M. A. Ryazanova

Effects of the alpha- and gamma-polymorphs of glycine on the behavior of catalepsy prone rats

Glycine is used to treat various health problems and is efficient in the treatment of the negative symptoms of schizophrenia. Since glycine exists as a few polymorphs, the aim of this work is to compare the effects of the alpha- and gamma-forms of glycine on the behavior of the genetic catalepsy (GC) strain of rats. Both polymorphs of glycine have been administered to rats orally as pure solid chemicals, and cataleptic behavior and behaviors in the open-field, elevated plus-maze, and light-dark box tests were studied. Both the alpha- and gamma-polymorphs of glycine increased exploratory activity in the open-field test, but only the gamma-polymorph had beneficial effects on catalepsy and exploratory activity in the light-dark box and reduced anxiety in the elevated plus-maze.

Comparative transcriptional profiling of renal cortex in rats with inherited stress-induced arterial hypertension and normotensive Wistar Albino Glaxo rats

BackgroundThe renal function plays a leading role in long-term control of arterial pressure. The comparative analysis of renal cortex transcriptome in ISIAH rats with inherited stress-induced arterial hypertension and normotensive WAG rats was performed using RNA-Seq approach. The goal of the study was to identify the differentially expressed genes (DEGs) related to hypertension and to detect the pathways contributing to the differences in renal functions in ISIAH and WAG rats.ResultsThe analysis revealed 716 genes differentially expressed in renal cortex of ISIAH and WAG rats, 42 of them were associated with arterial hypertension and regulation of blood pressure (BP). Several Gene Ontology (GO) terms significantly enriched with DEGs suggested the existence of the hormone dependent interstrain differences in renal cortex function. Multiple DEGs were associated with regulation of blood pressure and blood circulation, with the response to stress (including oxidative stress, hypoxia, and fluid shear stress) and its regulation. Several other processes which may contribute to hypertension development in ISIAH rats were: ion transport, regulation of calcium ion transport, homeostatic process, tissue remodeling, immune system process and regulation of immune response.KEGG analysis marked out several pathways significantly enriched with DEGs related to immune system function, to steroid hormone biosynthesis, tryptophan, glutathione, nitrogen, and drug metabolism.ConclusionsThe results of the study provide a basis for identification of potential biomarkers of stress-sensitive hypertension and for further investigation of the mechanisms that affect renal cortex function and hypertension development.

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.

The increase in the proportion of nervous animals bred for catatonia: The participation of central adrenoreceptors in catatonic reactions

Using a large amount of breeding material, the idea of D.K. Belyaev on the role of selection in the appearance of new behavioral and neuronal forms was confirmed. Experiments were performed using rats of the GC (genetics + catatonia) strain, which are prone to passive defensive reactions of cataleptic freezing. At the current breeding stage, elevation of the proportion of so-called “nervous” animals was demonstrated, both with respect to the expression of such reactions and their frequency. At this breeding stage, in the brains of GC rats, the mRNA levels of α1A- and α2A-adrenoreceptor genes were determined. A decrease of α1A-adrenoreceptor gene expression in the midbrain and medulla oblongata, along with elevation of α2A-adreno-receptor gene expression in the frontal cortex was observed. It was suggested that changes in the expression of α-adrenoreceptor genes could be caused by an increase in the proportion of nervous animals and could contribute to the akinetic behavioral component in GC rats.

Expression of the renin angiotensin system genes in the kidney and heart of ISIAH hypertensive rats

The content of mRNA of renin-angiotensin system (RAS) genes was measured in the kidney and heart of hypertensive ISIAH and normotensive WAG rats using the real-time PCR. A statistically significant decrease in the mRNA level of RAS genes was registered in the kidney of ISIAH rats, including Ren (by 45%), Ace (43%), AT1A (34%), COX-2 (50%). The level of myocardial expression of AT1A decreased by 28% while Ace expression increased by 80%. These results suggest reduction of renal RAS basal activity in the hypertensive ISIAH rats, and therefore this strain of rats may be referred to the group of models of low-renin hypertension. The ISIAH rats were also characterized by a two-fold increase in the connective tissue sodium concentration and also by a small (but statistically significant) increase in plasma sodium concentration (139 ± 0.3 mmol/l versus 136 ± 0.25 mmol/l in WAG rats). These results together with a tendency to a decrease of plasma aldosterone level also support existence of a classical low-renin hypertension in the ISIAH rats. It is suggested that altered function of renal ion channels represents a basis for the development of low renin hypertension in the ISIAH rats. In addition, impairments in renal system of NO synthesis may also contribute to the pathogenesis of arterial hypertension in the ISIAH rats.

Expression of Renin–Angiotensin System Genes in Brain Structures of ISIAH Rats with Stress-Induced Arterial Hypertension

We studied the expression of genes encoding angiotensinogen (Agt), renin (Ren), angiotensinconverting enzyme (ACE), and type 1 angiotensin receptor (AT1A) in the hypothalamus and medulla oblongata of hypertensive ISIAH rats and normotensive WAG rats. The amount of Agt mRNA in the hypothalamus of young ISIAH rats was increased by 30% compared to WAG controls. In the medulla oblongata of young ISIAH rats, the levels of mRNA of Agt and AT1A receptor were enhanced by 60% and 24%, respectively, compared to WAG rats. In adult animals, the expression of the studied genes did not differ from the control. It is concluded that changes in gene expression of the renin—angiotensin system in brain structures of ISIAH rats may contribute to the development of hypertension.

Gene Expression for the Renin System in the Myocardium of Hypertensive ISIAH Rats

The concentration of mRNA for angiotensin-converting enzyme (ACE) and angiotensin type 1A receptor (AT1A) in the myocardium of hypertensive ISIAH rats and normotensive WAG rats was measured by real-time PCR. Gene expression of the angiotensin type 1A receptor in the myocardium of 4-month-old ISIAH rats was lower than in WAG rats. The content of mRNA for angiotensin-converting enzyme in the myocardium of adult ISIAH rats was elevated by 80%. Therefore, the development of myocardial hypertrophy anticipates the increase in enzyme expression in the myocardium. Water deprivation (17 h) was accompanied by a decrease in the concentration of mRNA for angiotensin-converting enzyme in the myocardium of ISIAH rats, which did not differ from that in normotensive animals. Our results suggest that the decrease in cardiac preload and increase in plasma renin activity during dehydration reduce requirements for hyperactivity of the local cardiac renin—angiotensin system.

Neurohormonal changes during formation of latent inhibition in rats predisposed to catalepsy

The response of two monoaminergic systems to induction of latent inhibition has been studied in two rat strains. The noradrenergic system of the Wistar rat brain responded uniformly and systemically in the hippocampus, hypothalamus, amygdala, and frontal cortex. It has been shown that footshock induced a decrease in the norepinephrine level and the return of the mediator level to the control level in the “adaptation + footshock” groups for the four brain regions studied. Significant differences in norepinephrine levels were found in the “footshock” group in the hippocampus and hypothalamus of Wistar rats but not GC rats. The lowest serotonin level in the hippocampus was found in the “adaptation + footshock” group of the cataleptic strain. Opposite changes in corticosterone levels in the blood plasma of GC and Wistar rats were significant according to the F test (F[2, 70] = 3.908, p < 0.05). Differences in the testosterone levels between the two strains during induction of the latent inhibition were absent.

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.

Increase in the concentration of sEH protein in renal medulla of ISIAH rats with inherited stress-induced arterial hypertension

The concentration of soluble epoxide hydrolase (sEH) protein was studied in renal medulla of adult rats from hypertensive ISIAH strain and normotensive WAG strain. The sEH is a key enzyme in metabolism of epoxyeicosatrienoic acids capable of activating endothelial NO-synthase and nitrogen oxide formation, and therefore being vasodilators. An increase in the sEH protein concentration (that we found) allows one to assume that the oxidative stress is increased in the renal medulla of hypertensive rats, and the bloodflow is decreased.