Flávia Camargos de Figueirêdo Müller-Ribeiro

Emotional stress and sympathetic activity: Contribution of dorsomedial hypothalamus to cardiac arrhythmias

Maintenance of homeostasis in normal or stressful situations depends upon mechanisms controlling autonomic activity. Central requirement for changes in sympathetic output resulting from emotional stress must be adjusted to the input signals from visceral sensory afferent (feedback response) for an optimum cardiovascular performance. There is a large body of evidence indicating that emotional stress can lead to cardiovascular disease. Reviewing the descending pathways from dorsomedial hypothalamus, a key region involved in the cardiovascular response to emotional stress, we discuss the interactions between mechanisms controlling the sympathetic output to the cardiovascular system and the possible implications in cardiovascular disease.

Contribution of infralimbic cortex in the cardiovascular response to acute stress

The infralimbic region of the medial prefrontal cortex (IL) modulates autonomic and neuroendocrine function via projections to subcortical structures involved in the response to stress. We evaluated the contribution of the IL to the cardiovascular response evoked by acute stress. Under anesthesia (80 mg/kg ketamine-11.5 mg/kg xylazine), rats were implanted with telemetry probes or arterial lines for recording heart rate and blood pressure. Guide cannulas were implanted to target the IL for microinjection of muscimol (100 pmol/100 nl), N-methyl-d-aspartate (NMDA) (6 pmol/100 nl), or vehicle (100 nl). Microinjection of muscimol, an agonist of GABA(A) receptors, into the IL had no effect on stress-evoked cardiovascular and thermogenic changes in any of the paradigms evaluated (cage switch, restraint plus air-jet noise, or air-jet stress). However, microinjection of the excitatory amino acid NMDA into the IL attenuated the pressor and tachycardic response to air-jet stress. Pretreatment with the selective NMDA antagonist dl-2-amino-5-phosphonopentanoic acid (AP-5, 100 pmol/100 nl) blocked the effect of NMDA on the cardiovascular response to air-jet stress. We conclude that 1) the IL region is not tonically involved in cardiovascular or thermogenic control during stress or under baseline conditions, and 2) activation of NMDA receptors in the IL can suppress the cardiovascular response to acute stress exposure.

Synchronized activation of sympathetic vasomotor, cardiac, and respiratory outputs by neurons in the midbrain colliculi

The superior and inferior colliculi are believed to generate immediate and highly coordinated defensive behavioral responses to threatening visual and auditory stimuli. Activation of neurons in the superior and inferior colliculi have been shown to evoke increases in cardiovascular and respiratory activity, which may be components of more generalized stereotyped behavioral responses. In this study, we examined the possibility that there are command neurons within the colliculi that can simultaneously drive sympathetic and respiratory outputs. In anesthetized rats, microinjections of bicuculline (a GABA(A) receptor antagonist) into sites within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus evoked a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA). Each burst of RSNA had a duration of ∼300-400 ms and occurred slightly later (peak to peak latency of 41 ± 8 ms) than the corresponding burst of PNA. The bursts of RSNA and PNA were also accompanied by transient increases in arterial pressure and, in most cases, heart rate. Synchronized bursts of RSNA and PNA were also evoked after neuromuscular blockade, artificial ventilation, and vagotomy and so were not dependent on afferent feedback from the lungs. We propose that the synchronized sympathetic-respiratory responses are driven by a common population of neurons, which may normally be activated by an acute threatening stimulus.

Coordinated autonomic and respiratory responses evoked by alerting stimuli: Role of the midbrain colliculi.

Threatening stimuli trigger rapid and coordinated behavioral responses supported by cardiorespiratory changes. The midbrain colliculi can generate coordinated orienting or defensive behavioral responses, and it has been proposed that collicular neurons also generate appropriate cardiovascular and respiratory responses to support such behaviors. We have shown previously that under conditions where collicular neurons are disinhibited, coordinated cardiovascular, somatomotor and respiratory responses can be evoked independently of the cortex by auditory, visual and somatosensory stimuli. Here we report that these natural stimuli effectively increase inspiratory time most likely though phase switching. As a result the pattern of phrenic and sympathetic coupling is an inspiratory-related sympathoexcitation. We propose that blockade of tonic GABAergic input in the midbrain colliculi permits alerting stimuli to drive command neurons that generate coordinated cardiovascular, respiratory and motor outputs. The outputs of these command neurons likely interact with the central respiratory pattern generator, however the precise output pathways mediating the coordinated autonomic and respiratory responses remain to be determined.

Disinhibition of the midbrain colliculi unmasks coordinated autonomic, respiratory, and somatomotor responses to auditory and visual stimuli.

The midbrain superior and inferior colliculi have critical roles in generating coordinated orienting or defensive behavioral responses to environmental stimuli, and it has been proposed that neurons within the colliculi can also generate appropriate cardiovascular and respiratory responses to support such behavioral responses. We have previously shown that activation of neurons within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus can evoke a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity and phrenic nerve activity. In this study, we tested the hypothesis that, under conditions in which collicular neurons are disinhibited, coordinated cardiovascular, somatomotor, and respiratory responses can be evoked by natural environmental stimuli. In response to natural auditory, visual, or somatosensory stimuli, powerful synchronized increases in sympathetic, respiratory, and somatomotor activity were generated following blockade of GABAA receptors in a specific region in the midbrain colliculi of anesthetized rats, but not under control conditions. Such responses still occurred after removal of most of the forebrain, including the amygdala and hypothalamus, indicating that the essential pathways mediating these coordinated responses were located within the brain stem. The temporal relationships between the different outputs suggest that they are driven by a common population of command neurons within the colliculi.

Changes in systolic arterial pressure variability are associated with the decreased aerobic performance of rats subjected to physical exercise in the heat.

Enhanced cardiovascular strain is one of the factors that explains degraded aerobic capacity in hot environments. The cardiovascular system is regulated by the autonomic nervous system, whose activity can be indirectly evaluated by analyzing heart rate variability (HRV) and systolic arterial pressure (SAP) variability. However, no study has addressed whether HRV or SAP variability can predict aerobic performance during a single bout of exercise. Therefore, this study aimed to investigate whether there is an association between cardiovascular variability and performance in rats subjected to treadmill running at two ambient temperatures. In addition, this study investigated whether the heat-induced changes in cardiovascular variability and reductions in performance are associated with each other. Male Wistar rats were implanted with a catheter into their carotid artery for pulsatile blood pressure recordings. After recovery from surgery, the animals were subjected to incremental-speed exercise until they were fatigued under temperate (25°C) and hot (35°C) conditions. Impaired performance and exaggerated cardiovascular responses were observed in the hot relative to the temperate environment. Significant and negative correlations between most of the SAP variability components (standard deviation, variance, very low frequency [VLF], and low frequency [LF]) at the earlier stages of exercise and total exercise time were observed in both environmental conditions. Furthermore, the heat-induced changes in the sympathetic components of SAP variability (VLF and LF) were associated with heat-induced impairments in performance. Overall, the results indicate that SAP variability at the beginning of exercise predicts the acute performance of rats. Our findings also suggest that heat impairments in aerobic performance are associated with changes in cardiovascular autonomic control.

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.

Thermal biology in Brazil: a summary of a 100-year legacy.

Fl avia C F M€ uller-Ribeiro, Mauro A Griggio, Jacqueline Luz, and Cândido C Coimbra* Department of Physiology and Biophysics; Institute of Biological Sciences; Universidade Federal de Minas Gerais; Belo Horizonte, Brazil; PNPDPrograma de P os Graduaç~ao em Cîencias do Esporte; Universidade Federal de Minas Gerais; Belo Horizonte, Brazil; Department of Physiology; Universidade Federal de S~ao Paulo; S~ao

Evidence that central action of paraquat interferes in the dipsogenic effect of Ang II.

Paraquat is a widely used herbicide that may have central neurotoxic actions. In this study we investigated whether administration of paraquat in the central nervous system interferes with the physiological role of angiotensin II in regulating blood pressure, water intake and thermogenesis. Under tribromoethanol anesthesia (250 mg/kg, i.p.) guide canulas were implanted into the cerebral ventricle of male Wistar rats ( congruent with 300g) for microinjections of drugs. Four days later, a catheter was placed into the femoral artery to enable recording of cardiovascular parameters. After 24h, paraquat (38 or 44 nmol/2 microl), angiotensin II (Ang II, 1 nmol/2 microl) or the cholinergic agonist, carbachol (4 nmol/2 microl) were administered intracerebroventricular (icv) and physiological effects were measured. We observed that the dipsogenic action evoked by Ang II (8+/-2 ml) was markedly attenuated by previous icv injection of either 38 or 44 nmol paraquat (3+/-1 ml; P<0.05). However, the dipsogenic effect evoked by carbachol was not altered by pretreatment with paraquat (before 8+/-1 vs. after 6+/-2; P>0.05). Cardiovascular and thermogenic responses evoked by Ang II were not altered by paraquat. These results suggest that paraquat might selectively interfere with the drinking behavior mediated by the renin-angiotensin system in the central nervous system.