The role of oxytocin and vasopressin in the pathophysiology of heart failure in pregnancy and in fetal and neonatal life.

Pregnancy and early life create specific psychosomatic challenges for the mother and child, such as changes in hemodynamics, resetting of the water-electrolyte balance, hypoxia, pain, and stress, that all play an important role in the regulation of the release of oxytocin and vasopressin. Both of these hormones regulate the water-electrolyte balance and cardiovascular functions, maturation of the cardiovascular system, and cardiovascular responses to stress. These aspects may be of particular importance in a state of emergency, such as hypertension in the mother or severe heart failure in the child. In this review, we draw attention to a broad spectrum of actions exerted by oxytocin and vasopressin in the pregnant mother and the offspring during early life. To this end, we discuss the following topics: 1) regulation of the secretion of oxytocin and vasopressin and expression of their receptors in the pregnant mother and child, 2) direct and indirect effects of oxytocin and vasopressin on the cardiovascular system in the healthy mother and fetus, and 3) positive and negative consequences of altered secretion of oxytocin and vasopressin in the mother with cardiovascular pathology and in the progeny with heart failure. The present survey provides evidence that moderate stimulation of the oxytocin and vasopressin receptors plays a beneficial role in the healthy pregnant mother and fetus; however, under pathophysiological conditions the inappropriate action of these hormones exerts several negative effects on the cardiovascular system of the mother and progeny and may potentially contribute to the pathophysiology of heart failure in early life.

Impaired hypotensive effects of centrally acting oxytocin in SHR and WKY rats exposed to chronic mild stress.

The present study was designed to determine the role of centrally acting oxytocin (OT) in the regulation of blood pressure during chronic mild stress (CMS) in spontaneously hypertensive (SHR; n = 36) and normotensive Wistar-Kyoto (WKY; n = 38) rats. The rats were implanted with osmotic minipumps for intracerebroventricular infusions of 0.9% NaCl, OT, and oxytocin receptor antagonist (OTANT) and divided into two groups: SHR and WKY 1) exposed to 4-wk CMS and 2) not exposed to stress (controls). After 4 wk, hemodynamic parameters were recorded at rest and after an application of acute stressor [air-jet stress (AJS)]. Resting mean arterial blood pressure (MAP) was significantly lower in CMS-exposed SHR and WKY infused with OT than in the corresponding groups receiving saline. Exposure to CMS exaggerated the AJS-dependent pressor response in WKY receiving saline but not in the corresponding group of SHR. OT infusion reduced the AJS-dependent pressor response in both CMS-exposed and not exposed SHR and in CMS-exposed WKY. Intracerebroventricular infusion of OTANT potentiated the AJS-dependent pressor response in both stressed and not stressed WKY rats but not in SHR. The results show that centrally delivered OT decreases resting MAP during CMS in both SHR and WKY rats and that in SHR it reduces pressor responses to AJS under control and CMS conditions, whereas in WKY this effect is significant only after CMS exposure. The study indicates that endogenous centrally acting OT may play an essential role in buffering pressor responses to AJS in CMS-exposed and not exposed WKY rats and that this function is significantly impaired in SHR.

Aldosterone and mineralocorticoid receptors in regulation of the cardiovascular system and pathological remodelling of the heart and arteries.

In the review we discuss the role of mineralocorticoid receptors (MRs) in regulation and pathological remodelling of the cardiovascular system and the therapeutic potential of pharmacological targeting of MRs in cardiovascular diseases. MRs are expressed in organs involved in cardiovascular homeostasis: brain, heart, kidneys and vessels. The excessive activation of MRs has deleterious effects on the cardiovascular system through sympatho-excitation, elevated salt appetite, and renal retention of salt with consequent positive sodium balance, fibrosis and remodelling of the heart and arteries, and with propensity for atrial and ventricular arrhythmias. Hence, it provides basis for a common pathophysiological milieu of hypertension and heart failure. Furthermore, MR-mediated changes in the cardiovascular system are potentiated by renin-angiotensin system and activation of angiotensin type 1 receptors. Due to low selectivity, MRs bind both aldosterone and GCs - cortisol in humans and corticosterone in laboratory rodents. The binding of GCs to MRs is determined by availability of tissue specific 11ß-hydroxysteroid dehydrogenase of type 1 (11ß-HSD1) or type 2 (11ß-HSD2). 11ß-HSD1 metabolizes GCs to either active or inactive metabolites depending on the presence of special cofactors, whereas 11ß-HSD2 transforms GCs only into inactive metabolites allowing for selective stimulation of MRs by aldosterone. 11ß-HSD2 is expressed in the vascular wall, renal epithelium and some groups of cardiovascular neurons in the brain. In contrast, cardiac expression of 11ß-HSD2 is low, thus, both aldosterone and GCs interact with cardiac MRs. The importance of MRs in the cardiovascular pathology is reflected in clinical guidelines that recommend use of MR blockers, spironolactone and eplerenone, in the treatment of heart failure, myocardial infarction and hypertension. Furthermore, new MR blockers and selective inhibitors of 11ß-HSD1 have been developed and are currently tested in clinical trials.

Altered expression of V1a receptors mRNA in the brain and kidney after myocardial infarction and chronic stress.

Vasopressin released during myocardial infarction and in response to stress regulates blood pressure through multiple actions exerted in the brain, cardiovascular system and kidney. The aim of the present study was to determine whether myocardial infarction influences expression of vasopressin V1a receptor (V1aR) mRNA and protein in the brain and kidney and whether stress has an impact on expression of these parameters during the post-infarct state. Male, adult Sprague Dawley rats were subjected to myocardial infarction or sham surgery. Seven days later some rats were exposed to mild stress for 4weeks whereas other stayed at rest. Tissue fragments were harvested from four groups of rats (control, infarct, stress, infarct+stress). Expression of V1aR mRNA (Real time PCR) was determined in the preoptic, diencephalic, mesencephalopontine and medullary regions of the brain and in the renal cortex and medulla. Protein V1aR expression (Western blotting) was determined in the brain mesencephalopontine region and in the kidney medulla. In the preoptic, diencephalic, and mesencephalopontine regions, V1aR mRNA expression was significantly lower in the infarcted rats than in the sham-operated unstressed controls. The infarcted rats manifested also lower expression of V1aR protein in the mesencephalopontine region than the other groups. The stressed group demonstrated significantly higher V1aR mRNA expression in the brain medulla and in the renal cortex and renal medulla than the control group. In all brain regions and in the kidney, V1aR mRNA expression was significantly higher in the stressed rats than in the infarcted rats. The stressed rats showed also higher expression of V1aR protein in the renal medulla than the other groups. It is concluded that myocardial infarction and chronic stress cause significant but differential changes in the regulation of V1a receptors expression in the brain and the kidney.

Angiotensin converting enzyme inhibition reduces cardiovascular responses to acute stress in myocardially infarcted and chronically stressed rats.

Previous studies showed that chronically stressed and myocardially infarcted rats respond with exaggerated cardiovascular responses to acute stress. The present experiments were designed to elucidate whether this effect can be abolished by treatment with the angiotensin converting enzyme (ACE) inhibitor captopril. Sprague Dawley rats were subjected either to sham surgery (Groups 1 and 2) or to myocardial infarction (Groups 3 and 4). The rats of Groups 2 and 4 were also exposed to mild chronic stressing. Four weeks after the operation, mean arterial blood pressure (MABP) and heart rate (HR) were measured under resting conditions and after application of acute stress. The cardiovascular responses to the acute stress were determined again 24 h after administration of captopril orally. Captopril significantly reduced resting MABP in each group. Before administration of captopril, the maximum increases in MABP evoked by the acute stressor in all (infarcted and sham-operated) chronically stressed rats and also in the infarcted nonchronically stressed rats were significantly greater than in the sham-operated rats not exposed to chronic stressing. These differences were abolished by captopril. The results suggest that ACE may improve tolerance of acute stress in heart failure and during chronic stressing.

The effect of blockade of the central V1 vasopressin receptors on anhedonia in chronically stressed infarcted and non-infarcted rats.

Chronic mild stress (CMS) and myocardial infarction (MI) induce anhedonia, which is one of the symptoms of depression. The purpose of this study was to determine the role of the central V1 vasopressin receptors (V1R) in post-CMS and post-MI anhedonia. To this end, we investigated the effect of blockage the central V1R [28days of intracerebroventricular (ICV) infusion of V1 receptors antagonist (V1RANT)] on CMS-induced and the post-infarct anhedonia. The experiments were conducted on conscious MI or sham-operated (SO) rats that were either exposed to CMS for 20days or remained at rest. The sucrose/water intake ratio (S/W) was measured to determine hedonic behavior. Seven days after MI, the S/W was reduced. This effect was no longer present 37days after the infarction and was also absent in the SO rats. Exposure to CMS reduced the S/W in SO rats also. In the CMS-exposed MI rats, the S/W was similar to that in the CMS-exposed SO rats. ICV administration of V1RANT abolished reductions in the S/W in the CMS-exposed MI rats, however, it did not influence S/W in the SO rats exposed to CMS and in the MI and SO rats not exposed to CMS. We conclude that: (1) myocardial infarction and chronic stressing cause anhedonia, (2) myocardial infarction-induced anhedonia appears to be transient, (3) myocardial infarction does not potentiate CMS-induced anhedonia, and (4) CMS-induced anhedonia critically depends on the stimulation of the central V1 receptors.

Oxytocin differently regulates pressor responses to stress in WKY and SHR rats: the role of central oxytocin and V1a receptors.

The role of central oxytocin in the regulation of cardiovascular parameters under resting conditions and during acute stress was investigated in male normotensive Wistar-Kyoto (WKY; n = 40) and spontaneously hypertensive rats (SHR; n = 28). In Experiment 1, mean arterial blood pressure (MABP) and heart rate (HR) were recorded in WKY and SHR rats at rest and after an air-jet stressor during intracerebroventricular (ICV) infusions of vehicle, oxytocin or oxytocin receptor (OTR) antagonist. In Experiment 2, the effects of vehicle, oxytocin and OTR antagonist were determined in WKY rats after prior administration of a V1a vasopressin receptor (V1aR) antagonist. Resting MABP and HR were not affected by any of the ICV infusions either in WKY or in SHR rats. In control experiments (vehicle), the pressor response to stress was significantly higher in SHR. Oxytocin enhanced the pressor response to stress in the WKY rats but reduced it in SHR. During V1aR blockade, oxytocin infusion entirely abolished the pressor response to stress in WKY rats. Combined blockade of V1aR and OTR elicited a significantly greater MABP response to stress than infusion of V1a antagonist and vehicle. This study reveals significant differences in the regulation of blood pressure in WKY and SHR rats during alarming stress. Specifically, the augmentation of the pressor response to stress by exogenous oxytocin in WKY rats is caused by its interaction with V1aR, and endogenous oxytocin regulates the magnitude of the pressor response to stress in WKY rats by simultaneous interaction with OTR and V1aR.

Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases.

In spite of significant progress in pharmacotherapy the incidence of newly diagnosed cases of cardiovascular diseases and cardiovascular morbidity is alarmingly high. Treatment of hypertension or heart failure still remains a serious challenge. Continuous attempts are made to identify the mechanisms that decide about susceptibility to pathogenic factors, and to determine effectiveness of a specific therapeutic approach. Coincidence of cardiovascular diseases with metabolic disorders and obesity has initiated intensive research for their common background. In the recent years increasing attention has been drawn to disproportionately greater number of depressive disorders and susceptibility to stress in patients with coronary artery disease. An opposite relationship, i.e. a greater number of sudden cardiovascular complications in patients with depression, has been also postulated. Progress in functional neuroanatomy and neurochemistry provided new information about the neural network responsible for regulation of cardiovascular functions, metabolism and emotionality in health and under pathological conditions. In this review we will focus on the role of neuromodulators and neurotransmitters engaged in regulation of the cardiovascular system, neuroendocrine and metabolic functions in health and in pathogenesis of cardiovascular diseases and obesity. Among them are classical neurotransmitters (epinephrine and norepinephrine, serotonin, GABA), classical (CRH, vasopressin, neuropeptide Y) and newly discovered (orexins, apelin, leptin IL-1beta, TNF-alpha, ghrelin) neuropeptides, gasotransmitters, eicozanoids, endocannabinoids, and some other compounds involved in regulation of neuroendocrine, sympatho-adrenal and parasympathetic nervous systems. Special attention is drawn to those factors which play a role in immunology and inflammatory processes. Interaction between various neurotransmitter/neuromodulatory systems which may be involved in integration of metabolic and cardiovascular functions is analyzed. The survey gives evidence for significant disturbances in release or action of the same mediators in hypertension heart failure, obesity, diabetes mellitus, metabolic syndrome, starvation, chronic stress, depression and other psychiatric disorders. With regard to the pathogenic background of the cardiovascular diseases especially valuable are the studies showing inappropriate function of angiotensin peptides, vasopressin, CRH, apelin, cytokines and orexins in chronic stress, cardiovascular and metabolic diseases. The studies surveyed in this review suggest that multiple brain mechanisms interact together sharing the same neural circuits responsible for adjustment of function of the cardiovascular system and metabolism to current needs.

Role of neuropeptides in central control of cardiovascular responses to stress.

Neurogenic stress causes sudden acceleration of heart rate and elevation of arterial blood pressure. that may markedly increase the work load of the heart. Several recent clinical studies document significant role of stress in evoking sudden cardiovascular complications. It has been also shown that the cardiovascular responses to stress are significantly exaggerated during the post-infarct cardiac failure. This review emphasises important neuromodulatory role of some neuropeptides in regulation of the cardiovascular system during stress. A number of experimental data provide evidence that intensity of the cardiovascular responses to stress is regulated by neuropeptides. Vasopressin, angiotensin II and interleukin-1beta (IL-1beta) appear to be responsible for exaggeration of the cardiovascular responses to stress whereas oxytocin seems to act in the opposite way. Recent studies performed in our Department provide evidence for differential involvement of angiotensin II AT(1), vasopressin V(1a), IL-1 and oxytocin receptors in regulation of the cardiovascular responses to the alarming stress. Current evidence suggests that the enhanced stimulation of central AT(1) and V(1) receptors as well as the attenuated stimulation of oxytocin receptors account for exaggeration of the cardiovascular responses to the sudden alarming stress during the post-infarct state. Growing number of data indicate that angiotensin II significantly interacts with vasopressin, interleukin-1 and TNF-alpha systems in the central cardiovascular control under resting conditions. Some of the neuropeptides interact also during stress.

Central TNF-alpha elevates blood pressure and sensitizes to central pressor action of angiotensin II in the infarcted rats.

In patients with chronic heart failure (CHF) concentration of TNF-alpha is elevated. Enhanced synthesis of TNF-alpha was also found in the hypothalamus of rats shortly after induction of the myocardial infarct. Available evidence indicates that TNF-alpha increases sympathetic activity and enhances function of the renin-angiotensin-aldosterone system in peripheral tissues. The role of TNF-alpha in regulation of the cardiovascular system and its interactions with brain angiotensin II (ANGII) in CHF was evaluated in the following study. Fourteen Sprague-Dawley rats underwent left coronary artery ligation, implantation of lateral cerebral ventricle cannula and insertion of femoral artery catheter. Post-infarct CHF was confirmed by increased left ventricle end-diastolic pressure. Mean arterial blood pressure (MABP) and heart rate (HR) were recorded during 60 min of intracerebroventricular (i.c.v.) infusion of 0.9% NaCl (5 microl/hr) (control group, n = 7) or TNF-alpha (100 ng/5 microl/hr) (experimental group, n = 7). This was followed by i.c.v. injection of subpressor dose of ANGII (5 ng/2 microl/30 sec) and measurements were continued for 20 min. Infusion of TNF-alpha resulted in the increase of MABP without changes in HR. Administration of ANGII elicited significantly greater increase of MABP in rats pretreated with TNF-alpha. Present results indicate that TNF-alpha increases MABP in CHF and sensitizes to pressor effect of centrally administered ANGII.

Oxytocin in the cardiovascular responses to stress.

The present study was designed to determine the role of central oxytocin (OXY) in regulation of the cardiovascular responses to the alarming stress. Three groups of male, normotensive Sprague Dawley rats, received intracerebroventricular (i.c.v.) infusion of one of the following: 1) vehicle, 2) OXY or 3) OXY antagonist (OXANT). Mean arterial blood pressure (MABP) and heart rate (HR) were recorded at rest, during and after application of the alarming stressor (air jet). Under resting conditions the i.c.v. infusions of vehicle, OXY or OXYANT did not influence the cardiovascular parameters. The alarming stressor evoked significant increases in MABP and HR that were significantly greater in the rats receiving i.c.v. infusion of oxytocin antagonist than in those receiving vehicle or OXY. The study provides evidence that stimulation of the brain oxytocin receptors by endogenous oxytocin plays significant role in inhibition of cardiovascular responses to stress.

Enhanced expression of mineralocorticoid receptors in the heart after the myocardial infarct in rats.

Increasing evidence suggests that enhanced stimulation of the heart and kidney by mineralocorticoids plays significant role in development of the post-infarct cardiac failure. Because increased synthesis of mineralocorticoid receptors (MR) is one of the putative factors determining pathogenic effects of mineralocorticoids we decided to determine whether the myocardial infarct results in an enhanced expression of MR mRNA and MR protein. To this end male Sprague-Dawley rats were subjected either to ligation of the left coronary artery or to sham surgery. After four weeks expressions of MR mRNA and MR protein were evaluated in both groups of rats in the left (LV) and right (RV) ventricle walls, and in the renal cortex and renal medulla by means of semiquantitative PCR and Western blotting methods. Coronary ligation resulted in the myocardial infarction encompassing 30.2% +/- 1.9% (range 23-40%) of the left ventricle wall. In the infarcted rats expression of MR mRNA was significantly greater than in the sham-operated rats, both in the LV (P<0.02) and in the RV (P<0.005). In the left but not in the right ventricle increased MR mRNA expression was associated with significant increase in expression of MR protein (P<0.001). In the renal cortex and renal medulla MR mRNA and MR protein expression in the infarcted and the sham-operated rats did not differ. The study reveals that during the post-infarct state expression of MR mRNA is elevated in both cardiac ventricles while expression of MR mRNA protein is increased only in the left ventricle. The results suggest that the enhanced expression of mineralocorticoid receptors may contribute to enhanced effects of mineralocorticoids in the heart during the post-infarct state.

Upregulation of angiotensin AT1a receptors mRNA in the heart and renal medulla after myocardial infarction in rats.

The myocardial infarct causes prolonged activation of the renin-angiotensin system and profoundly influences cardiac performance and renal excretory capabilities. The aim of the present study was to determine whether the myocardial infarct is also associated with an altered expression of AT1a receptors (AT1aR) mRNA in the heart and the kidney. To this end male Sprague-Dawley rats were subjected either to the left coronary artery ligation or to the sham surgery. Four weeks after the surgery the animals were sacrificed. In 11 infarcted and 10 sham-operated rats expression of AT1aR mRNA in the walls of the left and right ventricle of the heart, and in the renal cortex and renal medulla was determined by semiquantitative PCR method. In another group of 10 infarcted and 14 sham-operated rats the diameter of cardiomyocytes in the left and right cardiac ventricle was determined. The size of the infarct in the rats used for mRNA determination and for morphometric measurements was equal to 29.4 +/- 1.8% and to 31.0 +/- 1.2 % of the left ventricular wall, respectively. Expression of AT1aR mRNA was significantly greater in the left (P< 0.01) and right ventricle (P<0.03) of the heart in the infarcted than in the sham operated rats. AT1aR mRNA expression was also significantly greater (P<0.02) in the renal medulla of the infarcted rats than in the renal medulla of the sham operated rats whereas no significant difference was found in the renal cortex. The myocardial infarct was associated with a significant increase of diameter of cardiomyocytes of the left ventricle of the heart (P< 0.0001), however there was no significant correlation between changes in AT1aR mRNA expression and diameter of cardiomyocytes. The results provide evidence that the myocardial infarct results in significant and prolonged upregulation of AT1a receptors mRNA expression in the heart and in the medullary region of the kidney.

Neuropeptides in neurogenic disorders of the cardiovascular control.

Growing number of studies reveal that the brain neural network plays significant role in the short-term and long-term regulation of the cardiovascular functions. The neurons involved in the complex neurogenic control of the cardiovascular system use classical neurotransmitters and nonconventional mediators such as peptides (angiotensin II, vasopressin, natriuretic peptides, endothelins, opioids, cytokines), steroids, ouabain-like factors and gaseous compounds. Among them the neuropeptides form a group of substances arising significant interest. Thanks to wide distribution of peptidergic neurons in the central nervous system, location of peptide receptors on neurons and glial cells, versatile but frequently overlapping mechanisms of activation of the intracellular processes the neuropeptides play significant role in short-term and long-term regulation of excitability and remodeling of the neurons. In several instances they modulate effects of the classical transmitting systems involved in regulation blood pressure, heart rate, water-electrolyte balance, metabolism, stress, pain, mood and memory. Prolonged activation or inhibition of specific neuropeptide pathways frequently results in long-lasting disorders of several regulatory systems. In this review this is exemplified by overactivity of angiotensin II, vasopressin and cytokines in the brain during hypertension, heart failure and stress. Multifarious actions of angiotensin II and vasopressin, and their mutual interaction with cytokines make of these neuropeptides excellent candidates for the compounds responsible for long-term resetting of the central cardiovascular control, and forming a link between the cardiovascular diseases, stress and mood disorders.

Expression of mineralocorticoid receptors mRNA in the brain, heart and kidney of Sprague Dawley rats with renovascular hypertension.

A large body of evidence indicates that mineralocorticoids play significant role in regulation of cardiovascular functions and in pathogenesis of several forms of hypertension by means of multiple effects exerted in the brain, heart and kidney. However, little is known about regulation of expression of mineralocorticoid receptors mRNA in the hypertensive states. The purpose of the present study was to determine whether expression of mineralocorticoid receptors mRNA is altered in the brain as well as in the left ventricle of the heart and in the kidney in the rats with the Goldblatt 2K,1C renovascular hypertension. Competitive PCR method was used for relative quantitative analysis of mineralocorticoid receptors mRNA in the brain, heart and kidney samples harvested from 12 to 14 weeks old, male Sprague Dawley rats subjected either to constriction of the left renal artery (n=8) or to the sham surgery (n=9). The 2K,1C rats manifested significantly higher systolic blood pressure (P<0.005) and significantly reduced weight of the left kidney (P<0.001) in comparison to the sham-operated rats. In both groups, mineralocorticoid receptors mRNA was well expressed in the preoptic, diencephalic, mesencephalopontine, medullary and cerebellar regions of the brain, and in the heart, renal cortex and the renal medulla. Significant differences were found between expression of MR mRNA in different brain regions. In the 2K,1C rats, expression of mineralocorticoid receptors mRNA was significantly lower than in the sham-operated rats in the mesencephalopontine (P<0.02) and medullary (P<0.005) regions of the brain as well as in the heart (P<0.030) and the renal medulla of the kidney (P<0.001). No significant differences were detected in the other brain regions and in the renal cortex. The results provide evidence that mineralocorticoid receptors mRNA expression is significantly diminished in the brain stem, the heart and the renal medulla of rats with the 2K,1C renovascular hypertension.

Fluid consumption, electrolyte excretion and heart remodeling in rats with myocardial infarct maintained on regular and high sodium intake.

The purpose of the study was to determine effect of high sodium intake on fluid and electrolyte turnover and heart remodeling in the cardiac failure elicited by myocardial infarction (MI). The experiments were performed on four groups of Sprague Dawley rats maintained on food containing 0.45% NaCl and drinking either water (groups 1, 2) or 1% NaCl (groups 3, 4). Groups 1 and 3 were sham-operated while in groups 2 and 4 MI was produced by the coronary artery ligation. In each group food and fluid as well as sodium intake, urine (Vu), sodium (UNaV), potassium (UKV) and solutes (UosmV) excretion were determined before and four weeks after the surgery. Size of the infarct, left ventricle (LV) weight and diameter of LV and right ventricle (RV) myocytes were determined during post-mortem examination. Before the surgery groups 3 and 4 ingested significantly more fluid and sodium, had higher Vu, UNaV, UKV and UosmV than the respective groups 1 and 2. In groups 2 and 4 MI resulted in significant decrease in Vu, UNaV and UosmV in comparison to the pre-surgical level. In Group 4 MI resulted also in a significant decrease of food and sodium intake. The MI size did not differ in groups 2 and 4 while diameter of LV myocytes was significantly greater in groups 2 and 4 than in groups 1 and 3, and in group 4 than in group 2. The study reveals that prolonged high sodium consumption increases fluid and electrolyte turnover both in the sham and in the MI rats and that the MI causes decrease in food and sodium intake in rats on high but not on regular sodium intake. In addition high sodium diet promotes development of greater post-MI hypertrophy of the LV myocytes.

Altered expression of angiotensin AT1a and vasopressin V1a receptors and nitric oxide synthase mRNA in the brain of rats with renovascular hypertension.

Previous studies revealed that the brain angiotensinergic, vasopressinergic and nitrergic systems are involved in regulation of blood pressure and that their function is altered in various forms of hypertension. The purpose of our investigation was to determine whether expression of AT1a angiotensin receptors (AT1aR) mRNA, V1a vasopressin receptors (V1aR) mRNA and neuronal nitric oxide synthase (NOS1) mRNA is altered in the brain of rats with the renovascular hypertension. Eight male Sprague Dawley (SD 2K,1C) rats were subjected to constriction of the left renal artery in order to produce the renovascular hypertension whereas nine SD rats underwent the sham surgery. In both groups blood pressure was determined before and after the surgery. Four weeks after the surgery the brain fragments were harvested for determination of mRNA expression. Competitive PCR method was applied for relative quantitative analysis of V1aR mRNA, AT1aR mRNA and NOS1 mRNA in the preoptic, diencephalic, mesencephalopontine, medullary and cerebellar fragments of the brain. Blood pressure was significantly higher in the 2K,1C than in the sham operated rats. In the preoptic, mesencephalopontine and medullary regions AT1aR mRNA expression was significantly lower in the 2K,1C rats than in the sham operated rats. The 2K,1C rats manifested also significantly higher expression of V1aR mRNA and NOS1 mRNA in the preoptic brain region in comparison to the sham operated rats. The study provides evidence for significant changes of expression of AT1aR mRNA, V1aR mRNA and NOS1 mRNA in the specific brain regions of rats with the renovascular hypertension.

Hypotensive function of the brain angiotensin-(1-7) in Sprague Dawley and renin transgenic rats.

Angiotensin-(1-7) (Ang-[1-7]) is present in the brain of normotensive Sprague Dawley (SD) rats, and its hypothalamic content is elevated in TGRmRen2(27) rats (TGR) with renin dependent transgenic hypertension. The purpose of the present study was to determine the role of intrabrain Ang-(1-7) in the regulation of cardiovascular functions in SD and TGR rats under resting conditions and during haemodynamic challenge produced by rapid bleeding. Two groups of experiments were performed on conscious SD and TGR rats that were chronically instrumented with a lateral cerebral ventricle (LCV) cannula and an intraarterial catheter. Blood pressure (MAP) and heart rate period (Hp=distance between two systolic peaks) were continuously monitored: 1) under resting conditions during an LCV infusion of either artificial cerebrospinal fluid (aCSF, 5 microl/hr) or Ang-(1-7) in aCSF (100 pmol/5 microl/hr), and 2) before and after haemorrhage performed during LCV infusion of either aCSF or Ang-(1-7) antagonist (A-779, 4 nmol/5 microl/hr). Cerebroventricular infusion of Ang-(1-7) did not affect baseline MAP in the SD rats but it caused a significant decrease in blood pressure in the TGR rats. In the control experiments, haemorrhage significantly reduced MAP in the SD and TGR rats and heart rate in the TGR rats. Cerebroventricular infusion of Ang-(1-7) antagonist eliminated posthaemorrhagic hypotension in both strains and bradycardia in the TGR rats. The results indicate that intrabrain Ang-(1-7) may contribute to posthaemorrhagic hypotension and bradycardia. Moreover, the manner in which it centrally regulates the cardiovascular functions in the SD and TGR rats may be considerably different.

Enhanced food and water intake in renin transgenic rats.

In short term experiments angiotensin II (Ang II) is a potent stimulant of thirst, however it is not known whether prolonged activation of the renin-angiotensin system is associated with chronic alteration of water or food intake. Renin transgenic rats TGRmRen(2)27 (TGR) exhibit significant elevation of AngII in the brain regions involved in regulation of body fluid balance. The purpose of the present study was to find out whether TGR rats manifest also different water (WI) and food (FI) intake and renal excretory functions in comparison to their parent Sprague Dawley (SD) strain. To this end 24 h WI and FI as well as urine excretion (Vu) and urinary outputs of solutes (Cosm), sodium (UNaV) and potassium (UKV) were compared under baseline conditions in 16 TGR and 15 SD rats having free access to water and food. In 15 TGR and 17 SD rats effect of 24 h dehydration on water intake was investigated. Under baseline conditions TGR rats consumed significantly greater amount of food and water than SD rats. Vu, UNaV and UKV were not significantly different in both strains. Cumulative water intakes in SD and TGR rats subjected to 24 h dehydration did not differ. The results reveal that under baseline conditions TGR rats manifest greater food and water intakes than SD rats whereas stimulation of thirst by water deprivation is similar in both strains. The results suggest that the ingestive behavior may be chronically altered by upregulation of the renin-angiotensin system.

Differential expression of vasopressin V1a and V1b receptors mRNA in the brain of renin transgenic TGR(mRen2)27 and Sprague-Dawley rats.

Recent evidence indicates that renin transgenic rats TGR(mRen2)27 (TGR) manifest increased activity of the central vasopressinergic system. Because one of the reasons for this finding could be an increased synthesis of vasopressin receptors, we determined in the present study expression of V1a and V1b vasopressin receptors (R) mRNA in the brain of TGR rats and of their parent Sprague-Dawley (SD) strain. Competitive PCR method was applied for quantitative analysis of V1a and V1b receptors mRNA in the preoptic, diencephalic, mesencephalopontine and medullary regions. V1aR mRNA expression was similar in SD and TGR rats in the preoptic, diencephalic and mesencephalopontine regions. In the medullary region expression of V1aR mRNA was significantly lower in TGR than in SD rats. V1bR mRNA did not differ in TGR and SD rats in the preoptic, diencephalic and medullary region whereas it was significantly elevated in the mesencephalopontine region. The results provide evidence for differential regulation of V1a and V1b receptors genes in the brain stem of TGR rats that is manifested by downregulation of V1aR mRNA in the medulla and upregulation of V1bR mRNA in the mesencephalopontine region.