Inherited Stress-induced Arterial Hypertension Research Articles

Genes Associated with Increased Stress Sensitivity in Hypertensive ISIAH Rats

Inherited stress-induced arterial hypertension (ISIAH) rats are characterized by increased stress reactivity of the hypothalamic-pituitary-adrenal and sympathoadrenal systems. The genetic basis of increased susceptibility to stress was studied in hypertensive ISIAH rats. Adrenal transcriptomes were sequenced in hypertensive ISIAH and normotensive WAG rats, and nine differentially expressed genes (DEGs) were found in the X-chromosome locus that was previously associated with mild emotional stress-induced increases in blood pressure and plasma corticosterone and an increased adrenal weight in ISIAH rats. An analysis of the functions performed by DEG-encoded proteins suggested the Sms (spermine synthase) gene to be the most likely candidate gene in the X-chromosome locus associated with an elevated stress susceptibility in ISIAH rats.

Effect of Skin Ion Channel TRPM8 Activation by Cold and Menthol on Thermoregulation and the Expression of Genes of Thermosensitive TRP Ion Channels in the Hypothalamus of Hypertensive Rats.

ISIAH (inherited stress-induced arterial hypertension) rats are characterized by high blood pressure and decreased Trpm8 gene expression in the anterior hypothalamus. Thermosensitive ion channel TRPM8 plays a critical role in the transduction of moderately cold stimuli that give rise to cool sensations. In normotensive animals, the activation of skin TRPM8 is known to induce changes in gene expression in the hypothalamus and induce alterations of thermoregulatory responses. In this work, in hypertensive rats, we studied the effects of activation of the peripheral TRPM8 by cooling and by application of a 1% menthol suspension on (1) the maintenance of body temperature balance and (2) mRNA expression of thermosensitive TRP ion channels in the hypothalamus. In these hypertensive animals, (1) pharmacological activation of peripheral TRPM8 did not affect the thermoregulatory parameters either under thermoneutral conditions or during cold exposure; (2) the expression of Trpm8 in the anterior hypothalamus approximately doubled (to the level of normotensive animals) under the influence of (a) slow cooling and (b) at pharmacological activation of the peripheral TRPM8 ion channel. The latter fact seems the quite important because it allows the proposal of a tool for correcting at least some parameters that distinguish a hypertensive state from the normotensive one.

Hypothalamic Norepinephrine Concentration and Heart Mass in Hypertensive ISIAH Rats Are Associated with a Genetic Locus on Chromosome 18.

The relationship between activation of the sympathetic nervous system and cardiac hypertrophy has long been known. However, the molecular genetic basis of this association is poorly understood. Given the known role of hypothalamic norepinephrine in the activation of the sympathetic nervous system, the aim of the work was to carry out genetic mapping using Quantitative Trait Loci (QTL) analysis and determine the loci associated both with an increase in the concentration of norepinephrine in the hypothalamus and with an increase in heart mass in Inherited Stress-Induced Arterial Hypertension (ISIAH) rats simulating the stress-sensitive form of arterial hypertension. The work describes a genetic locus on chromosome 18, in which there are genes that control the development of cardiac hypertrophy associated with an increase in the concentration of norepinephrine in the hypothalamus, i.e., genes involved in enhanced sympathetic myocardial stimulation. No association of this locus with the blood pressure was found. Taking into consideration previously obtained results, it was concluded that the contribution to the development of heart hypertrophy in the ISIAH rats is controlled by different genetic loci, one of which is associated with the concentration of norepinephrine in the hypothalamus (on chromosome 18) and the other is associated with high blood pressure (on chromosome 1). Nucleotide substitutions that may be involved in the formation or absence of association with blood pressure in different rat strains are discussed.

Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension.

Growing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis. Recent preclinical investigations point arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with nonproteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed. We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolite levels were amplified in normotonic but not in hypertensive rats following the treatment. The data indicate that L-norvaline is a potential antihypertensive agent and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon BP regulation.

Morphofunctional status of cardio-vascular system of rats with arterial hypertension

The aim: Was to clarify the general patterns of structural changes in the left ventricular myocardial capillaries in rats with spontaneous arterial hypertension. Materials and methods: Experiments were conducted on 50 ISIAH (inherited stress-induced arterial hypertension) line rats with arterial hypertension: juvenile young (45-day) and sexually mature (100-day) rats, as well as intact animals of the corresponding age. While extracted from the experiment rats of all experimental groups had their arterial pressure measured using a plethysmograph. Electron microscopic examination of the left ventricular myocardium and morphometric study of volumetric and quantitative densities, cross-section area, and form factor of micropinocytotic vesicles were conducted. Results: In sexually mature rats with arterial hypertension, a high level of pressure is maintained. In 45-day-old rats with arterial hypertension in endothelial cells of myocardial blood capillaries there is a hyperactivation of biosynthetic processes (euchromatic nucleus, large-sized mitochondria, ER canals, Golgi complex), which may be a manifestation of reactive processes in response to a non-stable increase in arterial pressure. In the 100-day rats with arterial hypertension, the mosaic of the ultrastructure of the myocardium blood vessels is preserved, but destructively-dystrophic changes become more expressive and involve not only the organelles but also the integrity of the endothelial cell itself. Destructively-dystrophic processes in rat capillaries are accompanied by compensatory and adaptive ones. This is manifested by activation of the transport of substances, both transendothelial and paracellular, and quantitative density of micropinocytotic vesicles increases statistically significantly. Conclusions: In myocardial capillaries of young (45-day) arterial hypertension rats, compensatory and adaptive changes are manifested by activation of biosynthetic processes in endothelial cells following a slight increase in micropinocytotic vesicles quantitative density and signs of destructive-dystrophic processes (minor edema and lysis of endothelial cell cytoplasm). In sexually mature (100-day) arterial hypertension rats in the blood capillaries of the myocardium, the destructive-degenerative changes increase is accompanied by preservation of signs of compensatory processes. Reducing the number of capillaries is offset by an increase in the number of micropinocytotic vesicles.

CARDIOVASCULAR SYSTEM OF THE MATURE RATS WITH CONGENITAL HYPOTHYROIDISM AND ARTERIAL HYPERTENSION

The aim: Studying changes in the ultrastructure of blood circulatory capillaries of the myocardium of mature rats with hypothyroidism and arterial hypertension. Materials and methods: Experiments were conducted on (240 days) 10 ISIAH (inherited stress-induced arterial hypertension) line rats with AH (arterial hypertension), 10 Wistar line rats with congenital hypothyroidism and 10 intact animals. Arterial pressure was measured, and the development of hypothyroidism was controlled by the immune enzyme method. The study of the left ventricle myocardium of the rat heart was carried out by electron microscopic and morphometric studies. Results: In in rats with AH the following changes were observed in the blood capillaries of the myocardium: decrease in the number of capillaries; disturbance of blood circulation; the number of organelles of the biosynthetic plan and structures involved in the transendothelial transfer of substances decreased in endothelial cells; lysis and edema of the latter; mucinous perivascular edema, confirmed by the accumulation of fine-fibrillar structures, collagen fibers, cellular detritus. By the same term, in the group with congenital hypothyroidism, dystrophic-destructive changes in the blood capillaries of the myocardium acquired the highest degree, which resulted in a decrease in their number due to destruction. Ultrastructure of the biosynthetic plan organelles and structures of the transendothelial transfer of substances were in decompensated state. Conclusions: The rats (in 240 days) with AH and congenital hypothyroidism express breakdown of compensatory processes in the capillaries of the myocardium. This is manifested by the further dilution of capillaries, the development of hypoxic state in them as well as mucinous edema of interstitium, the decrease of activity of biosynthetic and transport processes.

The differences in brain stem transcriptional profiling in hypertensive ISIAH and normotensive WAG rats

BackgroundThe development of essential hypertension is associated with a wide range of mechanisms. The brain stem neurons are essential for the homeostatic regulation of arterial pressure as they control baroreflex and sympathetic nerve activity. The ISIAH (Inherited Stress Induced Arterial Hypertension) rats reproduce the human stress-sensitive hypertensive disease with predominant activation of the neuroendocrine hypothalamic-pituitary-adrenal and sympathetic adrenal axes. RNA-Seq analysis of the brain stems from the hypertensive ISIAH and normotensive control WAG (Wistar Albino Glaxo) rats was performed to identify the differentially expressed genes (DEGs) and the main central mechanisms (biological processes and metabolic pathways) contributing to the hypertensive state in the ISIAH rats.ResultsThe study revealed 224 DEGs. Their annotation in databases showed that 22 of them were associated with hypertension and blood pressure (BP) regulation, and 61 DEGs were associated with central nervous system diseases. In accordance with the functional annotation of DEGs, the key role of hormonal metabolic processes and, in particular, the enhanced biosynthesis of aldosterone in the brain stem of ISIAH rats was proposed. Multiple DEGs associated with several Gene Ontology (GO) terms essentially related to modulation of BP were identified. Abundant groups of DEGs were related to GO terms associated with responses to different stimuli including response to organic (hormonal) substance, to external stimulus, and to stress. Several DEGs making the most contribution to the inter-strain differences were detected including the Ephx2, which was earlier defined as a major candidate gene in the studies of transcriptional profiles in different tissues/organs (hypothalamus, adrenal gland and kidney) of ISIAH rats.ConclusionsThe results of the study showed that inter-strain differences in ISIAH and WAG brain stem functioning might be a result of the imbalance in processes leading to the pathology development and those, exerting the compensatory effects. The data obtained in this study are useful for a better understanding of the genetic mechanisms underlying the complexity of the brain stem processes in ISIAH rats, which are a model of stress-sensitive form of hypertension.

A2140 Antisense containing nanocomposites in hypertension treatment in ISIAH rats

Objectives: Hypertension plays a central role in the development of severe complications, such as myocardial infarction and cerebral stroke. In this work, we studied the possibility of the treatment of hypertension by using TiO2∼PL-ODN-III and Si∼ODN-III nanocomposites containing conjugates of antisense oligonucleotides immobilized on TiO2 and Si nanoparticles. Methods: We used male hypertensive ISIAH (inherited stress-induced arterial hypertension) rats aged five months as a model of stress induced arterial hypertension. ISIAH rats were developed by long term selection for high blood pressure under emotional stress The inhibition of ACE1 was studied using the proposed nanocomposites using inhalation. Results: Inhalation of both modifications of oligonucleotides (TiO2∼PL-ODN-III & Si∼ODN-III) in a complex with nanoparticles led to a prolonged decrease in blood pressure in adult ISIAH rats. The maximal difference between the initial and minimal after inhalation BP levels was ∼30 mm Hg, and the average BP below the initial level by 22 mm Hg was maintained for two weeks in case of Si∼ODN-III usage. At the same time it was shown that inhalation of the nanocomposite bearing ODN against ACE1 significantly decreased expression of mRNA of the ACE1 gene in the lung tissue and ACE1 protein in the blood plasma. Conclusion: Development of methods for non-invasive application of antisense oligonucleotides in the composition with various nanocarriers opens new opportunities for the development of alternative methods of the struggle not only with hypertension, but also with other pathologies. The work was supported by the Russian Science Foundation, grant 16-15-10073

Hypotensive and neurometabolic effects of intragastric Reishi (Ganoderma lucidum) administration in hypertensive ISIAH rat strain

BackgroundAs the standard clinically used hypotensive medicines have many undesirable side effects, there is a need for new therapeutic agents, especially ones of a natural origin. PurposeOne possible candidate is extract from the mushroom Reishi (Ganoderma lucidum), which is used in the treatment and prevention of many chronic diseases. Study design and methodsTo study the effectiveness of Reishi, which grows in the Altai Mountains, as an antihypertensive agent, we intragastrically administered Reishi water extract to adult male hypertensive ISIAH (inherited stress-induced arterial hypertension) rats. ResultsAfter seven weeks, Reishi therapy reduced blood pressure in experimental animals at a level comparable to that of losartan. Unlike losartan, intragastric Reishi introduction significantly increases cerebral blood flow and affects cerebral cortex metabolic patterns, shifting the balance of inhibitory and excitatory neurotransmitters toward excitation. ConclusionChanges in cerebral blood flow and ratios of neurometabolites suggests Reishi has a potential nootropic effect.

Stress-sensitive arterial hypertension, haemodynamic changes and brain metabolites in hypertensive ISIAH rats: MRI investigation.

What is the central question of this study? Stress-sensitive arterial hypertension is considered to be controlled by changes in central and peripheral sympathetic regulating mechanisms, which eventually result in haemodynamic alterations and blood pressure elevation. Therefore, study of the early stages of development of hypertension is of particular interest, because it helps in understanding the aetiology of the disease. What is the main finding and its importance? Non-invasive in vivo investigation in ISIAH rats demonstrated that establishment of sustainable stress-sensitive hypertension is accompanied by a decrease in prefrontal cortex activity and mobilization of hypothalamic processes, with considerable correlations between haemodynamic parameters and individual metabolite ratios. The study of early development of arterial hypertension in association with emotional stress is of great importance for better understanding of the aetiology and pathogenesis of the hypertensive disease. Magnetic resonance imaging (MRI) was applied to evaluate the changes in haemodynamics and brain metabolites in 1- and 3-month-old inherited stress-induced arterial hypertension (ISIAH) rats (10male rats) with stress-sensitive arterial hypertension and in control normotensive Wistar Albino Glaxo (WAG) rats (eightmale rats). In the 3-month-old ISIAH rats, the age-dependent increase in blood pressure was associated with increased blood flow through the renal arteries and decreased blood flow in the lower part of the abdominal aorta. The renal vascular resistance in the ISIAH rats decreased during ageing, although at both ages it remained higher than the renal vascular resistance in WAG rats. An integral metabolome portrait demonstrated that development of hypertension in the ISIAH rats was associated with an attenuation of the excitatory and energetic activity in the prefrontal cortex, whereas in the WAG rats the opposite age-dependent changes were observed. In contrast, in the hypothalamus of 3-month-old ISIAH rats, an increase in energetic activity and prevalence of excitatory over inhibitory neurotransmitters was noticed. The blood flow through the main arteries showed a positive correlation with glutamate and glutamine levels in the hypothalamus and a negative correlation with the hypothalamic GABA level. The blood pressure values were positively correlated with hypothalamic choline levels. Thus, the early development of stress-sensitive hypertension in the ISIAH rats is accompanied by considerable changes both in brain metabolite ratios and in the parameters of blood flow through the main arteries.

Neonatal reflexes and behavior in hypertensive rats of ISIAH strain

Hypertension is one of the most common diseases in humans, and there is a special concern on the consequences of maternal hypertensive conditions for the health of newborns. An inherited stress-induced arterial hypertension (ISIAH) rat strain has been selected but only a few studies have addressed behavior in these rats. Body weight, neurodevelopmental reflexes, and neuronal density in the hippocampus were compared in ISIAH and normotensive WAG rats during their suckling period. Systolic and diastolic blood pressure (SBP, DBP), adult rat performance in the open field (OF), elevated plus maze (EPM), and novel object recognition (NOR) tests were evaluated at the age of 12–14weeks old. Body weight in pups did not differ significantly during the suckling period, while adult ISIAH rats were heavier than age-matched WAG rats and possessed the increased SBP and DBP. ISIAH pups were developmentally more advanced than WAG as indicated by grasp reflex and negative geotaxis reaction scores. This was associated with higher neuronal density in CA1 and CA3 hippocampal areas in ISIAH pups on postnatal day 6 as compared to WAG rats. Adult ISIAH rats demonstrated an increased locomotor and exploratory activity in the OF and EPM tests as well as low levels of anxiety. The NOR test revealed no significant difference in recognition but confirmed higher exploratory activity in ISIAH rats compared to WAG rats. The results indicate that hypertensive ISIAH rats feature accelerated development during their suckling period, and as adults, they are more active and less anxious than normotensive WAG rats.

Strain-specific single-nucleotide polymorphisms in hypertensive ISIAH rats

Single-nucleotide polymorphisms (SNPs) in the coding and regulatory regions of genes can affect transcription rate and translation efficiency, modify protein function, and, in some cases, cause the development of diseases. In the current study, the RNA-Seq approach has been used to discover strain-specific SNPs in ISIAH (inherited stress-induced arterial hypertension) rats, which are known as a model of stress-induced arterial hypertension. The comparison of the ISIAH SNPs with genome sequencing data available for another 42 rat strains and substrains, 11 of them known as hypertensive, showed a considerable genetic distance between the genotypes of ISIAH and all other rat strains and substrains. The study revealed 1849 novel SNPs specific for ISIAH rats and 158 SNPs present only in the genotypes of hypertensive rats. Amino acid substitutions with possible deleterious effect on protein function were detected. Several of them were found in the genes associated with hypertension. These SNPs may be considered as novel molecular targets for further studies aimed at assessing their potential in the therapy of stress-induced hypertension.

Effects of brain renin- angiotensin system inhibition in ISIAH rats with inherited stress-induced arterial hypertension

The renin-angiotensin system (RAS) is one of the main systems regulating arterial pressure and water-salt homeostasis of the body and is involved in the pathogenesis of cardiovascular diseases. Angiotensin peptides – products of enzymatic hydrolysis of angiotensinogen – can be synthesized not only in the blood stream, but also in tissues, including various regions of the brain. Studies of local tissue RAS in the context of arterial hypertension have been conducted for a long time. It has been shown that a steady arterial pressure increase is often associated with changes in the functioning of the central (brain) RAS in various animal models of hypertensive disease and in humans. Nevertheless, it is still not completely clear whether these changes alone are sufficient for the formation of hypertensive status, and whether the components of the central RAS can be used as targets for the treatment of hypertensive disease. Effects of prolonged inhibition of the brain RAS on blood pressure and expression of RAS genes in brain and kidney tissues in ISIAH (inherited stress-induced arterial hypertension) rats were studied. Inhibition was performed using widely used pharmacological agents, losartan and benazepril. Osmotic minipumps were used to deliver drugs to the lateral ventricle of the brain. It was shown that prolonged inhibition of the central RAS, AT1 receptors in particular, can lead to a decrease in blood pressure and significant changes in the level of expression of brain RAS genes in ISIAH rats. The mRNA level of RAS genes in the kidney does not significantly change due to this inhibition. Thus, the participation of the central RAS in the pathogenesis and maintenance of hypertensive status during stress induced form of hypertensive disease in ISIAH rats was confirmed.

Effects of reproductive technologies and SPF status on some physiological and behavioral characteristics in rats with arterial hypertension (ISIAH Strain)

Modern standards of Laboratory Animal Science include working with laboratory animals of a high quality, in particular, with specific pathogen-free (SPF) mice and rats. On the other hand, assisted reproductive technologies (ART) are widely used in modern medicine for human infertility treatment and genome resource banking. In the present study, a comparison of body weight, blood pressure (BP), and behavior in the elevated plus maze (EPM) test was made between three groups of ISIAH (inherited stress induced arterial hypertension) rats: a group of animals that were born and raised in a conventional animal facility and two groups from an SPF animal facility (animals born naturally and animals resulting from ART). There were no changes in BP between the groups, but the behavior of ISIAH rats differed depending on rearing conditions. In particular, the grooming time, as well as the number of defecations and the number of urinations during the test decreased in both groups of ISIAH rats born in the SPF animal facility as compared to ISIAH rats born in the conventional animal facility. The behavior of the ISIAH rat offspring resulting from ART was different from that of the naturally born group: the EPM test revealed reduced anxiety in the former. The results of the present study indicate that the rearing conditions and the reproductive technologies affect some behavioral characteristics in adult ISIAH rats, although they posessed arterial hypertension in all the conditions used in this study.

Genome-wide transcriptome analysis of hypothalamus in rats with inherited stress-induced arterial hypertension.

BackgroundThe hypothalamus has an important role in the onset and maintenance of hypertension and stress responses. Rats with inherited stress-induced arterial hypertension (ISIAH), reproducing the human stress-sensitive hypertensive state with predominant involvement of the neuroendocrine hypothalamic-pituitary-adrenal and sympathoadrenal axes, were used for analysis of the hypothalamus transcriptome.ResultsRNA-seq analysis revealed 139 genes differentially expressed in the hypothalami of hypertensive ISIAH and normotensive Wistar Albino Glaxo (WAG) rats. According to the annotation in databases, 18 of the differentially expressed genes (DEGs) were associated with arterial hypertension. The Gene Ontology (GO) functional annotation showed that these genes were related to different biological processes that may contribute to the hypertension development in the ISIAH rats. The most significantly affected processes were the following: regulation of hormone levels, immune system process, regulation of response to stimulus, blood circulation, response to stress, response to hormone stimulus, transport, metabolic processes, and endocrine system development. The most significantly affected metabolic pathways were those associated with the function of the immune system and cell adhesion molecules and the metabolism of retinol and arachidonic acid. Of the top 40 DEGs making the greatest contribution to the interstrain differences, there were 3 genes (Ephx2, Cst3 and Ltbp2) associated with hypertension that were considered to be suitable for further studies as potential targets for the stress-sensitive hypertension therapy. Seven DEGs were found to be common between hypothalamic transcriptomes of ISIAH rats and Schlager mice with established neurogenic hypertension.ConclusionsThe results of this study revealed multiple DEGs and possible mechanisms specifying the hypothalamic function in the hypertensive ISIAH rats. These results provide a basis for further investigation of the signalling mechanisms that affect hypothalamic output related to stress-sensitive hypertension development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0307-8) contains supplementary material, which is available to authorized users.

Behavior of rat neonates with inherited stress induced arterial hypertension

The hypertensive status of the mother can affect the behavioral traits of its offspring in early ontogeny. Rats with inherited stress-induced arterial hypertension (ISIAH) exhibit a delay in locomotor activity development as compared with WAG rats during the first week of life, but they show a higher locomotor activity in the open field test during the second week of development. Using the method of principal components, a higher level of exploratory behavior and a higher adaptability of ISIAH rat neonates as compared to WAG neonates were shown in the third week of postnatal development. Vibrissa growth and hair coat formation did not differ between the strains by the end of the second week.

Rederivation by embryo transfer in strains of laboratory mice and rats

Rederivation enables one to decontaminate colonies of laboratory mice and rats from specific pathogens and to convert them to the SPF (specified pathogen free) state. In this study the results of the rederivation of two unique rat strains that were selected at the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, viz., tame Norway rats, rats with inherited stress-induced arterial hypertension (ISIAH), and the ICR mouse strain, are presented. The SPF state of the rederivated rats was confirmed by indicator animals, which are also called sentinel animals. An optimized rederivation model of laboratory animals is suggested in the article, which includes a series of embryotechnological methods, viz., freezing and cryopreservation of embryos, their decontamination by washing in sterile media, cultivation for 48 h, and, finally, transfer to recipients (with the SPF state). As a result of the application of this model to the ICR strain mice, it was possible to obtain 39 offspring that were born in the conditions of an SPF animal facility. It is worth mentioning that the efficacy of the procedure is in agreement with international standards, with all three lines representing a specific phenotype after undergoing all the procedures of rederivation.

Возрастные структурно-функциональные особенности миоэндокринных клеток сердца у крыс в норме и при наследственной гипертензии

A qualitative and quantitative ultrastructural study of right atrial cardiomyocytes in WAG (normotensive control) and ISIAH (inherited stress-induced arterial hypertension) rats of different age (on day 18 of embryogenesis, on days 12 and 21 after birth, and at an age of 6 and 13 months) was performed. It was shown that, in embryos with an as yet incomplete atrial morphogenesis, secretory granules containing natriuretic peptides are actively formed, accumulated, and dissolved. In postnatal ontogeny, the secretory product is accumulated in atrial cells. In all ontogeny stages studied, the numerical density of secretory granules in the myoendocrine cells of hypertensive rats is greater and the qualitative composition of these granules is more diverse than in the control. It was established that, in atrial myocytes of ISIAH rats, the morphological signs of natriuretic peptide hypersecretion precede the development of genetically programmed high blood pressure. In adult hypertensive rats, hypertrophic and degenerative changes in myocytes are accompanied by excessive accumulation of secretory granules, some of which undergo intracellular degradation.

All signs of metabolic syndrome in the hypertensive ISIAH rats are associated with increased activity of transcription factors PPAR, LXR, PXR, and CAR in the liver

It is known that the metabolic syndrome (MS), which includes hypertension, dislipidemia, glucose intolerance, and obesity leads to cardiovascular diseases. The MS risk is growing catastrophically. Molecular mechanisms allowing to understand the reason of integrated dysfunctions, taking place at MS cases, have remained almost unstudied. The chronical stress plays a crucial role in MS development; therefore in the present work a hypertensive rat strain with Inherited Stress-Induced Arterial Hypertension (ISIAH) was used as a model. It was shown that ISIAH rat strain as compared with the control WAG rat strain is characterized by increased content of triglyceride, VLDL and LDL cholesterols, a decreased content of HDL cholesterol, a high level of apolipoprotein B-100, and decreased level of apolipoprotein A-I. The ISIAH rats body weight was higher as compared with WAG rats; ISIAH rats blood glucose content was higher too. Thus, strain hypertension for ISIAH rat is accompanied by dislipidemia, increased glucose content, and increased body weight, representing a whole set of MS signs. Since at MS cases the systemic abnormalities in lipid and carbohydrate metabolism take place, the functional activity of transcription factors (TFs) participating in integral regulation of lipid and carbohydrate metabolism genes in liver was measured. PPAR, LXR, PXR, CAR DNA-binding activity was increased in ISIAH rats, suggesting involvement of these TFs in MS development. Integrated investigation of PPAR, LXR, PXR, CAR regulatory mechanisms, signal transduction and transcriptional targets will provide insights into the pathogenesis of MS and offer valuable information for designing of drugs for MS treatment.

Genetic Control of the Corticosterone Level at Rest and Under Emotional Stress in ISIAH Rats with Inherited Stress-Induced Arterial Hypertension

The genetic background of the regulatory systems of the hypothalamic-pituitary-adrenal (HPA) axis in hypertension remains unclear. The inherited stress-induced arterial hypertension (ISIAH) and Wistar Albino Glaxo (WAG) normotensive rats were bred and their F2 progeny were used in a quantitative trait loci (QTL) analysis to identify genomic regions for plasma basal and stress-induced corticosterone levels, and for absolute and relative adrenal gland weights. The significant loci were found for stress-induced corticosterone on chromosome 9 and for adrenal weight on chromosome 6. The results may help to identify the genes controlling the trait phenotypes in the ISIAH rats characterized by the enhanced responsiveness to stressful stimulation.