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Introduction: The paraventricular nucleus of the hypothalamus (PVN) contains premotor neurons involved in the control of sympathetic vasomotor activity. It is known that the stimulation of specific areas of the PVN can lead to distinct response patterns at different target territories. The underlying mechanisms, however, are still unclear. Recent evidence from sympathetic nerve recording suggests that relevant information is coded in the power distribution of the signal along the frequency range. In the present study, we addressed the hypothesis that the PVN is capable of organizing specific spectral patterns of sympathetic vasomotor activation to distinct territories in both normal and hypertensive animals. Methods: To test it, we investigated the territorially differential changes in the frequency parameters of the renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), before and after disinhibition of the PVN by bicuculline microinjection. Subjects were control and Goldblatt rats, a sympathetic overactivity-characterized model of neurogenic hypertension (2K1C). Additionally, considering the importance of angiotensin II type 1 receptors (AT1) in the sympathetic responses triggered by bicuculline in the PVN, we also investigated the impact of angiotensin AT1 receptors blockade in the spectral features of the rSNA and sSNA activity. Results: The results revealed that each nerve activity (renal and splanchnic) presents its own electrophysiological pattern of frequency-coded rhythm in each group (control, 2K1C, and 2K1C treated with AT1 antagonist losartan) in basal condition and after bicuculline microinjection, but with no significant differences regarding total power comparison among groups. Additionally, the losartan 2K1C treated group showed no decrease in the hypertensive response triggered by bicuculline when compared to the non-treated 2K1C group. However, their spectral patterns of sympathetic nerve activity were different from the other two groups (control and 2K1C), suggesting that the blockade of AT1 receptors does not totally recover the basal levels of neither the autonomic responses nor the electrophysiological patterns in Goldblatt rats, but act on their spectral frequency distribution. Discussion: The results suggest that the differential responses evoked by the PVN were preferentially coded in frequency, but not in the global power of the vasomotor sympathetic responses, indicating that the PVN is able to independently control the frequency and the power of sympathetic discharges to different territories.

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Sepsis causes long-term disability, such as immune dysfunction, neuropsychological disorders, persistent inflammation, catabolism, and immunosuppression, leading to a high risk of death in survivors, although the contributing factors of mortality are unknown. The purpose of this experimental study in rats was to examine renal (rSNA) and splanchnic (sSNA) sympathetic nerve activity, as well as baroreflex sensitivity, in acute and chronic post-sepsis periods. The rats were divided into two groups: control group with naïve Wistar rats and sepsis group with 2-mL intravenous inoculation of Escherichia coli at 108 CFU/mL. Basal mean arterial pressure, heart rate, rSNA, sSNA, and baroreflex sensitivity were evaluated in all groups at the acute (6 h) and chronic periods (1 and 3 months). Basal rSNA and sSNA were significantly reduced in the surviving rats, as was their baroreflex sensitivity, for both pressor and hypotensive responses, and this effect lasted for up to 3 months. A single episode of sepsis in rats was enough to induce long-term alterations in renal and splanchnic sympathetic vasomotor nerve activity, representing a possible systemic event that needs to be elucidated. These findings showed that post-sepsis impairment of sympathetic vasomotor response may be one of the critical components in the inability of sepsis survivors to respond effectively to new etiological illness factors, thereby increasing their risk of post-sepsis morbidity.

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BACKGROUND: Knowledge of the central areas involved in the control of sympathetic vasomotor activity has advanced in the last few decades. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammal nervous system, and a microinjection of bicuculline, an antagonist of GABA type A (GABA-A) receptors, into the paraventricular nucleus of the hypothalamus (PVN) alters the pattern of sympathetic activity to the renal, splanchnic and lumbar territories. However, studies are needed to clarify the role of GABAergic inputs in other central areas involved in the sympathetic vasomotor activity. The present work studied the cardiovascular effects evoked by GABAergic antagonism in the PVN, RVLM and spinal cord. METHODS AND RESULTS: Bicuculline microinjections (400 pMol in 100 nL) into the PVN and rostral ventrolateral medulla (RVLM) as well as intrathecal administration (1.6 nmol in 2 µL) evoked an increase in blood pressure, heart rate, and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), inducing a higher coherence between rSNA and sSNA patterns. However, some of these responses were more intense when the GABA-A antagonism was performed in the RVLM than when the GABA-A antagonism was performed in other regions. CONCLUSIONS: Administration of bicuculline into the RVLM, PVN and SC induced a similar pattern of renal and splanchnic sympathetic vasomotor burst discharge, characterized by a low-frequency (0.5 Hz) and high-amplitude pattern, despite different blood pressure responses. Thus, the differential control of sympathetic drive to different targets by each region is dependent, in part, on tonic GABAergic inputs.

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The contribution of intrarenal alpha-2 adrenergic receptors in mediating the enhanced renal excretory responses evoked by the alpha-2-agonist xylazine was examined in a model of cirrhosis in rats. In sham-operated rats, xylazine (0.2 mg/kg, i.v.) increased diuresis and natriuresis (urine flow, control: 78 ± 12.1, 10 min: 155 ± 17, 20 min: 194 ± 19, 30 min: 146 ± 16, 40 min: 114 ± 13, 50 min: 95 ± 10.5 µl/min/g; urinary sodium excretion, control: 6.75 ± 2.08, 10 min: 7.12 ± 2.1, 20 min: 13.4 ± 4.6, 30 min: 14.6 ± 4.02, 40 min: 12.05 ± 2.35, 50 min: 12.7 ± 2.45 µeq/min/g), which was accompanied by a significant reduction in renal sympathetic nerve activity (RSNA) (control: 100, 10 min: 39.5 ± 5.8, 20 min: 53 ± 8.8, 30 min: 72 ± 7.0, 40 min: 83 ± 5.0, 50 min: 94 ± 6.1 AU). Xylazine (0.2 mg/kg) in cirrhotic animals, despite resulting in a significant reduction in RSNA (control: 100, 10 min: 73 ± 4.3*, 20 min: 70 ± 5.0*, 30 min: 76 ± 7.0*, 40 min: 85 ± 5.5*, 50 min: 92 ± 4.8* AU), was unable to increase natriuresis. A higher dose (20 mg/kg) of xylazine was not capable of increasing natriuresis and diuresis, even in the presence of a robust reduction in RSNA. Renal denervation did not alter the onset and time course of cirrhosis. The results indicated that during the development of cirrhosis, there is an adaptive process that disables the intrarenal alpha-2 adrenoceptor mechanisms that selectively promote water and urinary sodium excretion via a sympathetic renal nerve-independent mechanism. Thus, in cirrhotic rats, the diuresis/natriuresis induced by xylazine is independent on RSNA. Intrarenal and/or hormonal changes are probably involved in the impairment of xylazine-induced diuresis/natriuresis in cirrhosis.

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Angiotensin II (Ang II) acts as a pro-stress hormone, while other evidence indicates that angiotensin-(1-7) [Ang-(1-7)] attenuates physiological responses to emotional stress. To further test this hypothesis, in groups of 5-6 rats we evaluated autonomic, cardiovascular and behavioral parameters in male Sprague-Dawley (SD) and transgenic TGR(A1-7)3292 (TG) rats chronically overexpressing Ang-(1-7). Compared to SD rats, TG rats showed reduced baseline heart rate (HR; SD 380 ± 16 versus TG 329 ± 9 beats per minute (bpm), mean ± standard error of mean, p < .05) and renal sympathetic discharge (SD 138 ± 4 versus TG 117 ± 5 spikes/second, p < .05). TG rats had an attenuated tachycardic response to acute air-puff stress (ΔHR: SD 51 ± 20 versus TG 1 ± 3 bpm; p < .05), which was reversed by intracerebroventricular injection of the Mas receptor antagonist, A-779 (ΔHR: SD 51 ± 20 versus TG 63 ± 15 bpm). TG rats showed less anxious behavior on the elevated plus maze, as revealed by more entries into open arms (SD 2 ± 2 versus TG 47 ± 5% relative to total entries; p < .05), and more time spent in the open arms (SD 5 ± 4 versus TG 53 ± 9% relative to total time, p < .05). By contrast with SD rats, diazepam (1.5 mg/kg, intraperitoneally) did not further reduce anxious behavior in TG rats, indicating a ceiling anxiolytic effect of Ang-(1-7) overexpression. Ang-(1-7) concentrations in hypothalamus and plasma, measured by mass spectrometry were two- and three-fold greater, respectively, in TG rats than in SD rats. Hence, increased endogenous Ang-(1-7) levels in TG rats diminishes renal sympathetic outflow and attenuates cardiac reactivity to emotional stress, which may be via central Mas receptors, and reduces anxious behavior. Lay summaryWe used a genetically modified rat model that produces above normal amounts of a peptide hormone called angiotensin-(1-7) to test whether this peptide can reduce some of the effects of stress. We found that angiotensin-(1-7), acting in the brain, can reduce anxiety and reduce the increase in heart rate associated with emotional stress. These findings may provide a lead for design of new drugs to reduce stress.

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