Hypertension Induced by Angiotensin II and a High Salt Diet Involves Reduced SK Current and Increased Excitability of RVLM Projecting PVN Neurons. (vol 104, pg 2329, 2010)

Exercise Science, Health and Physical Education Department, Michigan Technological University, Houghton, Michigan
Journal of Neurophysiology (Impact Factor: 2.89). 11/2010; 104(5):2329-37. DOI: 10.1152/jn.01013.2009
Source: PubMed


Although evidence indicates that activation of presympathetic paraventricular nucleus (PVN) neurons contributes to the pathogenesis of salt-sensitive hypertension, the underlying cellular mechanisms are not fully understood. Recent evidence indicates that small conductance Ca(2+)-activated K(+) (SK) channels play a significant role in regulating the excitability of a key group of sympathetic regulatory PVN neurons, those with axonal projections to the rostral ventrolateral medulla (RVLM; i.e., PVN-RVLM neurons). In the present study, rats consuming a high salt (2% NaCl) diet were made hypertensive by systemic infusion of angiotensin II (AngII), and whole cell patch-clamp recordings were made in brain slice from retrogradely labeled PVN-RVLM neurons. To determine if the amplitude of SK current was altered in neurons from hypertensive rats, voltage-clamp recordings were performed to isolate SK current. Results indicate that SK current amplitude (P < 0.05) and density (P < 0.01) were significantly smaller in the hypertensive group. To investigate the impact of this on intrinsic excitability, current-clamp recordings were performed in separate groups of PVN-RVLM neurons. Results indicate that the frequency of spikes evoked by current injection was significantly higher in the hypertensive group (P < 0.05-0.01). Whereas bath application of the SK channel blocker apamin significantly increased discharge of neurons from normotensive rats (P < 0.05-0.01), no effect was observed in the hypertensive group. In response to ramp current injections, subthreshold depolarizing input resistance was greater in the hypertensive group compared with the normotensive group (P < 0.05). Blockade of SK channels increased depolarizing input resistance in normotensive controls (P < 0.05) but had no effect in the hypertensive group. On termination of current pulses, a medium afterhyperpolarization potential (mAHP) was observed in most neurons of the normotensive group. In the hypertensive group, the mAHP was either small or absent. In the latter case, an afterdepolarization potential (ADP) was observed that was unaffected by apamin. Apamin treatment in the normotensive group blocked the mAHP and revealed an ADP resembling that seen in the hypertensive group. We conclude that diminished SK current likely underlies the absence of mAHPs in PVN-RVLM neurons from hypertensive rats. Both the ADP and greater depolarizing input resistance likely contribute to increased excitability of PVN-RVLM neurons from rats with AngII-Salt hypertension.

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    • "Studies have demonstrated that estrogen plays protective roles in the pathological development of, and the incidence of, cardiovascular disorders [46-48]. Accumulating evidence shows that the neuronal activity of PVN-RVLM neurons is elevated by enhancing the intrinsic membrane activity or by eliminating inhibitory synaptic inputs in cardiovascular diseases, such as hypertension and chronic myocardial infarction [16,26,49]. Therefore, the E2-mediated modulation of PVN-RVLM neurons shown in this study (i.e., the diminution in IA density and the likely enhancement of membrane excitability) seems to be controversial with respect to the protective effects of E2 on the cardiovascular system because the modified pattern is more likely to reinforce the increase in neuronal excitability induced by abnormal cardiovascular conditions. "
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    ABSTRACT: The hypothalamic paraventricular nucleus (PVN) is an important site in the regulation of the autonomic nervous system. Specifically, PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM) play a regulatory role in the determination of the sympathetic outflow in the cardiovascular system. In the PVN-RVLM neurons, the estrogen receptor beta is expressed. However, to date, the effects of estrogen on PVN-RVLM neurons have not been reported. The present study investigated estrogen-mediated modulation of two voltage-gated potassium channel (Kv) subunits, Kv4.2 and Kv4.3, that are expressed predominantly in PVN neurons and the functional current of Kv4.2 and Kv4.3, the transient outward potassium current (IA). Single-cell real-time RT-PCR analysis showed that 17beta-estradiol (E2) replacement (once daily for 4 days) selectively down-regulated Kv4.2 mRNA levels in the PVN-RVLM neurons of ovariectomized female rats. There was no change in Kv4.3 levels. Whole-cell patch-clamp recordings demonstrated that E2 also diminished IA densities. Interestingly, these effects were most apparent in the dorsal cap parvocellular subdivision of the PVN. E2 also shortened a delay in the excitation of the PVN-RVLM neurons. These findings demonstrate that E2 exerts an inhibitory effect on the functions of IA, potentially by selectively down-regulating Kv4.2 but not Kv4.3 in PVN-RVLM neurons distributed in a specific parvocellular subdivision.
    Full-text · Article · Nov 2013 · BMC Neuroscience
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    • "Finally, high salt intake may have a key role in the development of hypertension (Chen et al., 2010). "
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    ABSTRACT: Objective: People with schizophrenia show a high incidence of metabolic syndrome, which is associated with a high mortality from cardiovascular disease. The aetiology of the metabolic syndrome in schizophrenia is multi-factorial and may involve antipsychotic treatment, high levels of stress and unhealthy lifestyle, such as poor diet. As a poor diet can predispose to the development of metabolic abnormalities, the aims of this review are to clarify: 1) the dietary patterns of patients with schizophrenia, 2) the association of these dietary patterns with a worse metabolic profile, and 3) the possible factors influencing these dietary patterns. Methods: A search was conducted on Pubmed, The Cochrane Library, Scopus, Embase, Ovid, Psychoinfo and ISI web of Knowledge from 1950 to the 1st of November 2011. 783 articles were found through the investigation of such databases. After title, abstract or full-text reading and applying exclusion criteria we reviewed 31 studies on dietary patterns and their effects on metabolic parameters in schizophrenia. Results: Patients with schizophrenia have a poor diet, mainly characterized by a high intake of saturated fat and a low consumption of fibre and fruit. Such diet is more likely to increase the risk to develop metabolic abnormalities. Data about possible causes of poor diet in schizophrenia are still few and inconsistent. Conclusion: Subjects with schizophrenia show a poor diet that partly accounts for their higher incidence of metabolic abnormalities. Further studies are needed to clarify the causes of poor diet and the role of dietary intervention to improve their physical health.
    Full-text · Article · Nov 2012 · Journal of Psychiatric Research
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    • "Importantly, a growing body of evidence supports overactivation of preautonomic PVN neurons and their descending pathways as a major mechanism contributing to sympathoexcitation, altered reflex function, and elevated blood pressure in hypertensive disorders (Allen 2002; Earle et al. 1992; Li and Pan 2007b; Martin and Haywood 1998). Several mechanisms have been proposed to mediate elevated preautonomic PVN neuronal activity in hypertension, including a shift in the balance of inhibitory/excitatory synaptic transmitters (Biancardi et al. 2010; Li and Pan 2007a, 2007b; Osborn et al. 2007), as well as changes in intrinsic conductances , including altered K and Ca 2 channel function (Chen et al. 2010; Sonner et al. 2008, 2011). For the most part, however, these studies focused on PVN-RVLM and PVN-IML neurons. "
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    ABSTRACT: Elevated sympathetic outflow and altered autonomic reflexes, including impaired baroreflex function, are common findings observed in hypertensive disorders. Although a growing body of evidence supports a contribution of preautonomic neurons in the hypothalamic paraventricular nucleus (PVN) to altered autonomic control during hypertension, the precise underlying mechanisms remain unknown. Here, we aimed to determine whether the intrinsic excitability and repetitive firing properties of preautonomic PVN neurons that innervate the nucleus tractus solitarii (PVN-NTS neurons) were altered in spontaneously hypertensive rats (SHR). Moreover, given that exercise training is known to improve and/or correct autonomic deficits in hypertensive conditions, we evaluated whether exercise is an efficient behavioral approach to correct altered neuronal excitability in hypertensive rats. Patch-clamp recordings were obtained from retrogradely labeled PVN-NTS neurons in hypothalamic slices obtained from sedentary (S) and trained (T) Wistar-Kyoto (WKY) and SHR rats. Our results indicate an increased excitability of PVN-NTS neurons in SHR-S rats, reflected by an enhanced input-output function in response to depolarizing stimuli, a hyperpolarizing shift in Na(+) spike threshold, and smaller hyperpolarizing afterpotentials. Importantly, we found exercise training in SHR rats to restore all these parameters back to those levels observed in WKY-S rats. In several cases, exercise evoked opposing effects in WKY-S rats compared with SHR-S rats, suggesting that exercise effects on PVN-NTS neurons are state dependent. Taken together, our results suggest that elevated preautonomic PVN-NTS neuronal excitability may contribute to altered autonomic control in SHR rats and that exercise training efficiently corrects these abnormalities.
    Preview · Article · Feb 2012 · Journal of Neurophysiology
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