A. L. Markel

Persistent hypotensive effect of l-DOPA given early during development to rats with inherited stress-induced arterial hypertension

A long-lasting decrease of the basal and stress-induced arterial blood pressure was obtained in rats with inherited emotional stress-induced arterial hypertension by means of injections of the dopamine precursor L-DOPA during early development (21-25 days after birth). The restoring effect of L-DOPA was produced through enhancement of synthesis of the brain noradrenaline and, perhaps, adrenaline. The effect was associated with a normalization of the response of the brain adrenergic system to noradrenaline and, presumably, with increase of tyrosine hydroxylase activity in the cortex and hindbrain.

TREATMENT WITH L-DOPA IN EARLY LIFE RESTORED PITUITARY-ADRENOCORTICAL RESPONSE TO EMOTIONAL STRESS IN ADULT RATS WITH INHERITED ARTERIAL HYPERTENSION

This study investigates the function of the hypothalamic-pituitary-adrenocortical system (HPAS) in adult rats with inherited stress-induced arterial hypertension (ISIAH rats) whose arterial blood pressure was lowered by the dopamine precursor L-DOPA treatment during early development (on days 21-25 of life). The response of the HPAS induced by emotional stress was significantly lower in intact ISIAH rats than in normotensive Wistar animals. Injections of L-DOPA on days 21-23 or 21-25 of postnatal life were followed by a long-lasting complete restoration of the emotional stress response in adult ISIAH rats. The restoring effect of L-DOPA was produced through enhancement of synthesis of the brain noradrenaline and, perhaps, adrenaline. The effect was associated with a normalization of the response of the brain adrenergic system to noradrenaline and did not relate to an increase of the plasma corticosterone level after L-DOPA administration in early ontogeny.

Aggressive Behavior: Genetic and Physiological Mechanisms

The paper presents a review of the literature on the genetic determination of intraspecific aggressive behavior, one of the most complex and universal forms of social behavior in animals on different rungs of the evolutionary ladder. We consider the existing experimental approaches and new opportunities based on recent molecular technologies. The comprehensive approach allows investigating the evolutionary, genetic, and biological roots of aggression and its manifestations under different environmental and social factors, as well as genetic predispositions. The social importance of the problem is noted. The review considers the phenomenology of aggression and mechanisms that stimulate or prevent it. It is supposed that the main social mechanism deterring aggression in a population is the dominance–subordination relationships. Neurobiological determinants of aggression and the role of hereditary factors in controlling aggressive behavior in animals and humans are considered. By the example of neurochemical brain changes in male mice exposed to repeated aggression in daily agonistic intermale interactions, we present the research model “from behavior to the gene.” It is noted in the discussion that the same genes that influence aggressiveness in human were revealed in the experimental studies in animals of different strains, as well as in knockout and transgenic animals. They include genes for transporters supporting serotonin reuptake and enzymes involved in the synthesis and catabolism of serotonin and catecholamines. In conclusion, we consider the prospects of transcriptome studies and problems of the epigenetic regulation of aggressive behavior.

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.

Prenatal modification of adrenocortical function of adult rats with hereditary arterial hypertension by hydrocortisone

A decisive role in the formation of hereditarily determined hypertension in rats is played by increased sympathetic nervous activity during the early period of development, linked with the pattern of central noradrenergic regulation of its tone [3]. In turn, the formation of noradrenalin mechanisms of the young rat brain during development depends on the maternal blood corticosteroid level during pregnancy [2]. Elevation of the blood corticosteroid level in pregnant normotensive females changes the noradrenergic system of the brain and the reactivity of the pituitary-adrenal complex in the adult progeny during exposure to emotional stress [7, 8]. The modifying action of glucocorticoids in the period of intrauterine development depends on the hereditary characteristics of the animals [3]. Meanwhile we know that reactivity to stress is an important factor in the pathogenesis of essential hypertension [4, 5, i0].

Parameters of Blood Flow in Great Arteries in Hypertensive ISIAH Rats with Stress-Dependent Arterial Hypertension.

Magnetic resonance angiography was used to examine blood flow in great arteries of hypertensive ISIAH and normotensive Wistar rats. In hypertensive ISIAH rats, increased vascular resistance in the basin of the abdominal aorta and renal arteries as well as reduced fraction of total renal blood flow were found. In contrast, blood flow through both carotid arteries in ISIAH rats was enhanced, which in suggests more intensive blood supply to brain regulatory centers providing enhanced stress reactivity of these rats characterized by stress-dependent 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.

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.

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.

Brain metabolites in ISIAH and Wistar rats

Hypertension is one of the most common human diseases, which leads to serious disturbances, such as myocardial infarction and stroke. A decrease in the neuron viability in different parts of the brain in humans with hypertension has been shown by nuclear magnetic resonance spectroscopy (NMRS). Translation of NMRS tools to the clinical practice requires the accumulation of empirical data on neurometabolic changes in a strictly controlled experiment. It is particularly interesting to compare the metabolic parameters of laboratory animals with the normal and high blood pressure maintained under standard conditions on the same diet. In this study, we examined the cortex and hypothalamus metabolites of ISIAH and Wistar male rats at the age of 8–9 weeks. The cortex and hypothalamus metabolites were measured in animals under isoflurane anesthesia using proton magnetic resonance spectroscopy (1Н MRS). Processing the primary data using the Partial Least Squares Discriminant Analysis (PLS-DA) allowed us to identify the main discriminating axis (Y1) and its variations, which showed the predominance of the excitatory neurometabolites (glutamine and glutamate) over the inhibitory ones (GABA and glycine). In the cortex, the Y1 axis values were lower in ISIAH rats than in Wistar rats. This indicates a decrease in the cortical excitability in hypertensive animals. In contrast, in the hypothalamus, the Y1 axis values were higher in ISIAH rats than in Wistar rats, and the predominance of the excitatory neurometabolites was positively correlated to the level of the mean blood pressure, which agrees well with the idea of caudal hypothalamic activation in hypertensive animal models.