[Metabolic disturbances as a factor of the pathogenesis of hypertensive disease and its clinical outcomes].

AIM: To identify and determine the mechanisms of an association between arterial hypertension (AH) and proatherogenic systemic metabolic disturbances in hypertensive disease (HD), as well as the possibility of eliminating these disturbances by antihypertensivetherapy. SUBJECTS AND METHODS: Fifty-four patients with HD and 64 persons randomly selected from an unorganized urban population were examined. Systolic and diastolic blood pressure (BP), insulin sensitivity, the most important metabolic parameters of lipids, lipoproteins, and glucose, the degree of systemic inflammation and oxidative stress, and the rate of lipoprotein proatherogenic and immunogenic modification were determined. RESULTS: All the patients with HD were found to have a regular concurrence of AH with systemic inflammation and activated free-radical reactions, metabolic abnormalities, such as atherogenic dyslipidemia, insulin resistance, atherogenic and immunogenic modified lipoproteins. Antihypertensive treatment failed to eliminate metabolic disturbances even when BP control was fully restored. CONCLUSION: AH and systemic metabolic disturbances in HD have a common pathogenetic basis and the treatment of hypertensive patients should provide the normalization of not only BP, but also inflammatory and oxidative status and systemic metabolism.

[Hypertrygliceridemia as a factor of atherogenesis: significance and mechanisms of action].

The aim of the study was to investigate the pattern of lipid and lipoprotein metabolism disturbances in patients with manifested clinical signs of coronary atherosclerosis. There was determined the significance of hypertrigliceridemia as the marker of these disturbances and its connection with other most important factors of atherogenesis such as insulin resistance, systemic inflammation, and oxidative stress, blood lipoprotein modification. The role of excessive alimentary lipid consumption as a factor, which initiates the hypertrigliceridemia development and accompanying activation of the other proatherogenic factors was determined with the use of acute lipid loading. It was established that hypertrigliceridemia is one of the most reliable signs ofatherosclerosis existence but it coincides as a rule with other signs of dislipidemia, a decrease in insulin sensitivity, systemic inflammation and lipid free radical oxidation development. The modification of blood lipoprotein and increase of blood atherogenic potentials were the integral effects of these factors. Significance of hypertrigliceridemia as the factor initiating all these disturbances both in normal volunteers and in examined patients was shown in conditions of acute lipid loading which was accompanied by the development of the whole complex of proatherogenic disturbances. It was established that the development of atherosclerosis is connected with the decrease of lipid tolerance and as a result the same lipid loading was accompanied with proportional increase of both hypertrigliceridemia and connected with it proatherogenic disturbances. The obtained data allowed concluding that hypertrigliceridemia is the factor which can initiate the proatherogenic systemic disturbances which include changes in lipid, lipoprotein and glucose metabolism, the development of insulin resistance, systemic inflammation and oxidative stress. These changes are pathogenically interconnected, capable to amplify one another and induce blood lipoprotein modification with appearance of both proatherogenic and autoantigenic propertries, which stipulate the role of hypertrigliceridemia in atherogenesis.

[The presence and characteristics of interrelations between lipid metabolism disorder and systemic inflammation].

The aim of the investigation was to determine the existence and describe interconnection between the lipid metabolism disturbances and development of systemic inflammation. The work was carried out on rabbits in two series of experiments: in the first one, the model of inflammation was reproduced by means of intravenous injection of bacterial lipopolysaccharide. In the second one, the model of lipid disturbances induced by lipids enriched diet was reproduced. In both series of experiments, the indexes of inflammation and oxidative stress intensity, metabolism of lipids and lipoproteins, insulin sensitivity, blood lipoprotein proatherogenic and immunogenic modification were determined. The data obtained confirmed the existence of distinct direct links between investigated influences: during the primary induced inflammation we observed pronounced disturbances in lipid and lipoprotein metabolism, while under the primary induction of lipid disturbances the systemic inflammation and oxidative stress were developed. The connection between the action of both influences was greatly mediated by their ability to induce insulin resistance. There was also shown that the interrelation between these factors is the cause of blood lipoprotein proatherogenic and immunogenic modification, which is the main effector mechanism of atherosclerosis development and progression.

[Hyperlipidemia and decrease of lipid tolerance as factors of atherogenesis].

In experiments performed on rabbits the influence of acute and chronic alimentary lipid loading on the pathogenic factors of atherosclerosis was examined. A single moderate lipid loading even in normal rabbits was established to induce a transitory development of the proatherogenic changes, which includes appearance of dislipidemia of diabetic type, activation of systemic inflammation and free radical reactions, blood lipoprotein modification. Prolonged keeping of rabbits on the diet enriched with lipids induced the development of complex changes which are typical for insulin resistance with specific lipid and lipoprotein metabolism disturbances, increased plasma atherogenic potential, activation of systemic inflammation and oxidative stress. We also noticed a sharp decrease of lipid tolerance and acute lipid loading was accompanied by more pronounced changes than in normal rabbits. The data show that the excessive consumption of alimentary lipids can induce the development and sharp activation of atherosclerosis pathogenic factors.

[Modified lipoproteins--their types and role in atherogenesis]. / Modifikovani lipoproteïny--typy ta rol' v aterohenezi.

In the performed clinical and experimental investigation there were determined the significance of lipoprotein modification in atherogenesis and the mechanisms of blood atherogenicity development. The pronounced changes of total blood cholesterol and the spectrum of lipoproteins in patients with coronary atherosclerosis were not regular and were noted only in 40-55% cases. The most regular was the increasing of blood atherogenicity, reflecting the appearance of the great amount of modified lipoproteins. One of the most important modifying factors was oxidative stress induced by the activation of blood inflammatory cells. These data were confirmed in investigations on children with acute respiratory inflammatory diseases and on rabbits with the models of acute inflammation. The other important mechanism of blood atherogenicity was the increasing of blood lipoproteins enriched with triglycerides; that led to secondary monocyte activation and oxidative stress development. The usage of lipid-lowering drug lipantil in coronary patients not only decreased the amount of cholesterol and tryglicerides in blood but also lowered blood atherogenicity and suppressed the oxidative stress. Thus the results show the existence of at least two ways of atherogenic lipoprotein formation--in the course of oxidative modification and under the enrichment with tryglicerides as a result of the lipolysis disturbances with subsequent slowing of the formation and elimination of these lipoprotein remnant forms from blood.

[The role of a systemic inflammatory process in the atherogenic modification of lipoproteins and the development of hypercholesterolemia]. / Rol' systemnoho zapal'noho protsesu v aterohennii modyfikatsiï lipoproteïniv i rozvytku hiperkholesterynemiï.

The aim of the investigation was the determination of the systemic inflammatory process significance as a casual factor of the atherogenic blood lipoprotein (LP) modification and hypercholesterolemia (HCE) development. The availability of the HCE and atherogenic LP in blood of the patients with chronic coronary disease was established to coincide with the distinct sighs of the inflammatory process such as monocytes activation and oxidative stress development. Under the primary character of the inflammation--in children with acute respiratory infectious diseases and in conditions of experimental rendering of acute inflammation in rabbits by the intravenous injection of latex microspheres or pyrogenal there was also determined the distinct dependence between monocytes activation, increasing in blood free radical processes intensity, LP atherogenic modification and HCE development. The dependence was confirmed by the results of the paired correlative analysis. The obtained data allowed to draw a conclusion that the systemic inflammatory process and induced by it free radicals reactions in blood were the independent causal factors of atherogenesis.

[The pathophysiological basis of the destabilization of the clinical course in ischemic heart disease]. / Patofiziolohichna osnova destabilizatsiï klinichnoho perebihu ishemichnoï khvoroby serdtsia.

The role of the coagulative blood system in initiation of acute coronary events was investigated on patients with different clinical forms of ischemic heart disease (IHD). The obtained results indicate that unstable angina (UA) and myocardial infarction (MI) are two independent forms of the acute IHD with distinct qualitative peculiarities. The most common feature of UA was an increase in the functional activity of platelets both in cases proceeded in MI and in uncomplicated cases. It means that these changes may be treated as the main pathogenic factor if UA but not as a mechanism of its transformation to MI. But high degree of the risk of MI development appears if these changes are combined with preceding significant disturbances in the haemostatic balance as a result of inhibition of the activity of anticoagulative and fibrinolytic blood systems. These data show that differentiation of the diagnosis between UA and MI in its initial stage and the choice of the treatment principles should be based on the careful investigation of the coagulative potential of blood and of its most important components.

[Activation of free-radical processes as a factor of ionizing radiation-induced changes in contractile activity of a vascular wall]. / Aktyvatsiia vilnoradykalnykh protseciv iak faktor porushennia skorochuvalnoi aktyvnosti sudynnoi stinky pid diieiu ionizuiuchoi radiatsii.

The influence of ionizing irradiation (1, 2 and 4 Gy 137Cs) on both the activity of free-radical processes in plasma, formed elements and aorta wall as well as on the character of contractile vascular reactions of isolated rings of thoracic aorta and carotid artery in rabbits has been studied. The experiments were carried out on the 7th day after the whole-body irradiation. The results indicate that simultaneously with the weakening of antioxidant mechanisms both endothelium-dependent and endothelium-independent vascular wall relaxation slightly decreases after 1 Gy exposure. Noradrenaline and KCI-induced contraction is shown to increase. However, these changes are not statistically significant. Irradiation in dose of 2 and 4 Gy considerably decreases endothelium-dependent relaxation. Nitroglycerin-induced relaxation greatly diminishes, KCI- and noradrenaline-induced constriction considerably increases in these conditions. The level of activation of free-radical processes considerably increases too. Thus, already on the 7th day after irradiation significant changes in reactivity of vascular wall are developed. Radiation injures both endothelium and vascular smooth muscle cells. The free-radical processes seem to be the main cause of radiation vascular damage, so there is a pronounced correlation between the changes of vascular contractile properties and the degree of activation of these processes.

[The vascular protective effect of the combined administration of magnesium chloride and antioxidants in prolonged hypercholesterolemia ]. / Angioprotektorna efectyvnist poiednanogo vykorystannia khlorystogo magniiu ta antyoksydantiv v umovakh tryvaloi giperkholesterynemii.

The angioprotective efficacy of combined application of magnesium chloride and antioxidants during prolonged hypercholesterolemia has been investigated on the experimental model of atherosclerosis in rabbits. The application of magnesium chloride and acetate tocopherol from the very beginning of the atherogenic diet is shown to exert a pronounced angioprotective effect preventing the development of structural and functional changes in the aorta wall. If the treatment is initiated against the background of the well developed atherosclerotic symptoms, its efficacy is less pronounced but remains still on a quite high level. These data indicate that combination of magnesium chloride and antioxidants has not only protective action but can also induce partial regression of the developed atherosclerotic changes.

[Character and mechanisms of changes in vascular wall reactivity in prolonged hypercholesterolemia]. / Kharakter i mekhanizmy izmenenii reaktivnosti sosudistoi stenki v usloviiakh dlitel'noi giperkholesterinemii.

Changes in the structure and functional properties of the vascular wall after 8 months of alimentary hypercholesterolemia (HCE) were studied. The experiments were conducted on the circular bands of the arch of the aorta in rabbits. Sharp inhibition of the reactivity of the vascular bands was established, which was associated first of all with thickening of the intima due to the development of fibro-atheromatous changes in it. At the same time, the smooth-muscle cells of the vascular wall maintained marked reactivity to various direct and receptor-mediated test effects. The functional significance of the endothelium in regulation of the vascular tonus, manifested by weakened endothelium-dependent relaxation, was sharply inhibited in the late stages of HCE. It is shown that reduction of the sensitivity of the smooth-muscle cells to the endothelium-dependent relaxation factor is the principal factor of weakening of the endothelium-dependent dilatational effects. After 8 months of HCE the aortic wall is capable of liberating a substance which is similar to the endothelium-dependent relaxation factor in its action, even when the thickened intima is completely removed.

[Efficacy of vascular wall protection from atherosclerotic damage using various calcium antagonists]. / Effektivnost' zashchity sosudistoi stenki ot ateroskleroticheskogo povrezhdeniia razlichnymi kal'tsievymi antagonistami.

The authors studied the effect of various calcium antagonists--verapamil (VP) and Mg2+ (MgCl2) on the character of affection of the vascular wall ulcer conditions of prolonged hypercholesterolemia (HCE). The blood cholesterol (CS) content increased by the end of the 8th month of HCE to eight-fold the value in intact animals. The specific atherosclerotic changes in this case occupied approximately 80% of the area of the thoracic aorta whose functional properties changed essentially. The values of constricting responses of bands to noradrenaline (NA) was 45% of that in intact rabbits, the dilatating responses to acetyl choline (AC) and nitroglycerin (NG) were 20% and 35% of those in intact animals, respectively. Combination of HCE with daily VP injection (1 mg) led to a decrease in the area of affection of the aorta by 20%, which hardly affected the severity of HCE. A slightly more pronounced than in animals only with HCE (controls) was the response of bands to NA, AC, and NG (by 5, 30, and 15%, respectively). The protective effect of MgCl2 (200 mg/kg) was more significant--the affected area of the thoracic aorta reduced by 50% as compared to the controls, the constricting response to NA was maintained at a level exceeding the control level by 25%, the dilatating responses to NG and AC exceeded the control values 2 and 1.5 times, respectively, on the average. The severity of HCE diminished by 50%. The results of the study indicate that the organic and, in particular, the inorganic blocking agents of the calcium canals possess a marked angioprotective action and may be applied for the prevention of vascular atherosclerosis.

[Functional state and adrenergic reactivity of the myocardium in experimental atherosclerosis]. / Funktsional'noe sostoianie i adrenoreaktivnost' miokarda pri éksperimental'nom ateroskleroze.

The authors studied the changes in the functional properties of a rabbit heart in protracted alimentary hypercholesterolemia (HCE). It is shown that HCE has a little effect on the characteristics of myocardial contractility and adrenergic sensitivity. In protracted HCE the probability of the occurrence of a myocardial own rhythm in response to the effect of isoprenaline increased. HCE with simultaneous vasopressin administration failed to change the contractile properties of the myocardium but had a marked effect on the adrenoreceptor apparatus. The sensitivity of muscles to isoprenaline and phenylephrine increased significantly. The possibility of the appearance of a myocardial own rhythm increased. The results of the study are indicative of the essential role of vasospasm in the development of atherosclerotic myocardial injuries.

[The effect of various regimens of postischemic reperfusion on the recovery of the functional activity of the myocardium]. / Vliianie razlichnykh rezhimov postishemicheskoi reperfuzii na vosstanovlenie funktsional'noi aktivnosti miokarda.

Postischemic reperfusion of isolated canine hearts after 30 min of 80-85% blood supply limitation was performed during 60 min with perfusion pressure raised to 135 mm Hg instead of 100 mm Hg in the control. The data obtained suggest that myocardial blood supply increased by reperfusion affected the restoration of cardiac function. The optimal result of the reperfusion was achieved in the condition of decreased perfusion pressure in the early phase of reperfusion combined with the Inosie-F infusion.

[The dynamic changes in the functional characteristics of the vascular endothelium and smooth muscle cells under conditions of long-term hypercholesterolemia]. / Dinamika izmenenii funktsional'nykh kharakteristik éndoteliia i gladkomyshechnykh kletok sosudov v usloviiakh dlitel'noi giperkholesterinemii.

The course of the rabbit aortic wall reactivity changes due to hypercholesterolemia involved, in the first place, the inhibition of the endothelium relaxing influence on the smooth muscle contractile activity and an increase in the muscle sensitivity to neurogenic and humoral tonic influences. Later, a sharp inhibition of the vessel's wall functional activity occurred due to a mechanical factor: the development of connective tissue which prevents active vascular reactions. Nevertheless, endothelial and smooth muscle cells functional activity was high enough. The main cause of the vascular reactivity disturbances involved structural changes in the vessel wall whilst the direct influence of high blood cholesterol was much less obvious.

[Effects of hypercholesterolemia on the electrical and contractile properties of the blood vessel wall]. / Vliianie giperkholesterinemii na élektricheskie i sokratitel'nye svoistva sosudistoi stenki.

The investigations were performed on the ring strips of rabbit aorta. The electrical activity of the vessels smooth muscle cells was registered by the "sucrose gap" method; the contractile activity of the strips was determined simultaneously. Experimental atherosclerosis was induced by keeping rabbits on a special diet enriched by cholesterol for 2 and 4 months. Strips were prepared with intact or mechanically removed endothelium. Hypercholesterolemia was shown to inhibit the reactivity of the vessel's wall to the weakening action of acetylcholine due to endothelial stimulation. The cause of these changes was the inhibition of the endothelial functional activity and inactivation of mechanisms by which endothelium influences smooth muscle cells.

[Mechanisms of verapamil prevention of disorders of cardiac contractile function during ischemia and reperfusion]. / Mekhanizmy preduprezhdeniia verapamilom narushenii sokratitel'noi funktsii serdtsa pri ishemii i reperfuzii.

A dog heart isolated according to Langendorf was used to study the effect of verapamil, used as a preventive measure, on the contractile function of the heart, its work and oxygen consumption, and the coronary blood flow in modelled coronary insufficiency and after restoration of blood supply to the myocardium. The results provide evidence that verapamil prevents significant decrease of the efficacy of myocardial functioning in ischemia, owing to which the heart maintains a higher level of performance under conditions of inadequate blood supply, the development of acidosis is prevented, and reperfusion disorders of cardiac function are removed completely. This effect is mediated to a great measure by maintenance of high economy of heart performance due to verapamil.

[Morphofunctional analysis of the efficacy of verapamil in experimental ischemia]. / Morfofunktsional'nyi analiz éffektivnosti verapamila pri éksperimental'noi ishemii.

The authors made a comparative analysis of structural and functional changes of the myocardium of 21 dogs after a 30 minute limitation of the blood circulation in the circumflex branch of the left coronary artery with subsequent 30-minute reperfusion during intravenous administration of verapamil in the period and before the beginning of limitation of the coronary circulation. Verapamil produced an essential cardioprotective effect during its preventive use. The effect was less pronounced when the agent was administered after the development of ischemia.

[Ionic mechanisms of endothelium-dependent relaxation of vascular smooth muscle under the action of acetylcholine]. / Ionnye mekhanizmy éndoteliizavisimogo rasslableniia gladkikh myshts sosudov pod deistviem atsetilkholina.

Acetylcholine and nitroglycerin were shown to induce relaxation in muscles of the ring vascular segments of canine coronary arteries and rabbit aortic archs, the magnitude of the reaction depending on the level of initial tonic tension. Methylene blue abolished the relaxation. Mechanical removal of endothelium abolished the reaction to acetylcholine but not to nitroglycerin. Verapamil decreased the relaxation by 70%. The endothelium-dependent relaxation seems to be connected mainly with a decrease in the calcium entering vascular smooth muscle cells through voltage-dependent channels.