active form characterized by structural disturbances in the recognition site, was able to induce only the initial phase of acidification. The thrombin recognition site modulators, alpha 1-thymosin and heparin, blocked the ability of the enzyme to induce the alkalinization of pHi. Nigericin stimulated the Na/H-exchange in mast cells. The rate of the Na/H-exchange activation determined with nigericin, decreased with an increase in the alpha-thrombin dose from 0.1 pM up to 10 nM. Activation of protein kinase C (PKC) in mast cells by PMA used at 1 nM and 10 nM led to the alkalinization of the cytoplasm as a result of the Na/H-exchange activation blocked by EIPA. The PKC inhibitor, H-7, suppressed the pHi increase induced by both PMA and alpha-thrombin. The alpha-thrombin-induced acidification of the cytoplasm was completely blocked by SITS in Ca(2+)-free media, whereas in media with Ca2+ SITS inhibited the pHi decline. Acidification of the cytoplasm by thrombin seems to be due to both Ca2+ influx and activation of Cl- fluxes. It is concluded that the observed activation of the Na/H-exchange by thrombin is induced by a cascade of intracellular reactions involving PKC.

In experiments on mice resident and stimulated thioglycolate macrophages the changes in cytoplasmic Ca2+ concentration Ca2+ have been studied by the use of the fluorescent probe fura-2. PAF acether (10(-7) M) raised Ca2+ by 300-400 nM within 1 min only in the stimulated macrophages. In the resident cells this increase was much less. In the presence of 2mM EGTA, PAF raised Ca2+ to a lesser extent. This suggests that PAF causes influx of exogenous Ca2+ through the receptor-mediated channels as well as releasing Ca2+ from intracellular stores.

In accordance with the results of examining 40 children with nephrotic and mixed glomerulonephritis, it has been established that in the pathogenesis of the nephrotic syndrome of paramount importance is imbalance of the output of renal prostanoids, manifesting in the predominance of the vasopressor and proaggregate fraction--thromboxane A2 and in the deficiency of its antagonist prostacyclin that exerts a protective action on glomerular filtration. Sodium and water retention in patients with the nephrotic syndrome favours an increase of the content of antidiuretic hormone and plasma renin activity.

Considerably increased production of cardiac prostanoids and intensified linoleic acid metabolism in the cardiac phospholipids were revealed in physiological myocardial hypertrophy in animals trained by swimming. The formation and secretion of cardiac prostanoids was found to be essentially reduced in pathological myocardial hypertrophy in rats with hereditarily determined arterial hypertension, which is attributed to inhibition of the metabolism of linoleic and linolenic acids in the cardiac phospholipids and to structural and functional disorders in the function of the heart.

The excretion of renal prostaglandins (PGE, PGF2 alpha, 6-keto-PGE1 alpha and TKB2) was studied in 45 children with chronic obstructive pyelonephritis in the presence of vesicoureteral reflux with account for the disease stage (partial remission--group I; total clinical and laboratory remission--group II) in various periods of surgical corrections of the impaired urodynamics in the area of vesicoureteral segments (in the early postoperative period of 12-14 days after the surgery; in the follow-up period of 6-12 months after the surgery). Preoperative observation of Group I children revealed a significant decrease in urinary PGF2 alpha excretion in the presence of an increase in the circadian TKB2 and 6-keto-PGF1 alpha excretion, whereas the patients from Group II who had normal levels of TKB2 and 6-keto-PGF1 alpha excretion, the levels of PGE and PGF2 alpha were lowered. The retention of sodium was documented in both groups. There was a total recovery of renal sodium and water excretion 6-12 months after the surgery. Children without the urinary syndrome (group II) demonstrated normalization of all secreted prostanoids, whereas in those with pronounced severity of pyelonephritis (group I), the excretion of sodium and diuresis were likely to be provided by hyperproduction of vasodilating sodium and diuretic PGE.

The radiological method was used to study the level of prostaglandins E + E, GF2 alpha and LTB4 in the blood plasma and the synovial fluid in 138 children with rheumatoid and other arthritis and noninflammatory diseases of the joints. The role of PGE + A and LTB4 in the pathogenesis of arthritis and low participation of PGF2 have been established. Determination of prostanoids in biological fluids can be used as an additional laboratory index to reveal the general and local activity of the pathological process in rheumatoid and other arthritis and distinguish them from noninflammatory diseases of the joints.

Experiments on 5 test and 16 control Wistar-Kyoto rats have shown that streptozocin diabetes mellitus complicated by proteinuria is characterized by the following changes of the fatty acid spectrum of platelet phospholipids: a decrease in the content of C18:2p6, C18:3p3, C20:4p6, C20:3p9, C20:5p3, in the sum of fatty acids of the linoleic group and the ratio of unsaturated/saturated fatty acids and an increase in the content of C18:0, C20:2p6 and C20:3p6. These changes were accompanied by an increase in the platelet aggregation ability, an increase in their synthesis of thromboxane A2 and a decrease in the synthesis of prostacyclin I2 by vascular endothelium and account for them, to a certain degree. The obtained results are promising with relation to achieving a positive effect of the diets, rich in linoleic acid, for prophylaxis of vascular complications in diabetes mellitus.

The authors studied the effect of diabetes mellitus on the renal prostanoid (PN) system in rats with spontaneous hypertension. Marked changes of renal PN excretion, biosynthesis, and metabolism were revealed. The absence of signs of diabetic nephropathy in rats with hereditary determined hypertension may be attributed to increased production of prostaglandin E and prostacyclin. These PN augment the renal blood flow, prevent sodium retention in the organism, and inhibit the progress of arterial hypertension which is one of the signs characteristic of diabetic nephropathy.

The binding 14C-aldosterone by plasma globulins in vitro was studied in healthy adolescents and in those with primary arterial hypertension (PAH). In most of the patients examined hyperaldosteronism was found, which was attended by an increased percentage of 14C-aldosterone binding with aldosterone binding globulin (ABG) and particularly with glucocorticoid binding globulin (GBG). One and half hours of walking caused n changes in the parameters studied in healthy adolescents; in those with hyperaldosteronism the content of aldosterone in blood was considerably reduced, while in patients with a normal initial aldosterone level in blood, it increased with no essential changes in the ability of plasma globulins to bind labelled aldosterone. Two-week treatment of PAH patients with propranolol caused a sharp increase in the plasma aldosterone content and 14C-aldosterone binding with ABG and GBG. It is concluded that the determination of labeled aldosterone binding by plasma proteins is important for indirect judgement of metabolic aldosterone clearance.

The effect of prostaglandin E2 on the biosynthesis of corticosteroids was studied in intact rabbits and in the ones with vasorenal hypertension in different periods of its development (1st group) and in the animals subjected to a spurious operation (2nd group). Prostaglandin added to an incubation medium was found to produce in intact rabbits a significant depression of the 11-dehydrocorticosterone and cortisone biosynthesis from progesterone-C14. In rabbits operated upon (1st and 2nd groups) prostaglandin E2 brought changes in the production of corticosteroids no sooner than in 1 month after surgery. In rabbits with vasorenal hypertension brought about through unilateral constriction of the renal artery with an intact second kidney the content of the labeled 11-desoxycorticosterone and 11-desoxycorticosol materially decreased under the effect of prostaglandin E2, while the biosynthesis of the end fractions--11-desoxycorticosterone, aldosterone and cortisone, would gain in intensity. These changes preceded somewhat the most significant rise of the arterial pressure. In the rabbits spuriously operated upon prostaglandin E2 increased the production of corticosteroids and 11-dehydrocorticosterone, low at that time. It is presumed that prostaglandin E2 produces a regulating influence on the processes of the corticosteroids biosynthesis both in normalcy and in vasorenal hypertension.

Structurally based resistance and vascular reactivity of the posterior body to noradrenaline were studied in normotensive rats and rats with DOCA-salt hypertension. The hypertension was induced in rats with intact sympathetic nervous system and in rats subjected to neonatal sympathectomy with guanethidine. During the prehypertensive stage, vascular sensitivity of the smooth muscles to noradrenaline was enhanced, with structural lesions being observed only in steady hypertension. Elevation of arterial pressure was accompanied by an increased vascular response to the stimulation of the sympathetic nerves. Sympathectomy prevented arterial pressure elevation and structural alterations in the vessels.

The elevation of the cardiac index was discovered at the initial stage of DOCA-salt hypertension in rats. The blood pressure rise at the stage of stable hypertension was caused by an increase in the total peripheral vascular resistance. Neonatal sympathectomy prevented the development of DOCA-salt hypertension and elevation of the cardiac index revealed in control sympathectomized rats.

The biosynthesis of PGE2, PGF2, PGI2 alpha from 14C-arachidonic acid and the catabolism of 3H--PGF1 alpha and 3H--PGE2 were studied in kidney, aorta and lung homogenates of young (1.5 months) and adult (3.5 months) Wistar rats. An increased synthesis of PGE2 was found in aorta and kidneys and PGI2 in lungs and heart of young rats. PGE2 alpha synthesis in kidneys and aorta underwent no alteration with age. The 3H--PGE2 catabolism in lungs and kidneys was more intensive in young rats whereas the 3H--PGF1 alpha degradation did not differ in various age groups but somewhat decreased with age in lungs. Close correlation was found between the biosynthetic coefficients PGF/PPE in kidneys and the AP level in young rats. A reciprocal interrelationship was found between the biosynthetic and the catabolic coefficients PGF/PGE in kidney, aorta and lungs of young and adult rats. This results in a balance of synthesis and catabolism of prostaglandins in kidney and lungs which prevents release of great quantities of prostaglandins from the sites of their synthesis into the systemic circulation. In other words, the processes of biosynthesis and catabolism of prostaglandins in the organism maintain a constant level of these biologically active substances in the systemic circulation.

Calcium binding was significantly reduced, and lipid microviscosity increased, in platelet membranes and erythrocyte shadows of spontaneously hypertensive rats (SHR). Their platelet sensitivity to calcium was already increased at the prehypertensive stage, and the rate of A23187-induced platelet aggregation was increased significantly by 24 weeks of life. The demonstrated biochemical properties of SHR's platelet membranes can account for their increased aggregative capacity and may be important in the pathogenesis of arterial hypertension.