Emerson Lopes Olivares

Cardiac effects of oxytocin: Is there a role for this peptide in cardiovascular homeostasis?

Oxytocin is well known for its role in reproduction. However, evidence has emerged suggesting a role in cardiovascular and hydroelectrolytic homeostasis. Although its renal effects have been characterized, the cardiac ones have not been much studied. Therefore, we aimed to investigate the cardiac effects of oxytocin both in vivo and in vitro. In unanesthetized rats (n=6) intravenous oxytocin (1 mug) decreased dP/dt(max) by 15% (P<0.05) and heart rate by 20% (P<0.001), at the first minute after injection. dP/dt(max) was still lower in OT-treated rats than in controls (n=8) after 15 min (P<0.05), while heart rate returned to control values after 5 min. In isolated hearts, oxytocin was able to promote negative inotropic and chronotropic effects. Perfusion with 10(-5), 10(-6) and 10(-7)M oxytocin resulted in approximately 60% (P<0.01), 25% (P<0.01) and 10% (P<0.05) reduction of left ventricle developed pressure, without effect in lower concentrations (10(-10) to 10(-8) M). Also, dP/dt(max) was reduced by 45 and 20% (10(-5) e 10(-6) M; P<0.01), while diastolic pressure raised and heart rate fell only with 10(-5)M oxytocin (P<0.05). Intravenous oxytocin (1 mug; n=6) increased arterial pressure by 22% at the first minute (+23+/-3 mm Hg; P<0.001), returning to control value thereafter. Thus, oxytocin is able to promote directly negative inotropic and chronotropic effects, but its in vivo effect also involves a reflex mechanism, originated from its pressor effect.

Dipsogenic stimulation in ibotenic DRN-lesioned rats induces concomitant sodium appetite

The main purpose of this study was to investigate whether dipsogenic stimuli influences the sodium appetite of rats with ibotenic acid lesion of the dorsal raphe nucleus (IBO-DRN). Compared to control, rats microinjected with phosphate buffer (PB-DRN), the ingestion of 0.3M NaCl was enhanced in IBO-DRN at 21 and 35 days after DRN lesion under a protocol of fluids and food deprivation. Despite of similar dipsogenic response observed both in IBO-DRN and PB-DRN treated with isoproterenol (ISO, 300 microg/kg, sc), the 0.3M NaCl intake was again significantly enhanced in IBO-DRN at 21 and 35 days post-lesion. Finally, treatment with polyethylene glycol (PEG, MW=20,000, 20%, w/v, 16.7 ml/kg, sc) induced higher dipsogenic response in IBO-DRN than PB-DRN at 21 day after lesion. In addition, IBO-DRN also expressed higher sodium appetite than PB-DRN, concomitantly with a drinking response. These results suggest that ibotenic lesion of DRN promote an increase of the brain angiotensinergic response, possibly settled within the subfornical organ, through paradigms which increase circulating ANG II levels. The current paper supports the hypothesis that the ibotenic lesion of DRN suppresses a serotonergic component implicated on the modulation of the sodium appetite and, therefore, furthering homeostatic restoration of extracellular fluid volume.

Assessment of brain AT1-receptor on the nocturnal basal and angiotensin-induced thirst and sodium appetite in ovariectomised rats.

Objective. Considering the controversial data regarding the role of the brain renin-angiotensin system (RAS) on the thirst and sodium appetite in ovariectomised rats, we aimed to evaluate the role of the brain angiotensin II (Ang II) AT1-receptor on the nocturnal fluids intake. Materials and methods. Groups of Wistar female rats were ovariectomised and chronically given oestrogen or vehicle to evaluate its influence on effects induced by i.c.v. injection of losartan,Ang I and Ang II. Results. The i.c.v. losartan decreased basal water intake in the ovariectomised group.Ang II but not Ang I-induced nocturnal dipsogenic and natriorexigenic responses in ovariectomised rats. In oestrogen-treated rats, both peptides increased fluids intake. Previously, i.c.v. losartan abolished these effects in all groups. Oestrogen replacement decreased the nocturnal fluids intake, attenuated the losartan and Ang II effects, and highlighted the Ang I response. Conclusions. The present study has shown for the first time the involvement of AT1-receptor in regulating nocturnal basal water and salt intake in ovariectomised rats. In addition, our data have revealed an unexpected increased brain Ang I-mediated fluid intake in oestrogen-treated ovariectomised compared to ovariectomised rats, which was blocked by previous i.c.v. losartan. Our data have therefore shown that oestrogen influences homeostatic behaviours dependent on brain RAS.

Time course of echocardiographic and electrocardiographic parameters in myocardial infarct in rats.

In animal models the evaluation of myocardial infarct size in vivo and its relation to the actual lesion found post mortem is still a challenge. The purpose of the current study was to address if the conventional electrocardiogram (ECG) and/or echocardiogram (ECHO) could be used to adequately predict the size of the infarct in rats. Wistar rats were infarcted by left coronary ligation and then ECG, ECHO and histopathology were performed at 1, 7 and 28 days after surgery. Correlation between infarct size by histology and Q wave amplitude in lead L1 was only found when ECGs were performed one day post-surgery. Left ventricular diastolic and systolic dimensions correlated with infarct size by ECHO on day 7 post-infarction. On days 7 and 28 post-infarction, ejection indexes estimated by M-mode also correlated with infarct size. In summary we show that conventional ECG and ECHO methods can be used to estimate infarct size in rats. Our data suggest that the 7-day interval is actually the most accurate for estimation of infarct size by ECHO.

Effect of brain serotoninergic stimulation on sodium appetite of euthyroid and hypothyroid rats

The aim of the present work was to investigate the role of the serotoninergic system in the control of sodium appetite of hypothyroid rats (HTR) by administering drugs that affect the serotoninergic activity, and to compare the same homeostatic behaviour in euthyroid rats (ETR) also given these drugs. Fenfluramine (FEN; 5.0 mg kg−1, I.P.), which releases serotonin in the brain, significantly reduced the intake of 1.8% NaCl in HTR subjected to water and sodium depletion (depleted) or water, sodium and food deprivation (deprived) by 31 and 45%, respectively, 120 min after FEN injection, compared to HTR that received vehicle alone. Similarly, administration of FEN to ETR reduced 1.8% NaCl intake in depleted and deprived rats by 64 and 46%, respectively. The presynaptic serotonin reuptake inhibitor fluoxetine (20.0 mg kg−1, I.P.) led to the inhibition of sodium appetite in HTR during the initial 30 min in depleted rats and for up to 60 min post‐injection in deprived rats, while sodium appetite inhibition persisted for longer periods in ETR. The 5HT2C receptor agonist mCPP (5.0 mg kg−1, I.P.) caused a drastic reduction in sodium appetite in HTR and ETR in depleted and deprived rats, respectively, after 120 min. Prior administration of the 5HT2C receptor antagonist LY53857 (5.0 mg kg−1, I.P.) completely blocked the inhibitory action of mCPP on sodium appetite in both HTR and ETR. In summary, our results suggest that the recruitment of serotoninergic neurons involved in the modulation of sodium appetite seems to be decreased in hypothyroidism due to a probable deficiency in the cerebral signalling pathway.

Administration of an anabolic steroid during the adolescent phase changes the behavior, cardiac autonomic balance and fluid intake in male adult rats.

Few data are available on adolescent users because most behavioral studies on anabolic-androgenic steroids (AAS) abuse have been performed in adults. Studies evaluating the impact of long-term effects of AAS abuse on the prepubertal phase are even more uncommon. Accordingly, this study was developed to test the hypothesis that changes induced by the use of AAS during the adolescent phase may be noted in the adult phase even when the AAS treatment cycle is discontinued. Therefore, not only behavioral changes but also possible autonomic and electrolyte disorders were evaluated. For this purpose, we used male prepubertal, 26-day-old (P26) Wistar rats that were treated with vehicle (control, n=10) or testosterone propionate (TP; 5 mg/kg intramuscular (IM) injection, AAS, n=10) five times per week for 5 weeks, totaling 25 applications during the treatment. Aggression tests were performed at the end of the cycle (P54-56), whereas open-field tests (OFTs), elevated plus maze (EPM) behavioral tests and measurements of heart rate variability (HRV), fluid intake and pathology were conducted in the adult phase (P87-92). The AAS group showed greater aggressiveness in the pubertal phase and higher levels of horizontal and vertical exploration and anxiety-related behavior in the adult phase than the control group (P<0.05). HRV tests showed an increase in sympathetic autonomic modulation, and hydroelectrolytic assessment showed lower basal intake levels of hypertonic saline than the control group (P<0.05), without statistically significant changes in the basal intake of water. These data together suggest that the use of AAS during the prepubertal phase induces behavioral, autonomic and hydroelectrolytic changes that manifest in the adult phase even when treatment is discontinued in late adolescence in rats.

Cellular cardiomyoplasty in large myocardial infarction: Can the beneficial effect be enhanced by ACE‐inhibitor therapy?

Cellular cardiomyoplasty with bone marrow derived stromal (MSC) and mononuclear (BMNC) cells has been shown to improve performance of infarcted hearts. We performed a comparative study with MSC and BMNC and tested the hypothesis that captopril treatment could enhance the beneficial effect of cell therapy in large myocardial infarctions.

Sleep deprivation alters thyroid hormone economy in rats

What is the central question of this study? The relationship between the thyroid system and sleep deprivation has seldom been assessed in the literature, and mounting evidence exists that sleep disturbances influence human lifestyles. The aim of this study was to investigate the hypothalamic–pituitary–thyroid axis and thyroid hormone metabolism in sleep‐deprived and sleep‐restricted rats. What is the main finding and its importance? Central hypothyroidism and high thyroxine (T4) to 3,5,3′‐triiodothyronine (T3) activation in brown adipose tissue were observed following sleep deprivation. Sleep‐restricted rats exhibited normal thyroid‐stimulating hormone and T4 concentrations despite increased circulating T3. Sleep recovery for 24 h did not normalize the high T3 concentrations, suggesting that high T3 is a powerful counterregulatory mechanism activated following sleep deprivation.

Role of renin-angiotensin system in development of heart failure induced by myocardial infarction in rats

We investigated the morphologic and functional changes of infarcted rat hearts under a paradigm of angiotensinconverting enzyme inhibition. Myocardial infarction was induced by left coronary artery ligation and a control group (SHAM) underwent sham-operation. Infarcted rats received normal drinking water with (CAP group) or without (INF group) captopril. Functional assessment was performed by electro (ECG) and echocardiogram (ECHO) just before and 21 days after surgery. The ECG of INF and CAP showed similar values and resembled healed infarct after surgery. The most outstanding differences between INF and CAP were the prevention of the increase of P-wave and attenuation both in rightward deviation of the QRS axis and Q-wave amplitude in CAP compared with INF. The ECHO showed that captopril treatment improved the diastolic filling more than systolic performance. Cardiac dilatation and left congestive heart failure were observed only in INF. Both infarcted groups showed a scar tissue in the left ventricular wall, but the INF showed a higher scar area than CAP (49.7+/-5.24 vs. 22.33+/-6.19 respectively). These data suggest that the renin-angiotensin system induces morphologic and functional changes in post-infarcted rat hearts and which can be assessed by non-invasive exams.

INHIBITION OF BRAIN RENIN–ANGIOTENSIN SYSTEM IMPROVES DIASTOLIC CARDIAC FUNCTION FOLLOWING MYOCARDIAL INFARCTION IN RATS

1 Recently, we demonstrated that oral captopril treatment improved diastolic function and attenuated cardiac remodelling after myocardial infarction (MI) in rats. Considering the feasible role of the brain renin–angiotensin system (RAS) in heart failure, in the present study we investigated the role of the captopril injected intracerebroventricularly (i.c.v.) on the progression of cardiac dysfunction. 2 Male Wistar rats underwent experimental MI or sham operation. Infarcted animals received daily i.c.v. injections of captopril (approximately 200 mg/kg; MI + Cap) or saline (MI) from 11 to 18 days after infarction. Electro‐ and echocardiogram assessments were performed before and after i.c.v. treatment (10 and 18 days after MI, respectively). Water and hypertonic saline ingestion were determined daily between 12 and 16 days after MI. 3 Electrocardiograms from the MI and MI + Cap groups showed signs that resembled large MI before and after i.c.v. treatment. However, despite similar systolic dysfunction observed in both groups, only captopril‐treated rats exhibited reduced left ventricular (LV) dilatation and improved LV filling, as assessed by echocardiograms, and low levels of water ingestion compared with the saline‐treated control group. 4 The results of the present study suggest that the brain RAS may participate in the development of cardiac dysfunction induced by ischaemia and that inhibition of the brain RAS may provide a new strategy for the prevention of diastolic dysfunction.