RESUMO
Previous studies have shown that 17ß-estradiol plays a cardioprotective role in the central nervous system (CNS) of male rats. The aim of the present study was to determine the influence of 17ß-estradiol on sympathetic vasomotor activity and blood pressure in a renovascular hypertensive Goldblatt two-kidney one-clip (2K-1C) male rat model. We also determined the influence of angiotensin II AT1 receptor on the expression of estrogen receptors (ERα, ERß, and G protein-coupled ER (GPER)) in the rostral ventrolateral medulla (RVLM) of Goldblatt rats. Experiments were performed in Goldblatt and age-matched control rats six weeks after clipping of renal artery to induce hypertension. Microinjection of 17ß-estradiol into the RVLM led to a greater reduction in mean arterial pressure and renal sympathetic nerve activity in controls than in 2K-1C rats. Microinjection of the GPER agonist G-1 into the RVLM led to a significantly greater increase in mean arterial pressure and renal sympathetic nerve activity in 2K-1C rats. Expression levels of estrogen receptors GPER and ERα, but not ERß, were significantly higher in the RVLM of 2K-1C rats than in that of the control rats. Chronic treatment with losartan significantly reduced the expression levels of estrogen receptors in the RVLM of 2K-1C rats. Taken altogether, the data suggest that the imbalance of actions between ERα and GPER, particularly with the predominance of GPER in the RVLM, contributes to sympathetic overactivation in male rats with Goldblatt hypertension. AT1-Angiotensin II receptor in the RVLM upregulated estrogen receptor expression in male Goldblatt rats.
Assuntos
Hipertensão Renovascular , Hipertensão , Ratos , Masculino , Animais , Hipertensão Renovascular/metabolismo , Receptores de Estrogênio , Receptor alfa de Estrogênio , Pressão Sanguínea , Estradiol/farmacologiaRESUMO
Spinal cord neurons contribute to elevated sympathetic vasomotor activity in renovascular hypertension (2K1C), particularly, increased actions of angiotensin II. However, the origin of these spinal angiotensinergic inputs remains unclear. The present study aimed to investigate the role of spinal angiotensin II type 1 receptor (AT1) receptors in the sympathoexcitatory responses evoked by the activation of the rostral ventrolateral medulla (RVLM) in control and 2K1C Goldblatt rats. Hypertension was induced by clipping of the left renal artery. After 6 weeks, a catheter (PE-10) filled with losartan was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of glutamate microinjection into the RVLM on blood pressure (BP), heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated in the presence or absence of spinal AT1 blockade. Tachycardic, pressor, and renal sympathoexcitatory effects caused by RVLM activation were significantly blunted by losartan in 2K1C rats, but not in control rats. However, no differences were found in the gene expression of angiotensin-converting enzyme, angiotensinogen, and renin in the spinal cord segments between the groups. In conclusion, acute sympathoexcitation induced by RVLM activation is dependent on the spinal AT1 receptor in Goldblatt, but not in control, rats. The involvement of other central cardiovascular nuclei in spinal angiotensinergic actions, as well as the source of angiotensin II, remains to be determined in the Goldblatt model.
Assuntos
Hipertensão/fisiopatologia , Rim/inervação , Bulbo/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Medula Espinal/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Hipertensão/metabolismo , Masculino , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Chronic nicotine exposure may increase cardiovascular risk by impairing the cardiac autonomic function. Besides, physical exercise (PE) has shown to improve cardiovascular health. Thus, we aimed to investigate the effects of PE on baroreflex sensitivity (BRS), heart rate variability (HRV), and sympathetic nerve activity (SNA) in chronically nicotine-exposed rats. Male Wistar rats were assigned to four independent groups: Control (treated with saline solution), Control+Ex (treated with saline and submitted to treadmill training), Nicotine (treated with Nicotine), and Nicotine+Ex (treated with nicotine and submitted to treadmill training). Nicotine (1 mg·kg-1) was administered daily for 28 consecutive days. PE consisted of running exercise (60%-70% of maximal aerobic capacity) for 45 min, 5 days per week, for 4 weeks. At the end of the protocol, cardiac BRS, HRV, renal SNA (rSNA), and renal BRS were assessed. Nicotine treatment decreased absolute values of HRV indexes, increased low frequency/high frequency ratio of HRV, reduced the bradycardic and sympatho-inhibitory baroreceptor reflex responses, and reduced the rSNA. PE effectively restored time-domain HRV indexes, the bradycardic and sympatho-inhibitory reflex responses, and the rSNA in chronic nicotine-treated rats. PE was effective in preventing the deterioration of time-domain parameters of HRV, arterial baroreceptor dysfunction, and the rSNA after nicotine treatment.
Assuntos
Barorreflexo , Animais , Frequência Cardíaca , Nicotina , RatosRESUMO
Previous studies have been described changes in brain regions contributing to the sympathetic vasomotor overactivity in Goldblatt hypertension (2K1C). Furthermore, changes in the spinal cord are also involved in the cardiovascular and autonomic dysfunction in renovascular hypertension, as intrathecal (i.t.) administration of Losartan (Los) causes a robust hypotensive/sympathoinhibitory response in 2K1C but not in control rats. The present study evaluated the role of spinal γ-aminobutyric acid (GABA)-ergic inputs in the control of sympathetic vasomotor activity in the 2K1C rats. Hypertension was induced by clipping the renal artery. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of i.t. injection of bicuculline (Bic) on blood pressure (BP), renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated over 40 consecutive minutes in the presence or absence of spinal AT1 antagonism. I.t. Bic triggered a more intense pressor and sympathoexcitatory response in 2K1C rats, however, these responses were attenuated by previous i.t. Los. No differences in the gene expression of GAD 65 and GABA-A receptors subunits in the spinal cord segments were found. Thus, the sympathoexcitation induced by spinal GABA-A blockade is dependent of local AT1 receptor in 2K1C but not in control rats. Excitatory angiotensinergic inputs to sympathetic preganglionic neurons are tonic controlled by spinal GABAergic actions in Goldblatt hypertension.
Assuntos
Angiotensina II/metabolismo , Hipertensão Renovascular/tratamento farmacológico , Losartan/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Masculino , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: -8⯱â¯3 vs. -52⯱â¯9 spikes/s after 120'). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80' after administration (CTL vs. 2K1C - 80â¯min: -10⯱â¯2 vs. -32⯱â¯6∗; 100â¯min: -15⯱â¯4 vs. -37⯱â¯9∗; 120â¯min: -12⯱â¯5 vs. -37⯱â¯8∗ spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.
Assuntos
Hipertensão Renovascular/fisiopatologia , Rim/efeitos dos fármacos , Medula Espinal/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Fármacos Atuantes sobre Aminoácidos Excitatórios/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/metabolismo , Rim/inervação , Ácido Cinurênico/farmacologia , Losartan/farmacologia , Masculino , Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologiaRESUMO
BACKGROUND: Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin-angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance. AIM: The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system. METHODS: After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated. RESULTS: High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (-0.7±0.2 vs. -1.5±0.1 spikes/s/mm Hg) and cardiac (-0.9±0.14 vs. -1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys. CONCLUSIONS: Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats.
Assuntos
Hipertensão Renovascular/fisiopatologia , Pressorreceptores/fisiopatologia , Sistema Renina-Angiotensina , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Frequência Cardíaca , Hipertensão Renovascular/urina , Masculino , Estresse Oxidativo , Pressorreceptores/efeitos dos fármacos , Ratos Wistar , Cloreto de Sódio/efeitos adversosRESUMO
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.
RESUMO
The effects of chronic treatment with digitoxin on arterial baroreceptor sensitivity for heart rate (HR) and renal sympathetic nerve activity (rSNA) control, cardiopulmonary reflex, and autonomic HR control in an animal model of heart failure (HF) were evaluated. Wistar rats were treated with digitoxin, which was administered in their daily feed (1 mg/kg per day) for 60 days. The following 3 experimental groups were evaluated: sham, HF, and HF treated with digitoxin (HF + DIG). We observed an increase in rSNA in the HF group (190 ± 29 pps, n = 5) compared with the sham group (98 ± 14 pps, n = 5). Digitoxin treatment prevented an increase in rSNA (98 ± 14 pps, n = 7). Therefore, arterial baroreceptor sensitivity was decreased in the HF group (-1.24 ± 0.07 bpm/mm Hg, n = 8) compared with the sham group (-2.27 ± 0.23 bpm/mm Hg, n = 6). Digitoxin did not alter arterial baroreceptor sensitivity in the HF + DIG group. Finally, the HF group showed an increased low frequency band (LFb: 23 ± 5 ms(2), n = 8) and a decreased high frequency band (HFb: 77 ± 5 ms(2), n = 8) compared with the sham group (LFb: 14 ± 3 ms(2); HFb: 86 ± 3 ms(2), n = 9); the HF+DIG group exhibited normalized parameters (LFb: 15 ± 3 ms(2); HFb: 85 ± 3 ms(2), n = 9). In conclusion, the benefits of decreasing rSNA are not directly related to improvements in peripheral cardiovascular reflexes; such occurrences are due in part to changes in the central nuclei of the brain responsible for autonomic cardiovascular control.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Digitoxina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Cardiotônicos/farmacologia , Digitoxina/farmacologia , Ecocardiografia Doppler , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
The present study sought to determine the involvement of median preoptic nucleus (MnPO) in the regulation of the cardiovascular function and renal sympathetic activity in normotensive (NT) and spontaneously hypertensive rats (SHR). MnPO inhibition evoked by Muscimol (4mM) nanoinjections, elicited fall in MAP and renal sympathoinhibition in NT-rats. Surprisingly, in SHRs these responses were greater than in NT-rats. These results demonstrated, for the first time that MnPO was involved in the tonic control of sympathetic activity in NT and SHRs. Furthermore, our data suggest the MnPO involvement in the increased sympathetic outflow and consequent arterial hypertension observed in SHRs.
Assuntos
Área Pré-Óptica/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Microinjeções , Muscimol/farmacologia , Inibição Neural/efeitos dos fármacos , Área Pré-Óptica/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHRRESUMO
Renal artery stenosis is the main cause of renovascular hypertension and results in ischemic nephropathy characterized by inflammation, oxidative stress, microvascular loss, and fibrosis with consequent functional failure. Considering the limited number of strategies that effectively control renovascular hypertension and restore renal function, we propose that cell therapy may be a promising option based on the regenerative and immunosuppressive properties of stem cells. This review addresses the effects of mesenchymal stem cells (MSC) in an experimental animal model of renovascular hypertension known as 2 kidney-1 clip (2K-1C). Significant benefits of MSC treatment have been observed on blood pressure and renal structure of the stenotic kidney. The mechanisms involved are discussed.