Natália Veronez da Cunha

Decreased endothelial nitric oxide, systemic oxidative stress, and increased sympathetic modulation contribute to hypertension in obese rats

We investigated the involvement of nitric oxide (NO) and reactive oxygen species (ROS) on autonomic cardiovascular parameters, vascular reactivity, and endothelial cells isolated from aorta of monosodium glutamate (MSG) obese rats. Obesity was induced by administration of 4 mg/g body wt of MSG or equimolar saline [control (CTR)] to newborn rats. At the 60th day, the treatment was started with N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg) or 0.9% saline. At the 90th day, after artery catheterization, mean arterial pressure (MAP) and heart rate were recorded. Plasma was collected to assess lipid peroxidation. Endothelial cells isolated from aorta were evaluated by flow cytometry and fluorescence intensity (FI) emitted by NO-sensitive dye [4,5-diaminofluoresceindiacetate (DAF-2DA)] and by ROS-sensitive dye [dihydroethidium (DHE)]. Vascular reactivity was made by concentration-response curves of acetylcholine. MSG showed hypertension compared with CTR. Treatment with L-NAME increased MAP only in CTR. The MSG induced an increase in the low-frequency (LF) band and a decrease in the high-frequency band of pulse interval. L-NAME treatment increased the LF band of systolic arterial pressure only in CTR without changes in MSG. Lipid peroxidation levels were higher in MSG and were attenuated after L-NAME. In endothelial cells, basal FI to DAF was higher in CTR than in MSG. In both groups, acetylcholine increased FI for DAF from basal. The FI baseline to DHE was higher in MSG than in CTR. Acetylcholine increased FI to DHE in the CTR group, but decreased in MSG animals. We suggest that reduced NO production and increased production of ROS may contribute to hypertension in obese MSG animals.

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.

Renal sympathetic nerve activity is increased in monosodium glutamate induced hyperadipose rats.

The literature suggests that both obesity and hypertension are associated with increased sympathetic nerve activity. In the present study we evaluated the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) in hyperadipose rats induced by neonatal administration of monosodium glutamate (MSG). Neonatal Wistar male rats were injected with MSG (4 mg/g body weight ID) or equimolar saline (control) for 5 days. At 90th day, all rats were anesthetized (urethane 1.4 g/kg) and prepared for MAP, HR and renal sympathetic nerve activity recordings. The anesthetized MSG rats presented baseline hypertension and increased baseline RSNA compared with control. Our results suggest the involvement of the renal sympathetic nervous system in the physiopathology of the MSG obesity.

COX-2 inhibition does not reverse the increased sympathetic modulation in MSG obese rats

We evaluate the effects of chronic treatment with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, on blood pressure (BP) and heart rate variability (HRV) in obese rats induced by neonatal monosodium glutamate (MSG). The animals were treated with celecoxib or saline for 30 days (from the 60th to the 90th day of age). On the 90th day, the MSG obesity induced an increase in the low-frequency (LF) component (CTR=5.69±18.30ms(2), MSG=38.49±6.27ms(2)) and a decrease in the high-frequency (HF) component of HRV (CTR=71.48±6.22ms(2), MSG=50.94±7.03ms(2)), which were unchanged by celecoxib treatment. We suggest that HRV in MSG obesity involves a greater sympathetic modulation not related with COX-2 products.

Involvement of the paraventricular nucleus (PVN) of hypothalamus in the cardiovascular alterations to head up tilt in conscious rats.

We evaluated the involvement of paraventricular nucleus (PVN) in the changes in mean arterial pressure (MAP) and heart rate (HR) during an orthostatic challenge (head up tilt, HUT). Adult male Wistar rats, instrumented with guide cannulas to PVN and artery and vein catheters were submitted to MAP and HR recording in conscious state and induction of HUT. The HUT induced an increase in MAP and HR and the pretreatment with prazosin and atenolol blocked these effects. After inhibition of neurotransmission with cobalt chloride (1 mM/100 nl) into the PVN the HR parameters did not change, however we observed a decrease in MAP during HUT. Our data suggest the involvement of PVN in the brain circuitry involved in cardiovascular adjustment during orthostatic challenges.

Direct renin inhibitor therapy and swimming training: hemodynamic and cardiac effects in hypertensive and normotensive rats.

Abstract Purpose: This study aimed to analyze the hemodynamic and cardiac effects of direct renin inhibitor (DRI) treatment and swimming training in hypertensive rats. Methods: Seventy-seven rats were divide into eight groups: sedentary normotensive (SN), trained normotensive (TN), sedentary normotensive treated with DRI (SN_DRI), trained normotensive treated with DRI (TN_DRI), sedentary hypertensive (SH), trained hypertensive (TH), sedentary hypertensive treated with DRI (SH_DRI), trained hypertensive treated with DRI (TH_DRI). Swimming training occurred for up to 60 min, five times a week for four weeks. The hypertensive animals were treated with 20 mg ċ kg−1 ċ day−1 L-NAME for four weeks. Groups treated with DRI received 10 mg ċ kg−1 ċ day−1 of aliskiren for four weeks. After the treatment period, all the animals underwent femoral artery catheterization surgery for direct measurement of cardiovascular variables. Results: The SH group presented hypertension (136.4 ± 5.0 mmHg) compared to the SN (107.1 ± 1.7 mmHg). The TH group showed lower mean arterial pressure (MAP) than the SH (121.1 ± 1.3 mmHg), but the treatment with DRI did not attenuate hypertension (128.2 ± 4.9 mmHg). The analysis of collagen areas demonstrated that treatment with DRI may attenuate cardiac remodeling in situations of hypertension, in the condition of treatment alone or combined with physical training. Conclusion: Both interventions in combination may be more effective at reducing cardiovascular risk in hypertensive subjects.

iNOS inhibition improves autonomic dysfunction and oxidative status in hypertensive obese rats.

ABSTRACT It has been suggested that nitric oxide (NO) from iNOS source is involved in inflammation and oxidative stress, and hypertension in obese subjects involves an inflammatory process. However, no study evaluated the participation of iNOS inhibition on cardiovascular, autonomic, and inflammatory parameters in obese rats. Obesity was induced by the administration of 4 mg/g body weight of monosodium glutamate (MSG) or equimolar saline (CTR) in newborn rats. On the 60th day, treatment with aminoguanidine (Amino, 50 mg/kg), an iNOS inhibitor, or 0.9% saline, was started. On the 90th day, mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious rats and autonomic modulation was conducted with the CardioSeries software. Plasma samples were collected to assess lipid peroxidation and prostaglandins (PGE2). In addition, iNOS immunohistochemistry in cardiac tissue was evaluated. MSG rats showed hypertension compared to CTR, and Amino treatment did not reverse it. Obese rats presented increased sympathetic and decreased parasympathetic modulation to the heart, reverted by Amino treatment. Plasma PGE2 was increased in obese rats, and Amino treatment decreased. Obese rats presented increased plasma lipoperoxidation, which was decreased after Amino treatment. Also, cardiac iNOS immunohistochemistry was decreased after Amino treatment. Our data suggest that iNOS activation is involved in the systemic and cardiac mechanisms of oxidative stress, inflammation, and autonomic dysfunction derived from obesity.