Epigenetic studies suggest that diseases that develop in adulthood are related to certain conditions to which the individual is exposed during the initial stages of life. Experimental evidence has demonstrated that offspring born to mothers maintained on high-Na diets during pregnancy have higher mean arterial pressure (MAP) in adulthood. Although these studies have demonstrated the importance of prenatal phases to hypertension development, no evidence regarding the role of high Na intake during postnatal phases in the development of this pathology has been reported. Therefore, in the present study, the effects of Na overload during childhood on induced water and Na intakes and on cardiovascular parameters in adulthood were evaluated. Experiments were carried out in two groups of 21-d-old rats: experimental group, maintained on hypertonic saline (0·3 M-NaCl) solution and food for 60 d, and control group, maintained on tap water and food. Later, both groups were given water and food for 15 d (recovery period). After the recovery period, chronic cannulation of the right femoral artery was performed in unanaesthetised rats to record baseline MAP and heart rate (HR). The experimental group was found to have increased basal MAP (98·6 (SEM 2·6) v. 118·3 (SEM 2·7) mmHg, P, 0·05) and HR (365·4 (SEM 12·2) v. 398·2 (SEM 7·5) beats per min, P, 0·05). There was a decrease in the baroreflex index in the experimental group when compared with that in the control group. A water and Na intake test was performed using furosemide. Na depletion was found to induce an increase in Na intake in both the control and experimental groups (12·1 (SEM 0·6) ml and 7·8 (SEM 1·1), respectively, P , 0·05); however, this increase was of lower magnitude in the experimental group. These results demonstrate that postnatal Na overload alters behavioural and cardiovascular regulation in adulthood.Key words: Hypertension: Water intake: Sodium intake: Postnatal periodThe maintenance of a stable internal environment is the main target of all physiological processes (1,2) , which is positively correlated with the regulation of ionic concentrations in the intracellular and extracellular compartments. Among the different types of inorganic salts present in the body fluids, NaCl is the most predominantly consumed salt and Na concentration is directly related to the maintenance of body fluid homeostasis (1,2) . Changes in Na concentrations result in an osmotic flux between the intracellular and extracellular compartments. Na influx or efflux affects the concentrations of all the other components in these compartments. Therefore, it is not surprising that many homeostatic mechanisms exist to maintain plasma Na concentrations with a limited rate of variation.The regulation of blood pressure (BP) involves complex mechanisms, including local, hormonal, neuronal and renal regulation, that, working together, are responsible for the redistribution of blood through changes in peripheral vascular resistance and cardiac output. Experimental evidence has demons...

Key points Rats subjected to sustained hypoxia (SH) present increases in arterial pressure (AP) and in glutamatergic transmission in the nucleus tractus solitarius (NTS) neurons sending projections to ventrolateral medulla (VLM). Treatment with minocycline, a microglial inhibitor, attenuated the increase in AP in response to SH. The increase in the amplitude of glutamatergic postsynaptic currents in the NTS‐VLM neurons, induced by postsynaptic mechanisms, was blunted by minocycline treatment. The number of microglial cells was increased in the NTS of vehicle‐treated SH rats but not in the NTS of minocycline‐treated rats. The data show that microglial recruitment/proliferation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS‐VLM neurons, which may contribute to the observed increase in AP. Abstract Short‐term sustained hypoxia (SH) produces significant autonomic and respiratory adjustments and triggers activation of microglia, the resident immune cells in the brain. SH also enhances glutamatergic neurotransmission in the NTS. Here we evaluated the role of microglial activation induced by SH on the cardiovascular changes and mainly on glutamatergic neurotransmission in NTS neurons sending projections to the ventrolateral medulla (NTS‐VLM), using a microglia inhibitor (minocycline). Direct measurement of arterial pressure (AP) in freely moving rats showed that SH (24 h, fraction of inspired oxygen (FI,O2) 0.1) in vehicle and minocycline (30 mg/kg i.p. for 3 days)‐treated groups produced a significant increase in AP in relation to control groups under normoxic conditions, but this increase was significantly lower in minocycline‐treated rats. Whole‐cell patch‐clamp recordings revealed that the active properties of the membrane were comparable among the groups. Nevertheless, the amplitudes of glutamatergic postsynaptic currents, evoked by tractus solitarius stimulation, were increased in NTS‐VLM neurons of SH rats. Changes in asynchronous glutamatergic currents indicated that the observed increase in amplitude was due to postsynaptic mechanisms. These changes were blunted in the SH group previously treated with minocycline. Using immunofluorescence, we found that the number of microglial cells was increased in the NTS of vehicle‐treated SH rats but not in the NTS neurons of minocycline‐treated rats. Our data support the concept that microglial activation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS‐VLM neurons, which may contribute to the increase in AP observed in this experimental model.

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Despite several studies describing the electrophysiological properties of RVLM presympathetic neurons, there is no consensus in the literature about their pacemaking property, mainly due to different experimental approaches used for recordings of neuronal intrinsic properties. In this review we are presenting a historical retrospective about the pioneering studies and their controversies on the intrinsic electrophysiological property of auto-depolarization of these cells in conjunction with recent studies from our laboratory documenting that RVLM presympathetic neurons present pacemaking capacity. We also discuss whether increased sympathetic activity observed in animal models of neurogenic hypertension (CIH and SHR) are dependent on changes in the intrinsic electrophysiological properties of these cells or due to changes in modulatory inputs from neurons of the respiratory network. We also highlight the key role of INaP as the major current contributing to the pacemaking property of RVLM presympathetic neurons.

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The brainstem nucleus tractus solitarii (nTS) processes and modulates the afferent arc of critical peripheral cardiorespiratory reflexes. Sensory afferents release glutamate to initiate the central component of these reflexes, and glutamate concentration is critically controlled by its removal via astrocytic neurotransmitter transporters. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nTS providing tonic and phasic modulation of neuronal activity. GABA is removed from the extracellular space through GABA transporters (GATs), however, the role of GATs in nTS synaptic transmission and their influence on cardiorespiratory function is unknown. We hypothesized that GATs tonically restrain nTS inhibitory signaling and given the considerable nTS GABA-glutamate cross-talk, modify excitatory signaling and thus cardiorespiratory function. Reverse transcription real-time polymerase chain reaction (RT-PCR), immunoblot and immunohistochemistry showed expression of GAT-1 and GAT-3 mRNA and protein within the rat nTS, with GAT-3 greater than GAT-1, and GAT-3 colocalizing with astrocyte S100B. Recordings in rat nTS slices demonstrated GAT-3 block decreased spontaneous inhibitory postsynaptic current (IPSC) frequency and reduced IPSC amplitude evoked from electrical stimulation of the medial nTS. Block of GAT-3 also increased spontaneous excitatory postsynaptic current (EPSC) frequency yet did not alter sensory afferent-evoked EPSC amplitude. Block of GAT-3 in the nTS of anesthetized rats increased mean arterial pressure, heart rate, sympathetic nerve activity, and minute phrenic nerve activity. These results demonstrate inhibitory and excitatory neurotransmission in the nTS is significantly modulated by endogenous GAT-3 to influence basal cardiorespiratory function.

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Obstructive sleep apnea patients face episodes of chronic intermittent hypoxia (CIH), which has been suggested as a causative factor for increased sympathetic activity (SNA) and hypertension. Female rats exposed to CIH develop hypertension and exhibit changes in respiratory-sympathetic coupling, marked by an increase in the inspiratory modulation of SNA. We tested the hypothesis that enhanced inspiratory-modulation of SNA is dependent on carotid bodies (CBs) and are associated with changes in respiratory network activity. For this, in CIH-female rats we evaluated the effect of CBs ablation on respiratory-sympathetic coupling, recorded from respiratory neurons in the working heart-brainstem preparation and from NTS neurons in brainstem slices. CIH-female rats had an increase in peripheral chemoreflex response and in spontaneous excitatory neurotransmission in NTS. CBs ablation prevents the increase in inspiratory modulation of SNA in CIH-female rats. Pre-inspiratory/inspiratory (Pre-I/I) neurons of CIH-female rats have a reduced firing frequency. Post-inspiratory neurons are active for a longer period during expiration in CIHfemale rats. Further, using the computational model of a brainstem respiratory-sympathetic network, we demonstrate that a reduction in Pre-I/I neuron firing frequency simulates the enhanced inspiratory SNA modulation in CIH-female rats. We conclude that changes in respiratory-sympathetic coupling in CIH-female rats is dependent on CBs and it is associated with changes in firing properties of specific respiratory neurons types.