Rodrigo C. de Menezes

Sympathetic cutaneous vasomotor alerting responses (SCVARs) are associated with hippocampal theta rhythm in non-moving conscious rats.

Alerting stimuli that cause sympathetic cutaneous vasomotor alerting responses (SCVARs) in the thermoregulatory vascular bed of the rabbit ear pinna also induce theta (5-8 Hz) rhythm in the hippocampal EEG, a marker that the animal is engaged with the environment. The present study determines the relation between SCVARs in the thermoregulatory tail artery vascular bed and hippocampal EEG theta rhythm in Sprague-Dawley rats. A Doppler ultrasonic flow probe chronically implanted around the base of the tail artery was used to measure SCVARs. Unipolar electrodes were implanted in the hippocampus (CA1 region) to measure EEG. Six standard non-noxious brief alerting stimuli were administered during continuous recording of tail blood flow and EEG. The SCVAR index was calculated as the percentage fall from pre-alerting blood flow values. After stimuli the SCVAR index for the tail artery blood flow was 84+/-2% of the pre-alerting control. In contrast, the same stimuli caused little fall in blood flow within the superior mesenteric bed (SCVAR index=18+/-2%). The proportion of theta power in the total frequency range (0-20 Hz) increased significantly after alerting stimuli (46+/-2% vs. 29+/-1% before stimuli, p<0.05). Theta proportion began to increase approximately 0.5 s after the stimuli and preceded SCVARs by approximately 1 s. The SCVAR index was correlated with the magnitude of the increment in theta power. Our study demonstrates that alerting responses resulting in selective vasoconstriction of the tail vascular bed are associated with hippocampal theta rhythm in conscious rats.

SR59230A, a beta-3 adrenoceptor antagonist, inhibits ultradian brown adipose tissue thermogenesis and interrupts associated episodic brain and body heating

Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80-100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats. SR59230A (1, 5, or 10 mg/kg ip), but not vehicle, decreased iBAT, body, and brain temperatures in a dose-dependent fashion (log-linear regression P < 0.01, R(2) = 0.3, 0.4, and 0.4, respectively, n = 10). Ultradian increases in BAT, brain, and body temperature were interrupted by administration of SR59230A (10 mg/kg ip) compared with vehicle, resuming after 162 ± 24 min (means ± SE, n = 10). SR59230A (10 mg/kg ip) caused a transient bradycardia without any increase in tail artery blood flow. In anesthetized rats, SR59230A reduced cooling-induced increases in iBAT temperature without affecting cooling-induced increases in iBAT sympathetic nerve discharge. Inhibition of BAT thermogenesis by SR59230A, thus, reflects direct blockade of beta-3 adrenoceptors in BAT. Interruption of episodic ultradian increases in body and brain temperature by SR59230A suggests that BAT thermogenesis makes a substantial contribution to these increases.

High fat diet induced-obesity facilitates anxiety-like behaviors due to GABAergic impairment within the dorsomedial hypothalamus in rats.

HighlightsHFD facilitates the development of anxiety‐related behavior.Muscimol intra‐dorsomedial hypothalamus has an anxiogenic effect in obese rats.BMI intra‐dorsomedial hypothalamus does not cause an anxiogenic effect in obese rats.Memory acquisition and locomotor activity are not altered by GABAergic manipulation. ABSTRACT Overweight and obesity are conditions associated with an overall range of clinical health consequences, and they could be involved with the development of neuropsychiatric diseases, such as generalized anxiety disorder (GAD) and panic disorder (PD). A crucial brain nuclei involved on the physiological functions and behavioral responses, especially fear, anxiety and panic, is the dorsomedial hypothalamus (DMH). However, the mechanisms underlying the process whereby the DMH is involved in behavioral changes in obese rats still remains unclear. The current study further investigates the relation between obesity and generalized anxiety, by investigating the GABAA sensitivity to pharmacological manipulation within the DMH in obese rats during anxiety conditions. Male Wistar rats were divided in two experimental groups: the first was fed a control diet (CD; 11% w/w) and second was fed a high fat diet (HFD; 45% w/w). Animals were randomly treated with muscimol, a GABAA agonist and bicuculline methiodide (BMI), a GABAA antagonist. Inhibitory avoidance and escape behaviors were investigated using the Elevated T‐Maze (ETM) apparatus. Our results revealed that the obesity facilitated inhibitory avoidance acquisition, suggesting a positive relation between obesity and the development of an anxiety‐like state. The injection of muscimol (an anxiolytic drug), within the DMH, increased the inhibitory avoidance latency in obese animals (featuring an anxiogenic state). Besides, muscimol prolonged the escape latency and controlling the possible panic‐like behavior in these animals. Injection of BMI into the DMH was ineffective to produce an anxiety‐like effect in obese animals opposing the results observed in lean animals. These findings support the hypotheses that obese animals are susceptible to develop anxiety‐like behaviors, probably through changes in the GABAergic neurotransmission within the DMH.

Increased activity of the renin-angiotensin and sympathetic nervous systems is required for regulation of the blood pressure in rats fed a low-protein diet.

•u2002 What is the central question of this study? Is the increase in blood pressure observed in rats fed a low protein diet due to overactivation of sympathetic and renin angiontensin systems? •u2002 What is the main finding and its importance? The data show an increase in the expression of angiotensin II type 1 receptors and an incrased sympathetic activity in this experimental model, suggesting that both systems are contributing to the high blood pressure observed in these animals.

Brown adipose tissue thermogenesis precedes food intake in genetically obese Zucker (fa/fa) rats

In Sprague-Dawley rats, brown adipose tissue (BAT) thermogenesis occurs in an episodic ultradian manner (BAT on-periods) as part of the basic rest-activity cycle (BRAC). Eating occurs approximately 15min after the onset of BAT on-periods. Zucker obese (fa/fa) rats eat larger less frequent meals than control rats. In chronically instrumented conscious unrestrained Zucker obese rats we examined ultradian fluctuations in BAT, body and brain temperatures, and the relation between BAT temperature and eating. The interval between BAT temperature peaks for the 12hour dark phase was 121±3 (mean±SE) min for Zucker obese rats and 91±3min for control lean rats (p<0.01). Corresponding values for the light phase were 148±6 and 118±4min (p<0.01). Mean BAT and body temperatures were lower in Zucker obese rats, in comparison with lean controls, during both BAT on-periods and BAT off-periods. Mean brain temperatures were lower during BAT off-periods. Amplitudes of the BRAC-related increases in all 3 temperatures were greater in the Zucker obese rats. Meal onset in Zucker obese rats commenced 15±1min after the onset of a BAT on-period, not significantly different for the delay observed in lean control rats (18±1min, p>0.05). Thus periods between eating are increased in the Zucker obese rats, but the action of leptin, absent in these animals, is not crucial for the timing of eating in relation to increases in BAT and body temperature. Lack of the normal excitatory action of leptin on brain-regulated BAT sympathetic discharge could also contribute to lower BAT thermogenesis in Zucker obese rats.

The implication of protein malnutrition on cardiovascular control systems in rats

The malnutrition in early life is associated with metabolic changes and cardiovascular impairment in adulthood. Deficient protein intake-mediated hypertension has been observed in clinical and experimental studies. In rats, protein malnutrition also increases the blood pressure and enhances heart rate and sympathetic activity. In this review, we discuss the effects of post-weaning protein malnutrition on the resting mean arterial pressure and heart rate and their variabilities, cardiovascular reflexes sensitivity, cardiac autonomic balance, sympathetic and renin-angiotensin activities and neural plasticity during adult life. These insights reveal an interesting prospect on the autonomic modulation underlying the cardiovascular imbalance and provide relevant information on preventing cardiovascular diseases.

New insights on amygdala: Basomedial amygdala regulates the physiological response to social novelty.

The amygdala has been associated with a variety of functions linked to physiological, behavioral and endocrine responses during emotional situations. This brain region is comprised of multiple sub-nuclei. These sub-nuclei belong to the same structure, but may be involved in different functions, thereby making the study of each sub-nuclei important. Yet, the involvement of the basomedial amygdala (BMA) in the regulation of emotional states has yet to be defined. Therefore, the aim of our study was to investigate the regulatory role of the BMA on the responses evoked during a social novelty model and whether the regulatory role depended on an interaction with the dorsomedial hypothalamus (DMH). Our results showed that the chemical inhibition of the BMA by the microinjection of muscimol (γ-aminobutyric acid (GABAA) agonist) promoted increases in mean arterial pressure (MAP) and heart rate (HR), whereas the chemical inhibition of regions near the BMA did not induce such cardiovascular changes. In contrast, the BMA chemical activation by the bilateral microinjection of bicuculline methiodide (BMI; GABAA antagonist), blocked the increases in MAP and HR observed when an intruder rat was suddenly introduced into the cage of a resident rat, and confined to the small cage for 15min. Additionally, the increase in HR and MAP induced by BMA inhibition were eliminated by DMH chemical inhibition. Thus, our data reveal that the BMA is under continuous GABAergic influence, and that its hyperactivation can reduce the physiological response induced by a social novelty condition, possibly by inhibiting DMH neurons.

Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats

A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine—a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p > 0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart.

Nitric oxide modulates blood pressure through NMDA receptors in the rostral ventrolateral medulla of conscious rats.

The rostral ventrolateral medulla (RVLM) is an important site of cardiovascular control related to the tonic excitation and regulating the sympathetic vasomotor tone through local presympathetic neurons. Nitric oxide (NO) has been implicated in the modulation of neurotransmission by several areas of the central nervous system including the RVLM. However the pathways driving NO affects and the correlation between NO and glutamate-induced mechanisms are not well established. Here, we investigate the influence of NO on the cardiovascular response evoked by the activation of NMDA and non-NMDA glutamatergic receptors in the RVLM in conscious rats. For that, we examined the influence of acute inhibition of the NO production within the RVLM, by injecting the nonselective constitutive NOS inhibitor, l-NAME, on responses evoked by the microinjection of excitatory amino acids l-glutamate, NMDA or AMPA agonists into RVLM. Our results show that the injection of l-glutamate, NMDA or AMPA agonists into RVLM, unilaterally, induced a marked increase in the mean arterial pressure (MAP). Pretreatment with l-NAME reduced the hypertensive response evoked by the glutamate injection, and also abolished the pressor response induced by the injection of NMDA into the RVLM. However, blocking the NO synthesis did not alter the response produced by the injection of AMPA agonist. These data provide evidence that the glutamatergic neurotransmission within the RVLM depends on excitatory effects exerted by NO on NMDA receptors, and that this mechanism might be essential to regulate systemic blood pressure.

Increased α1-adrenoreceptor activity is required to sustain blood pressure in female rats under food restriction

AIMSnWe evaluated the effect of food restriction (FR) on the various reflexes involved in short term cardiovascular regulation; we also evaluated the contribution of the sympathetic nervous systemand of the plasmatic nitric oxide (NO) in the development of the counterregulatory cardiovascular changes triggered by FR.nnnMAIN METHODSnFemale rats were subjected to FR for 14 days, and after this period biochemical measurements of biochemical parameters were performed. For physiological tests, animals were anaesthetised, and a catheter was inserted into the femoral artery and vein for the acquisition of blood pressure and heart hate, and drug infusion, respectively.We then tested the Bezold–Jarisch reflex, the baroreflex and chemoreflex and the effect of the infusion of adrenergic receptor antagonists in control and food restricted animals.nnnKEY FINDINGSnThe rats subjected to severe FR presented biochemical changes characteristic of malnutrition with a great catabolic state. FR also led to hypotension and bradycardia besides reducing the plasmatic concentration of NO. Moreover, activation of the Bezold–Jarisch reflex induced a more pronounced hypotensive response in animals subjected to FR. Intravenous infusion of a α1-adrenoreceptor antagonist induced a greater hypotensive response and a more pronounced tachycardic response in animals under food restriction,while the infusion of β-adrenoreceptor antagonist induced lower increases in blood pressure in these animals.nnnSIGNIFICANCEnOur results suggest that an increased α1-adrenoreceptor activity in the resistance arteries coupled with a reduction of plasmatic NO contributes in a complementary manner to maintain the blood pressure levels in animals under FR.