THE MECHANISMS CONTRIBUTING TO THE DEVELOPMENT OF ARTERIAL HYPERTENSION, ADVANTAGES AND DISADVANTAGES OF THE ASSOCIATED EXPERIMENTAL MODELS (REVIEW).

Arterial hypertension is one of most common diseases in the world with variable etiologies, yet the exact cause cannot always be found. It is classified as essential (primary) or secondary hypertension. Unlike secondary hypertension, primary hypertension has no known cause. Animal models have been used to investigate the pathophysiology of the disease and for testing new treatment strategies. Using animal models to better understand the etiology, prevention, and treatment of hypertension depends on their accuracy for representing human disease. Current challenges in this field include the development of models mimicking the common hypertensive syndromes and the development of new prevention and treatment strategies. Animal models may be beneficial to address these challenges. While choosing the appropriate model of hypertension, scientists need to choose between small and large animal models. The research scope and objectives, experimental expenses, animal welfare, and practical suitability should all be considered. The advantages and disadvantages of these models need to be assessed in detail in order to select the best model. From the many models of arterial hypertension, it can be distinguish different models of essential and secondary arterial hypertension. Of the essential arterial hypertension three main methods are noteworthy, pharmacological, environmental conditions, and genetic model. As for secondary hypertension, it can be challenged by physical methods such as renal artery clipping or its microembolization.

ENDOCANNABINOIDS RECEPTORS MEDIATED CENTRAL AND PERIPHERAL EFFECTS (REVIEW).

The present article is devoted to the action of endocannabinoids via stimulation of their corresponding receptors. It is well established the existence of three type of endocannabinoids (ECS) such as anandamide (AA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PE) providing their effects by activation of CB1 and CB2 ECS receptors. AA is a partial agonist for both receptors, having more affinity for CB1 receptors, while 2-AG reveals an equal agonistic properties to both of them in contrast to PE, which may bind to a unidental "CB2-like" receptors. CB1 receptors are distributed in the central and peripheral nervous system being identified in the greater amounts in the brain cortex, basal ganglia, spinal cord, cerebellum, hippocampus and olfactory areas, owing for the modulatory action of ECS on cognitive function, memory, behaviour, emotion and locomotor activity. Their location in the periaqueductal grey matter and dorsal spinal cord may explain their involvement in pain sensation and modulation. Colocallization of the CB1 receptors with the oroxinergic projection system in the lateral hypothalamus is responsible for their implication in feeding behaviour. CB2 receptors were found in the cells of immune system (spleen, macrophages). It should be noted that ECS may also play a role in the regulation of fertility and pre-and postnatal development. The stimulation of ECS receptors is associated with the activation of MAPK, PI/PKB and MEK/ERK signalling pathways with increased activity of different transcription factors. CB1 receptors are involved in neuronal exitability by decreasing synaptic input, implying retrograde transmission and presynaptic inhibition resulting in reduction of neurotransmitter release. In the article it is also described an ionic mechanisms of release of ECS and the steps of their synthesis as well as participation of a transporter in ECS uptaken process in neurons and astrocytes. Aside from this it is proposed the mechanisms of analgesic action of ECS especially concerning reduction in neuropathic pain in comparison to opioids and possible involvement of α2-adrenoceptors in antinociceptive activity of ECS. Some analgesic properties of ECS is due to their inhibitory action on cyclooxygenase-2 (COX-2). Recent evidences showed that regarding antinociceptive action of ECS along with CB1 receptors most significant receptors are PPAR-alpha and TRPV receptors. There are controversial data concerning the influence of ECS on cognitive function. Knockout mices with the absence of CB1 receptors have showed improved memory and long-term potentiation proofing the significant role of ECS in the disorders of "old memories". Some data suggests that genetic or pharmacological inhibition of COX-2 activity may reduce disorders in hippocampal long-term synaptic plasticity and fear memory, as well as supports improving effects of tetrahydrocannabinoids (THC) on neurodegenerative processes such as Alzheimer's disease, because THC facilitates to marked expression of an important endopeptidase neprilysin for degradation of AB proteins. A number of evidence indicates the possible involvement of ECS in schizophrenia and major depressive disorders. Assumingly such beneficial effect of ECS is associated with M1/M2 microglial polarization process. In conclusion it is suggested that ECS as natural ligand for their corresponding receptors provide wide spectrum of pharmacological effects may become an interesting targets for future therapeutic intervention.

STATIN-ASSOCIATED INTOLERANCE AND ITS PREVENTION.

The review analyzes the literature data, which covers the intolerance of statins associated with myopathy. The article gives a definition of statin intolerance, analyzed data from a randomized, controlled trials, where are indicated frequency of statin-associated myopathy, its symptoms in juxtaposition with an increase in creatine kinase activity. It is noted that the frequency of complications depends on the applied statin, its dose, duration, the use of other risk factors that contribute to the development of myopathy. It is indicated that polypharmacy - the joint use of statins with such drugs as anti-inflammatory (glucocorticoids), immunosuppressants (cyclosporine), antipsychotics, antiviral (protease inhibitors), macrolides, antifungal, lipid modifying (gemfibrozole), cytochrome P450 inhibitors and substances causing dependence (alcohol, opioids) may contribute to the development of statin-associated myopathy. Risk factors are also age over 75 years, low body mass index, female gender, high level of physical activity, multi-system diseases - hypothyroidism, diabetes, infections, hepatic dysfunction, biliary obstruction, organ transplantation, severe injuries, hypovitaminosis D, metabolic lesions, etc. Methods of therapy of patients with statin-associated myopathy, namely, dose changes, duration of administration, regimen of application (twice a week instead of daily), replacement of the drug and the use of other lipid-lowering agents, as well as nutritional and complementary therapy are considered.

[EFFECT OF ACETYLCYSTEINE, CORVITIN AND THEIR COMBINATION ON THE FUNCTIONAL STATE OF LIVER IN RATS WITH PARACETAMOL INDUCED TOXIC HEPATITIS].

Nowadays drug-induced hepatotoxicity is urgent problem worldwide. Currently more than 1000 drugs are hepatotoxic and most often are the reason of acute fulminant hepatitis and hepatocellular failure, the states requiring liver transplantation. The paracetamol induced liver toxicity is related with accumulation of its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is the free radical and enhances peroxidation of lipids, disturbs the energy status and causes death of hepatocytes. During our research we investigated and assessed the efficacy of acetylcysteine, corvitin and their combination in rat model of paracetamol induced acute toxic hepatitis. The study was performed on mature white male Wistar rates with body mass 150-180 g. 50 rats were randomly divided into 5 groups (10 rats in each group). To get the model of acute toxic hepatitis single intraperitoneal injection of paracetamol solution was used (750 mg/kg). Toxic hepatitis was treated with intrapertoneal administration of 40mg/kg acetylcysteine or 100mg/kg corvitin, as well as with combination of these drugs. Monotherapy with acetylcysteine and corvitin of paracetamol induced toxic hepatitis improved the liver function, decreased relative mass of the liver and animal mortality. The treatment of toxic hepatitis was most effective in the case of simultaneous administration of acetylcysteine and corvitin. The normal value of laboratory tests (ALT, ACT, alkaline phosphatase, total and unconjugated bilirubin) was reached and mortality was not more observed. On the bases of obtained data was concluded that acetylcysteine and corvitin have almost equal hepatoprotective activity. The combination of two drugs actually improves the liver function. The most pronounced hepatoprotective effect may be due to synergic action of acetylcysteine and corvitin and such regime can be recommended for correction of liver function.

[ACTION OF L-CARNITINE, CORVITIN AND THEIR COMBINATION ON FUNCTIONAL STATE OF LIVER IN EXPERIMENTAL MODEL OF REYE SYNDROME IN RATS].

Administration of Aacetylsalicylic acid in children with viral infections (influence B, chickenpox) can be related with development of Reye syndrome - severe encephalopathy and liver insufficiency with mortality in 50% of cases. During Reye syndrome most important is deficiency of carnitine and hepatocyte damage. Decreased amount of carnitine impairs the energy function of mitochondria and gluconeogenesis as well as production of urea. As a result develops toxic encephalopathy and liver insufficiency. The goal of the research was assessment of efficacy of L-Carnitine, Corvitin and their combination on functional state of liver in experimental model of Reye Syndrome in rats. The study was performed on mature white male Wistar rates with body mass 150-180g. 50 rats were randomly divided into 5 groups (10 rats in each group). The model of Reye syndrome was induced in accordance with A.Vengersky's method. Intraperitoneal administration of 4-pentenoic acid was performed once daily during seven days, the used dosage was 20mg/kg. The treatment of toxic hepatitis was carried with intraperitoneal administration of L-Carnitine 300mg/kg, Corvitine 100mg/kg and concurrent administration of these drugs. Monotherapy with Corvitin and L-Carnitin successfully improved liver function and equally decreased indicators of hepatocyte's cytolyses and increased levels of glucose and urea. The markers of cholestasis was slightly more improved during use of L-Carnitine. Simultaneous use of both drugs was effective in rats with Reye syndrome, indicators of liver damage normalized and herewith, no mortality outcome was observed. The most pronounced hepatoprotective effect of concurrent administration of L-Carnitine and Corvitin may be due to synergic action of these drugs and such regime can be recommended for correction of liver function during Reye syndrome.