Stress-sensitive Arterial Hypertension Research Articles

Age-Dependent Changes in the Relationships between Traits Associated with the Pathogenesis of Stress-Sensitive Hypertension in ISIAH Rats

Hypertension is one of the most significant risk factors for many cardiovascular diseases. At different stages of hypertension development, various pathophysiological processes can play a key role in the manifestation of the hypertensive phenotype and of comorbid conditions. Accordingly, it is thought that when diagnosing and choosing a strategy for treating hypertension, it is necessary to take into account age, the stage of disorder development, comorbidities, and effects of emotional–psychosocial factors. Nonetheless, such an approach to choosing a treatment strategy is hampered by incomplete knowledge about details of age-related associations between the numerous features that may contribute to the manifestation of the hypertensive phenotype. Here, we used two groups of male F2(ISIAHxWAG) hybrids of different ages, obtained by crossing hypertensive ISIAH rats (simulating stress-sensitive arterial hypertension) and normotensive WAG rats. By principal component analysis, the relationships among 21 morphological, physiological, and behavioral traits were examined. It was shown that the development of stress-sensitive hypertension in ISIAH rats is accompanied not only by an age-dependent (FDR < 5%) persistent increase in basal blood pressure but also by a decrease in the response to stress and by an increase in anxiety. The plasma corticosterone concentration at rest and its increase during short-term restraint stress in a group of young rats did not have a straightforward relationship with the other analyzed traits. Nonetheless, in older animals, such associations were found. Thus, the study revealed age-dependent relationships between the key features that determine hypertension manifestation in ISIAH rats. Our results may be useful for designing therapeutic strategies against stress-sensitive hypertension, taking into account the patients’ age.

In vivo hypotensive effect of aminosilanol-based nanocomposites bearing antisense oligonucleotides

The search for new effective drugs for the treatment of arterial hypertension continues to be an urgent task. We studied the effect of aminosilanol nanocomposites (Si∼ODN) that contained antisense oligonucleotides on the blood pressure in the hypertensive ISIAH rat strain, an experimental model of stress-sensitive arterial hypertension. The intraperitoneal, intravenous, and inhalation administration of Si∼ODN targeted to mRNAs of the AT1A, ADRB1, and ACE1 genes decreased systolic blood pressure by 12–40 mm Hg. The use of scrambled oligonucleotides led to no antisense effect. The proposed in vivo delivery system was shown to be suitable for oligonucleotides with both natural and modified internucleotide bonds. The Si∼ODN nanocomposites demonstrated the absence of toxicity under the studied conditions. The intravenous administration of a fluorescently labeled nanocomposite led to its accumulation in the animal's liver and kidneys, and when inhaled, a certain amount was detected in the brain. The content of the label reaches a maximum one day after the treatment and is almost eliminated from the body in two weeks. The best way to correct hypertension in ISIAH rats using the studied nanocomposites may be periodic inhalation of the nanocomposite that carries an oligonucleotide targeted to ACE1-mRNA.

Stress-sensitive arterial hypertension and tolerance to the salt loading in the ISIAH rats

Stress-sensitive arterial hypertension and tolerance to the salt loading in the ISIAH rats

A15069 Nanocomposite (Si-ODN-II), containing antisense oligonucleotides targeted to mRNA of the beta-1-adrenoreceptors for hypertension therapy in rats with stress-sensitive arterial hypertension (ISIAH rats)

Objectives: The study of the possibility of gene therapy of hypertensive disease using nanocomposite (Si-ODN-II), containing silicon and antisense oligonucleotides directed to mRNA of the beta 1-adrenoreceptors in rats with stress-sensitive hypertension (ISIAH rats). Methods: We used the ISIAH rats, hypertension of which was the result of a severe hereditary predisposition to the development of hypertensive state provoked by emotional stress. PCR real-time revealed enhanced mRNA of Adrb1 receptors in myocardium of the intact ISIAH rats. The inhibition of expression Adrb1 gene was studied using intravenous administration of the Si∼ODN-II antisense nanocomposites. Results: Stimulations of the beta 1-adrenoreceptors cause an increase in the frequency and strength of the heartbeats and are one of the factors in the development of hypertensive disease. Beta-blockers help to slow down the heart rhythm and lower the blood pressure. At the first stage of the work, high expression of the mRNA of the Adrb1 gene in the myocardium in intact ISIAH rats was observed. Further, we investigate the action of the Si ∼ODN-II nanocomposite with antisense ODN to the mRNA of Adrb1 gene on arterial pressure using intravenous administration. Intravenous injection of Si∼ODNI nanocomposite into the ISIAH rats led to a drop in blood pressure of 10–12 mm Hg for four to five days. Conclusion: The study revealed high expression of mRNA Adrb1 in the myocardium of ISIAH rats. Using of Si∼ODN-II nanoparticles with antisense ODN to beta 1-adrenergic receptors by intravenous administration led to a prolonged decrease in arterial pressure in the ISIAH rats, which is an advantage over traditional drugs and has an perspective to be used in clinical practice. The work was supported by the Russian Science Foundation, grant 16–15-10073.

Stress, Genes, and Hypertension. Contribution of the ISIAH Rat Strain Study.

Acute psychoemotional stress is one of the causes of a sharp increase in blood pressure. However, the question if the stress may promote the hypertensive disease development is still open. This review aims, firstly, to show that the genetically determined enhanced responsiveness to stress is linked to sustained hypertension development and, secondly, to characterize the main physiological mechanisms and genetic factors implicated in the pathogenesis of stress-sensitive hypertension. Recent findings helped to characterize the main neuroendocrine mechanisms and the specificity of the genetic background contributing to the stress-sensitive hypertension development in the ISIAH rats. The ISIAH rat strain, which is an original model of the stress-sensitive arterial hypertension, can be considered as "living" proof that the genetic predisposition to increased stress-reactivity can lead to the development of persistent stress-dependent arterial hypertension. The ISIAH rat strain is characterized by the genetically determined enhanced response of the neuroendocrine and renal regulatory systems to stress and is a suitable model that allows one to explore the genetic and physiological mechanisms involved in stress-sensitive hypertension development. There are common genetic loci (QTLs) associated with both basal and stress-induced blood pressure (BP) levels as well as QTLs associated with BP and other traits, which may be related to hypertension development in ISIAH rats. Multiple genes differentially expressed in the target organs/tissues of hypertensive ISIAH and normotensive control rats are associated with many biological processes and metabolic pathways involved in stress response and arterial hypertension. The genotype of ISIAH rats is characterized by numerous specific and common SNPs as compared with other models of hypertensive rats. The results of the studies are valuable for the search for genetic markers specific for stress-induced arterial hypertension, as well as for the selection of new molecular targets that may be potentially useful for prevention and/or therapy of hypertensive disease.

Behavioral activity and immune effects of the stress exposures and susceptibility to glucocorticoid drug in inherited stress-induced arterial hypertension rat strain with stress-sensitive arterial hypertension

Behavioral activity and immune effects of the stress exposures and susceptibility to glucocorticoid drug in inherited stress-induced arterial hypertension rat strain with stress-sensitive arterial hypertension

Soluble epoxide hydrolase (sEH) as a potential target for arterial hypertension therapy

Using ISIAH rat strain, an animal model for stress-sensitive form of arterial hypertension, a comparison of the brain stem, hypothalamus, adrenal gland, and kidney transcriptomes for identification of the key genes involved in the development of the stress-sensitive form of arterial hypertension was conducted. Our studies revealed Ephx2 gene encoding soluble epoxide hydrolase (sEH), whose transcription level was significantly higher in all the examined organs. On the basis of other studies and our previous investigations, we concluded the necessity of further studies of Ephx2 gene and an encoded sEH protein as a potential target for pharmacological treatment of stress-sensitive arterial hypertension.

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.

Toward Gene Therapy of Hypertension: Experimental Study on Hypertensive ISIAH Rats.

TiO2-based nanocomposites were prepared to deliver oligonucleotides into cells. The nanocomposites were designed by the immobilization of polylysine-containing oligonucleotides on TiO2-nanoparticles (TiO2·PL-DNA). We showed for the first time the possibility of using the proposed nanocomposites for treatment of hypertensive disease by introducing them into hypertensive ISIAH rats developed as a model of stress-sensitive arterial hypertension. The mRNA of the gene encoding angiotensin I-converting enzyme (ACE1) involved in the synthesis of angiotensin II was chosen as a target. Administration (intraperitoneal injection and inhalation) of the nanocomposite showed a significant (by 20-30mm Hg) decrease in systolic blood pressure when the nanocomposite contained the ACE1 gene-targeted oligonucleotide. When using the oligonucleotide with a random sequence, no effect was observed. Further development and improvement of the inhalation nanocomposite drug delivery to systemic hypertensive disease treatment promises new possibilities for clinical practice.

Molecular determinants of the adrenal gland functioning related to stress-sensitive hypertension in ISIAH rats.

BackgroundThe adrenals are known as an important link in pathogenesis of arterial hypertensive disease. The study was directed to the adrenal transcriptome analysis in ISIAH rats with stress-sensitive arterial hypertension and predominant involvement in pathogenesis of the hypothalamic-pituitary-adrenal and sympathoadrenal systems.ResultsThe RNA-Seq approach was used to perform the comparative adrenal transcriptome profiling in hypertensive ISIAH and normotensive WAG rats. Multiple differentially expressed genes (DEGs) related to different biological processes and metabolic pathways were detected.The discussion of the results helped to prioritize the several DEGs as the promising candidates for further studies of the genetic background underlying the stress-sensitive hypertension development in the ISIAH rats. Two of these were transcription factor genes (Nr4a3 and Ppard), which may be related to the predominant activation of the sympathetic-adrenal medullary axis in ISIAH rats. The other genes are known as associated with hypertension and were defined in the current study as DEGs making the most significant contribution to the inter-strain differences. Four of them (Avpr1a, Hsd11b2, Agt, Ephx2) may provoke the hypertension development, and Mpo may contribute to insulin resistance and inflammation in the ISIAH rats.ConclusionsThe study strongly highlighted the complex nature of the pathogenesis of stress-sensitive hypertension. The data obtained may be useful for identifying the common molecular determinants in different animal models of arterial hypertension, which may be potentially used as therapeutic targets for pharmacological intervention.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3354-2) contains supplementary material, which is available to authorized users.

The gene-expression profile of renal medulla in ISIAH rats with inherited stress-induced arterial hypertension.

BackgroundThe changes in the renal function leading to a reduction of medullary blood flow can have a great impact on sodium and water homeostasis and on the long-term control of arterial blood pressure. The RNA-Seq approach was used for transcriptome profiling of the renal medulla from hypertensive ISIAH and normotensive WAG rats to uncover the genetic basis of the changes underlying the renal medulla function in the ISIAH rats being a model of the stress-sensitive arterial hypertension and to reveal the genes which possibly may contribute to the alterations in medullary blood flow.ResultsMultiple DEGs specifying the function of renal medulla in ISIAH rats were revealed. The group of DEGs described by Gene Ontology term ‘oxidation reduction’ was the most significantly enriched one. The other groups of DEGs related to response to external stimulus, response to hormone (endogenous) stimulus, response to stress, and homeostatic process provide the molecular basis for integrated responses to homeostasis disturbances in the renal medulla of the ISIAH rats. Several DEGs, which may modulate the renal medulla blood flow, were detected. The reduced transcription of Nos3 pointed to the possible reduction of the blood flow in the renal medulla of ISIAH rats.ConclusionsThe generated data may be useful for comparison with those from different models of hypertension and for identifying the common molecular determinants contributing to disease manifestation, which may be potentially used as new pharmacological targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0462-6) contains supplementary material, which is available to authorized users.

Genetic loci for spleen weight and blood pressure in ISIAH rats with inherited stress-induced arterial hypertension

Recently, the important role of the spleen function in hypertension development was demonstrated. In this study, the genetic control of absolute and relative spleen weight was investigated to reveal the genetic loci common for spleen traits and for arterial blood pressure at rest and under the emotional stress conditions in the ISIAH rats with inherited stress-induced arterial hypertension. The search for genetic loci for absolute and relative spleen weight was performed on 6-month old F2 (ISIAH x WAG) hybrid males derived from a cross of hypertensive ISIAH and normotensive WAG rats. One significant QTL mapped on chromosome 1 and 5 suggestive loci were found for relative spleen weight. Four suggestive loci were detected for absolute spleen weight. All detected loci were novel. The significant QTL on chromosome 1 was common for relative spleen weight and arterial blood pressure at rest and under the emotional stress conditions in ISIAH rats. The results suggest that the manifestation ofthe stress-sensitive arterial hypertension in ISIAH rats may be related to the changes in genetic control of the spleen function.

The Genetic Control of Blood Pressure and Body Composition in Rats with Stress-Sensitive Hypertension

The genetic basis of the stress-sensitive arterial hypertension was investigated using the quantitative trait loci (QTL) approach. Two groups of F2 (inherited stress-induced arterial hypertension [ISIAH] × Wistar albino Glaxo [WAG]) hybrid males of different age (3–4 months old and 6 months old) were tested for blood pressure at rest and stressed conditions and for body composition traits. Several novel loci for the traits were determined. Some loci for blood pressure and organ weight were mapped to the same genetic region in rats of different age. The dynamic change of QTL effects in two rat groups of different age might reflect the process of stress-sensitive hypertension development.

Neuroendocrine profiling in inherited stress-induced arterial hypertension rat strain with stress-sensitive arterial hypertension

The functions of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems were studied in rats with inherited stress-induced arterial hypertension (ISIAH strain). A characteristic feature of the ISIAH strain is an increase in arterial blood pressure measured both under basal conditions and after restraint stress in particular. In the control ISIAH rats, the basal plasma ACTH concentration was slightly lower than that in the normotensive Wistar albino Glaxo (WAG) rats, and no differences were found in plasma corticosterone. However, the 0.5-h restraint stress produced higher activation of the adrenal cortex in the ISIAH rats. Gluco- and mineralocorticoid responses to the blood volume reduction stresses and ACTH and corticosterone responses to social stress were stronger in the ISIAH than in the control WAG rats. An increase in epinephrine content in adrenals in the basal state and enhanced response of the sympathetic adrenal medullary system to handling stress were observed in the ISIAH rats. Restraint stress produced significantly higher expression of genes encoding corticotropin-releasing hormone-mRNA in hypothalamus and proopiomelanocortin-mRNA in pituitary in the ISIAH than in the WAG rats. Restraint stress produced a decrease in glucocorticoid receptor (GR) gene expression (GR-mRNA) in hippocampus in the ISIAH, but not in the WAG rats. A persistent increase in tyrosine hydroxylase-mRNA in adrenals of the ISIAH rats was found. It is concluded that the ISIAH rat strain is an appropriate model of stress-sensitive hypertension with the predominant involvement of the hypothalamic adrenal cortical and sympathetic adrenal medullary systems in its pathogenesis.

Comparative analysis of the persistence of a conditioned passive avoidance reflex in rats with different forms of inherited hypertension

The characteristics of anxiety behavior and reproduction of a conditioned passive avoidance reflex acquired in response to a single combination with an unconditioned aversive stimulus were studied in NISAG rats with inherited stress-sensitive arterial hypertension and spontaneously hypertensive SHR rats. SHR rats were characterized by hyperactive behavior, very low levels of anxiety, and poor reproduction of the conditioned reflex as compared with NISAG and control Wistar and WAG rats. Intermediate-anxiety NISAG rats showed no difficulties in acquiring and subsequently retaining the conditioned reflex. These differences in the ability to undergo single-combination learning in rats with different forms of hypertension suggest that memory processes are independent of elevated arterial blood pressure. The effects of the genetic characteristics of behavior and emotional status of these animals on memory are discussed.

Manifestation of Oxidative Stress in the Pathogenesis of Arterial Hypertension in ISIAH Rats

The ISIAH rat strain with stress-sensitive arterial hypertension was intentionally selected to study the role of stress as a factor in the development of arterial hypertension. This study aimed to determine the role of reactive oxygen and nitrogen species (ROS and RNS) in the pathogenesis of hypertension in ISIAH rats. The nitric oxide concentrations measured by EPR were found to be significantly higher for hypertensive ISIAH rats compared with that for normotensive Wistar rats in both the aortic wall (2 times) and cerebellum (1.5 times). The activity of superoxide dismutase measured in the blood of ISIAH rats was found to be about 1.5 times lower compared with that of Wistar rats. These data support the suggestion that ROS and RNS, including superoxide radicals and nitric oxide, may play an important role in development of stress-induced hypertension in ISIAH rats. The tissue content of reduced thiols has been considered as a marker of oxidative damage. To study the tissue oxidative status we used an EPR method for quantitative determination of SH groups. The concentration of reduced thiols in the blood of ISIAH rats was much lower than that in Wistar rats (0.6 ± 0.05 and 1.57 ± 0.1 mM, respectively).