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

NEW FINDINGS: 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 (10 male rats) with stress-sensitive arterial hypertension and in control normotensive Wistar Albino Glaxo (WAG) rats (eight male 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.

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), angiotensin-converting 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.

Norepinephrine content in the hypothalamus and medulla oblongata of ISIAH rats is regulated by several genetic loci.

Five genetic loci regulating epinephrine content in rat hypothalamus and two loci in the medulla oblongata were identified using polymorphic microsatellite DNA markers. Allele polymorphism of these loci determines the differences between norepinephrine levels in brain compartments of hypertensive ISIAH and normotensive WAG rats. The interactions between the detected epinephrine-regulating loci are additive.

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.

[Characteristics of glucocorticoid receptor gene expression in spontaneously hypertensive rat strain]. / Osobennosti ékspressii gena gliukokortikoidnogo retseptora u gipertenzivnykh krys linii NISAG.

In ISIAH rat strain with stress-sensitive form of hypertension, the expression level of glucocorticoid receptor (GR) gene has been evaluated in hippocampus, hypothalamus and pituitary under basal and 2-hr restraint stress conditions. Corticosterone (CS) level in peripheral blood was also evaluated. Normotensive WAG strain was used as a control. Under basal condition, there were no interstrain differences in GR-mRNA level in any brain region under study. However, under stress condition, ISIAH rats demonstrated a significant fall of GR-mRNA in hippocampus and increase the pituitary gland as compared to basal level. On the contrary, no differences with basal level were found in stressed WAG rats. CS concentration in blood was nearly the same in nonstressed WAG and ISIAH rats. Stress influence led to a marked increase of CS in both strains. However CS level was significantly higher in stressed ISIAH rats than in stressed WAG group.

Selenium content and blood antioxidant activity in rats with hereditary arterial hypertension during experimental myocardial infarction.

The dynamics of selenium content in the plasma, lymph, and myocardium and plasma antioxidant activity were studied in male NISAG (hereditary stress-induced arterial hypertension) and Wistar rats with acute myocardial infarction and during recovery. In NISAG rats the decrease in selenium content correlated with the decrease in antioxidant activity. This probably aggravates the symptoms of experimental myocardial infarction in animals with hereditary arterial hypertension.

[Oxidative stress in pathogenesis of arterial hypertension in ISIAH rats]. / Rol' oksidativnogo stressa v patogeneze arterial'noi gipertenzii u krys linii NISAG.

The NO-synthase activity and the rate of NO production in the rat aortic wall and cerebellum were 2-1.5-fold higher in the ISIAH rats than in normotensive WAG rat strain. In contrast, the superoxide dismutase (SOD) activity was significantly reduced in the ISIAH rats. The blood level of reduced thiols was also much lower in the ISIAH rats. The findings suggest that oxidative stress may play a significant role in pathogenesis of stress-sensitive hypertension in the ISIAH rat strain.

[The brain catecholaminergic system during the long-term correction of hereditary arterial hypertension]. / Katekholaminergicheskaia sistema mozga pri dlitel'noi korrektsii nasledstvennoi arterial'noi gipertenzii.

L-DOPA administration to 21--25-day-old rats with inherited stress-induced arterial hypertension (ISIAH rats)lowered arterial pressure both at rest and in emotional stress in adult rats. The effect seems to be due to enhancement of the brain catecholamine synthesis rather than the peripheral one in early ontogenesis. The long-term hypotensive effect of the L-DOPA was supposed to be caused in part by changes revealed in the brain catecholaminergic system.

[Genetic correlation between the arterial pressure response during emotional stress and the alpha1-adrenoreceptor concentration in brain regions]. / Geneticheskaia korreliatsiia reaktsii arterial'nogo davleniia pri émotsional'nom stresse s kontsentratsiei alpha1-adrenoretseptorov v otdelakh mozga.

Arterial blood pressure reactivity to the emotional stress and brain alpha 1-adrenoreceptors concentrations were studied in hypertensive (ISIAH strain) and normotensive (Wistar strain) rats and their F1 and F2 hybrids. Significant correlations between the stress-induced increase in the arterial blood pressure and the amount of alpha 1-adrenoreceptors in hypothalamus (+0.46) and medulla (+0.38) were found in the F2. This cosegregation may point to the significant role of genetically determined peculiarities of expression of alpha 1-adrenoreceptors in brain regions during pathogenesis of arterial hypertension in the ISIAH strain.

[The effect of pharmacologic blockade of serotonin receptors (S2) on arterial pressure in rats with 2 forms of hereditary arterial hypertension]. / Vliianie farmakologicheskoi blokady serotoninovykh (S2) retseptorov na arterial'noe davlenie u krys s dvumia formami nasledstvennoi arterial'noi gipertenzii.

The influence of blockade of serotonin S2 receptors with ketanserin was studied in two strains of rats with inherited arterial hypertension: spontaneously hypertensive rats (SHR strain) and rats with inherited stress-induced arterial hypertension (ISIAH strain). It was found that peripheral injection of ketanserin produced a greater decrease of arterial blood pressure than i.c.v. administration. ISIAH rats were more sensitive to the hypotensive effect of ketanserin when compared to normotensive Wistar or SHR rats.

[Genetic and physiological mechanisms of the hypertensive reaction in emotional stress in rats]. / Genetiko-fiziologicheskie mekhanizmy gipertenzivnoi reaktsii pri émotsional'nom stresse u krys.

The experiments were performed on rats of three inbred strains (Wistar, August, and Spreg-Dowley). Arterial pressure was measured during acute emotional stress. The reactivity of arteries to vasopressor stimuli, the corticosteroid function, and the humoral pressor activity of plasma were also studied to investigate some physiologic mechanisms of genetically determined differences in the level of arterial pressure during stress. It was established that the rat strains which were examined did not differ in the level of arterial pressure at rest, but showed marked differences in pressure under conditions of stress: the greatest rise in pressure was noted among August rats, the least among Wistar rats, while animals of the Spreg-Dowley strain occupied an intermediate position. It is concluded that inter-strain differences in the pressor reaction reflect genetical peculiarities in the system of nonspecific stress reactivity of animals.