Dysautonomias in Parkinson's disease: cardiovascular changes and autonomic modulation in conscious rats after infusion of bilateral 6-OHDA in substantia nigra.

It is important to elucidate the mechanism of dysautonomias in patients with Parkinson's disease; therefore, this study aimed to investigate the cardiovascular and autonomic changes that occur in an animal model of Parkinsonism. Adult male Wistar rats were anesthetized before bilateral microinfusions of 6-hydroxydopamine (6-OHDA) into the substantia nigra. The sham group underwent the same surgical procedure but received vehicle. After 7 days, the mean arterial pressure (MAP) and heart rate (HR) were measured, and various drugs were injected into conscious rats through cannulas previously implanted in the femoral artery and vein. Spectral analyses of systolic arterial pressure (SAP) and pulse interval (PI) were conducted with the CardioSeries software as the spontaneous baroreflex gain and effectivity. The animals were subjected to α-, ß-adrenergic, or muscarinic receptor antagonism. For confirmation of the lesion, the levels of dopamine in the striatum were quantified by high-performance liquid chromatography. Animals that underwent 6-OHDA microinfusion had lower MAP and HR compared with those in the sham group. Spectral analysis of SAP showed that 6-OHDA animals exhibited a decrease in the sympathetic component. The PI values did not differ between groups. After the administration of muscarinic and ß-adrenergic antagonists, the cardiovascular measures did not differ between the groups. However, upon administration of the α-adrenergic antagonist, the 6-OHDA animals exhibited a lower decrease in the MAP. We report cardiovascular impairments in 6-OHDA animals, possibly due to decreased sympathetic activity. Determination of the origin of these changes (central or peripheral) requires further investigation.

Physical exercise affects the epigenetic programming of rat brain and modulates the adaptive response evoked by repeated restraint stress.

Epigenetics has recently been linked to molecular adaptive responses evoked by physical exercise and stress. Herein we evaluated the effects of physical exercise on global DNA methylation and expression of the Dnmt1 gene in the rat brain and also verified its potential to modulate responses evoked by repeated restraint stress (RRS). Wistar rats were classified into the following experimental groups: (1) physically active (EX): animals submitted to swimming during postnatal days 53-78 (PND); (2) stress (ST): animals submitted to RRS during 75-79PND; (3) exercise-stress (EX-ST): animals submitted to swimming during 53-78PND and to RRS during 75-79PND, and (4) control (CTL): animals that were not submitted to intervention. Samples from the hippocampus, cortex and hypothalamus were obtained at 79PND. The global DNA methylation profile was assessed using an ELISA-based method and the expression of Dnmt1 was evaluated by real-time PCR. Significantly increased methylation was observed in the hypothalamus of animals from the EX group in comparison to CTL. Comparative analysis involving the EX-ST and ST groups revealed increased global DNA methylation in the hippocampus, cortex, and hypothalamus of EX-ST, indicating the potential of physical exercise in modulating the responses evoked by RRS. Furthermore, decreased expression of the Dnmt1 gene was observed in the hippocampus and hypothalamus of animals from the EX-ST group. In summary, our data indicate that physical exercise affects DNA methylation of the hypothalamus and might modulate epigenetic responses evoked by RRS in the hippocampus, cortex, and hypothalamus.

Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA.

OBJECTIVE: Evaluate the effects caused by L-DOPA on cardiovascular and autonomic parameters in an animal model of Parkinsonism induced by 6-hydroxydopamine (6-OHDA). METHODS: Adult male Wistar rats were subjected to bilateral microinfusion of 6-OHDA or saline (sham group) in the substantia nigra, and treated by gavage with L-DOPA or water for 7 days after surgery. On the 6th day the rats were subjected to femoral artery catheterization for cardiovascular recording. Mean arterial pressure (MAP) and heart rate (HR) were evaluated at baseline and during head up tilt (HUT) protocol. Spectral analysis of cardiovascular variability was performed using the V2.4 CardioSeries software v2.4. The lesion was quantified by dopamine levels in the striatum. RESULTS: Dopamine levels in the striatum were decreased in 6-OHDA rats (sham: 4.79 ± 0.49 ng/mg; 6-OHDA: 1.99 ± 0.68 ng/mg) and were not recovered by Prolopa treatment. Baseline values of MAP and HR were not different between groups. HUT induced an increase in MAP and HR (ΔMAP: 17 ± 1 mm Hg, ΔHR: 39 ± 4 bpm) that were attenuated in 6-OHDA and in Prolopa treated animals. At baseline, the systolic arterial pressure (SAP) variance was lower in the 6-OHDA AND sham prolopa groups. Spontaneous baroreflex sensitivity was higher at baseline in the 6-OHDA group as compared to all studied groups. CONCLUSIONS: Our data suggest that treatment with Prolopa did not interfere with cardiovascular variables at baseline. However, during HUT, the 6-OHDA and Prolopa control animals presented a lower cardiovascular compensation, suggesting a possible autonomic impairment in Parkinsonism induced by 6-OHDA.

Excitatory effects of nitric oxide within the rostral ventrolateral medulla of freely moving rats.

The aim of the present study was to examine the participation of NO in the rostral ventrolateral medulla (RVLM) of freely moving rats. We utilized NO donors and L-arginine, which were microinjected into the RVLM. Unilateral microinjection (100 nL) of 2.5 nmol sodium nitroprusside produced a biphasic response consisting of an initial, rapid increase in arterial pressure (AP) from 125+/-5 to 161+/-8 mm Hg (P<.01) and a second, long-lasting response with a progressive increase in AP (maximum delta peak, 34+/-9 mm Hg; P<.01). Another NO donor, S-nitroso-N-acetylpenicillamine (SNAP; 2.5 nmol), also produced immediate hypertension from 118+/-5 mm Hg to 168+/-7 mm Hg (P<.01) but without the second, long-lasting response. L-Arginine (5, 24, and 140 nmol) produced a gradual increase in AP. L-Glutamate (5 nmol) microinjected into the RVLM produced an increase in AP from 122+/-9 mm Hg to 171+/-8 mm Hg (P<.01) and bradycardia from 342+/-10 to 315+/-8 beats/min. This AP response was significantly attenuated, from 115+/-7 to 128+/-9 mm Hg (P<.05), after microinjection of methylene blue (3 nmol) without alterations in heart rate. These results indicate that NO may have an excitatory effect on the RVLM of freely moving rats, probably in association with glutamatergic synapses via cGMP mechanisms.

Nitric oxide-dependent guanylyl cyclase participates in the glutamatergic neurotransmission within the rostral ventrolateral medulla of awake rats.

A well-known action of nitric oxide (NO) is to stimulate the soluble form of guanylyl cyclase, evoking an accumulation of cyclic GMP in target cells. The aim of the present study was to examine the effects of inhibition of guanylyl cyclase dependent on NO during cardiovascular responses induced by L-glutamate and S-nitrosoglutathione (SNOG) microinjected into the rostral ventrolateral medulla (RVLM) of awake rats. Three days before the experiments, adult male Wistar rats (280 to 320 g) were anesthetized for implantation of guide cannulas to the desired stereotaxic position (AP=-2.5 mm, L=1.8 mm) in relation to lambda. The cannulas were fixed to the skull with acrylic cement. Twenty-four hours before the experiments, a femoral artery and vein were cannulated for recording arterial pressure (AP) and heart rate (HR) and injection of anesthetic. Unilateral microinjections (100 nL) of L-glutamate (5 nmol/L) and SNOG (2.5 nmol/L) were made into the histologically confirmed RVLM. The cardiovascular responses to these drugs were evaluated before and after microinjection (3 nmol/L, 200 nL) of either methylene blue or oxodiazoloquinoxaline (ODQ). The hypertensive effect of L-glutamate was attenuated by 74% after methylene blue (DeltaAP=49+/-8 to 13+/-4 mm Hg) and by 80.5% after ODQ (DeltaAP=30+/-2 to 6+/-2 mm Hg). The increase in AP produced by SNOG was fully blocked by ODQ (DeltaAP=39+/-8 to 1+/-2 mm Hg). These data indicate that cyclic GMP mechanisms have a key role in glutamatergic neurotransmission in the RVLM of awake rats, and it is most probable that NO participates in this response.

Cardiovascular effects produced by microinjection of angiotensins and angiotensin antagonists into the ventrolateral medulla of freely moving rats.

In this study we determined the cardiovascular effects produced by microinjection of angiotensin peptides [Angiotensin-(1-7) and Angiotensin II] and angiotensin antagonists (losartan, L-158,809, CGP 42112A. Sar1-Thr8-Ang II, A-779) into the rostral ventrolateral medulla of freely moving rats. Microinjection of angiotensins (12.5-50 pmol) produced pressor responses associated to variable changes in heart rate, usually tachycardia. Unexpectedly, microinjection of both AT1 and AT2 ligands produced pressor effects at doses that did not change blood pressure in anesthetized rats. Conversely, microinjection of Sar1-Thr8-Ang II and the selective Ang-(1-7) antagonist, A-779, produced a small but significant decrease in MAP an HR. These findings suggest that angiotensins can influence the tonic activity of vasomotor neurons at the RVLM. As previously observed in anesthetized rats, our results further suggest a role for endogenous Ang-(1-7) at the RVLM. The pressor activity of the ligands for AT1 and AT2 angiotensin receptor subtypes at the RVLM, remains to be clarified.

Cardiovascular and autonomic modulation by the central nervous system after aerobic exercise training.

The autonomic nervous system plays a key role in maintaining homeostasis under normal and pathological conditions. The sympathetic tone, particularly for the cardiovascular system, is generated by sympathetic discharges originating in specific areas of the brainstem. Aerobic exercise training promotes several cardiovascular adjustments that are influenced by the central areas involved in the output of the autonomic nervous system. In this review, we emphasize the studies that investigate aerobic exercise training protocols to identify the cardiovascular adaptations that may be the result of central nervous system plasticity due to chronic exercise. The focus of our study is on some groups of neurons involved in sympathetic regulation. They include the nucleus tractus solitarii, caudal ventrolateral medulla and the rostral ventrolateral medulla that maintain and regulate the cardiac and vascular autonomic tonus. We also discuss studies that demonstrate the involvement of supramedullary areas in exercise training modulation, with emphasis on the paraventricular nucleus of the hypothalamus, an important area of integration for autonomic and neuroendocrine responses. The results of these studies suggest that the beneficial effects of physical activity may be due, at least in part, to reductions in sympathetic nervous system activity. Conversely, with the recent association of physical inactivity with chronic disease, these data may also suggest that increases in sympathetic nervous system activity contribute to the increased incidence of cardiovascular diseases associated with a sedentary lifestyle.

Cox-2 inhibition attenuates cardiovascular and inflammatory aspects in monosodium glutamate-induced obese rats.

AIMS: the purpose of the present work was to investigate the effect of cyclooxygenase-2 (COX-2) inhibition on the cardiovascular and inflammatory aspects promoted by monosodium glutamate (MSG)-induced obesity in rats. MAIN METHODS: Neonatal Wistar male rats were injected with MSG (4 mg/g body weight ID) or equimolar saline (control). Treatment with celecoxib (50 mg/kg ip) or saline (0.9% NaCl ip) began at 60 days of age. At 90 days, all rats were anesthetized for catheterization of the femoral artery, and the mean arterial pressure (MAP) and heart rate (HR) were recorded once consciousness was regained. KEY FINDINGS: MSG obese rats were hypertensive (MAP=138±4 mm Hg) compared with controls (MAP=118±2 mm Hg). After treatment with celecoxib, the hypertension was attenuated (MAP=126±2 mm Hg) in obese rats without changes in HR. The retroperitoneal and periepididymal fat weighed more in obese rats (Obese: Retro=7.08±0.51, Peri=6.36±0.81, CONTROL: Retro=3.60±0.46; Peri=3.24±0.42), but celecoxib did not alter these parameters. Plasma nitric oxide levels were not different between groups. However, the level of plasma prostaglandins, the immunohistochemical staining of COX-2 in cardiac tissue and plasma lipoperoxidation were higher in obese rats, and celecoxib attenuated these parameters. MSG produced liver steatosis that was also attenuated following celecoxib treatment. SIGNIFICANCE: Our data demonstrate an association between increased blood pressure and products of COX-2 in obese rats, suggesting a role for prostaglandins in the hypertensive and inflammatory aspects of MSG-induced obesity.

Cardiovascular and autonomic modulation by the central nervous system after aerobic exercise training

The autonomic nervous system plays a key role in maintaining homeostasis under normal and pathological conditions. The sympathetic tone, particularly for the cardiovascular system, is generated by sympathetic discharges originating in specific areas of the brainstem. Aerobic exercise training promotes several cardiovascular adjustments that are influenced by the central areas involved in the output of the autonomic nervous system. In this review, we emphasize the studies that investigate aerobic exercise training protocols to identify the cardiovascular adaptations that may be the result of central nervous system plasticity due to chronic exercise. The focus of our study is on some groups of neurons involved in sympathetic regulation. They include the nucleus tractus solitarii, caudal ventrolateral medulla and the rostral ventrolateral medulla that maintain and regulate the cardiac and vascular autonomic tonus. We also discuss studies that demonstrate the involvement of supramedullary areas in exercise training modulation, with emphasis on the paraventricular nucleus of the hypothalamus, an important area of integration for autonomic and neuroendocrine responses. The results of these studies suggest that the beneficial effects of physical activity may be due, at least in part, to reductions in sympathetic nervous system activity. Conversely, with the recent association of physical inactivity with chronic disease, these data may also suggest that increases in sympathetic nervous system activity contribute to the increased incidence of cardiovascular diseases associated with a sedentary lifestyle.