Effect of Qigong on hypertension: a randomised controlled study

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Control of hypothalamic-pituitary-adrenal stress axis activity by the intermediate conductance calcium-activated potassium channel, SK4

NON-TECHNICAL SUMMARY: Our ability to respond to stress is critically dependent upon the release of the stress hormone adrenocorticotrophic hormone (ACTH) from corticotroph cells of the anterior pituitary gland. ACTH release is controlled by the electrical properties of corticotrophs that are determined by the movement of ions through channel pores in the plasma membrane. We show that a calcium-activated potassium ion channel called SK4 is expressed in corticotrophs and regulates ACTH release. We provide evidence of how SK4 channels control corticotroph function, which is essential for understanding homeostasis and for treating stress-related disorders. ABSTRACT: The anterior pituitary corticotroph is a major control point for the regulation of the hypothalamic–pituitary–adrenal (HPA) axis and the neuroendocrine response to stress. Although corticotrophs are known to be electrically excitable, ion channels controlling the electrical properties of corticotrophs are poorly understood. Here, we exploited a lentiviral transduction system to allow the unequivocal identification of live murine corticotrophs in culture. We demonstrate that corticotrophs display highly heterogeneous spontaneous action-potential firing patterns and their resting membrane potential is modulated by a background sodium conductance. Physiological concentrations of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) cause a depolarization of corticotrophs, leading to a sustained increase in action potential firing. A major component of the outward potassium conductance was mediated via intermediate conductance calcium-activated (SK4) potassium channels. Inhibition of SK4 channels with TRAM-34 resulted in an increase in corticotroph excitability and exaggerated CRH/AVP-stimulated ACTH secretion in vitro. In accordance with a physiological role for SK4 channels in vivo, restraint stress-induced plasma ACTH and corticosterone concentrations were significantly enhanced in gene-targeted mice lacking SK4 channels (Kcnn4(−/−)). In addition, Kcnn4(−/−) mutant mice displayed enhanced hypothalamic c-fos and nur77 mRNA expression following restraint, suggesting increased neuronal activation. Thus, stress hyperresponsiveness observed in Kcnn4(−/−) mice results from enhanced secretagogue-induced ACTH output from anterior pituitary corticotrophs and may also involve increased hypothalamic drive, thereby suggesting an important role for SK4 channels in HPA axis function

Effects of chronic captopril treatment on the electrical-microstimulation-induced blood pressure changes and electrophysiological properties of cardiovascular neurons in the rostral ventrolateral medulla of the spontaneously hypertensive rat

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Responses of cardiovascular neurons in the rostral ventrolateral medulla of the normotensive Wistar Kyoto and spontaneously hypertensive rats to iontophoretic application of angiotensin II

In female pentobarbital-anesthetized Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), changes in spontaneous discharges of cardiovascular neurons in the rostral ventrolateral medulla (RVL) in response to iontophoretic application of angiotensin II (Ang II) were studied and compared. It was found that iontophoretic application of Ang II to RVL increased the spontaneous neuronal activities of 30% of the cardiovascular neurons in both types of rats and that the increase was significantly greater in SHR than in WKY. In both types of rats, there was an increase in arterial blood pressure in response to iontophoretic release of Ang II to RVL. The pressor response was accompanied by tachycardia, which was significantly greater in SHR than in WKY. The present study provides evidence that Ang II acts directly on cardiovascular neurons in RVL, and in SHR, an enhanced sensitivity and responsiveness of the RVL cardiovascular neurons to Ang II may augment the sympathetic outflow from RVL and contribute to the genesis of hypertension.link_to_subscribed_fulltex

Electrophysiological properties of neurons in the rostral ventrolateral medulla of normotensive and spontaneously hypertensive rats

Single unit activities were recorded from the rostral ventrolateral medulla (RVL) of pentobarbital-anesthetized normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Throughout the recording period, arterial blood pressures of WKY (mean arterial pressure, MAP = 103.1 mm Hg) and SHR (MAP = 159.2 mm Hg) remained stable at the respective basal levels. The units recorded in this study were all spontaneously active and cardiac-locked. Two types of discharge patterns, namely single and double discharges, were identified. These single and double discharge units were found to distribute randomly in RVL. In WKY, 92.6% of RVL neurons exhibited single discharges whereas in SHR, the majority (57%) of RVL neurons exhibited double discharges. The mean firing rate of single discharge units in RVL of SHR was significantly higher than that of WKY, whereas the mean firing rate of double discharge units in WKY was similar to that of SHR. About half of the units studied were also tested for antidromic collision; all units tested could be antidromically activated from the intermediolateral column (IML) of the thoracic spinal cord and the lowest threshold sites were consistently localized within IML. In both groups of rats, the axonal conduction velocity of RVL neurons showed a bimodal distribution viz. the fast and slow conducting axons. The mean conduction velocities of each of these two groups of neurons in WKY and SHR were similar. Most of the double discharge units in WKY and SHR belonged to the fast conducting type. In comparison with WKY, the present findings in SHR demonstrated that the majority of RVL units exhibited double discharge pattern with a fast conduction velocity, and the remaining RVL units showed single discharge pattern with a higher firing rate and regularity. These properties of RVL neurons may probably contribute to the enhanced sympathetic outflow from RVL of SHR and in turn account for the higher BP observed in SHR.link_to_subscribed_fulltex

Effects of angiotensin II on the spontaneous activity of rostral ventrolateral medullary cardiovascular neurons and blood pressure in spontaneously hypertensive rats

The interactive role of rostral ventrolateral medulla (RVL) cardiovascular neurons and brain angiotensin II (Ang II) in regulating the arterial blood pressure was examined by recording simultaneously the spontaneous activity of these spinal projecting neurons and the arterial blood pressure in the pentobarbital-anesthetized spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar Kyoto rat (WKY). It was found that Ang II elicited dose-dependent excitatory responses in a subpopulation of RVL cardiovascular neurons, followed by a subsequent increase in blood pressure. These effects of Ang II were significantly greater in SHR than in WKY. The effects were attenuated or abolished by co- administration of Ang II antagonist, [Sar1, Ile8]-Ang II. Pre- administration of [Sar1, Ile8]-Ang II to RVL using bilateral microinjection attenuated the blood pressure effects of intracerebroventricularly administered Ang II by as much as 70%. These results indicated that spinal projecting RVL cardiovascular neurons are important in mediating the pressor action of Ang II. The enhanced sensitivity and responsiveness of RVL cardiovascular neurons to Ang II may be pertinent to the genesis of hypertension in adult SHR.link_to_subscribed_fulltex

Effects of [Sar1, Ile8]-angiotensin II on rostral ventrolateral medulla neurons and blood pressure in spontaneously hypertensive rats

The present study was an attempt to determine the influence of brain angiotensin II, the activity of which is known to be higher in spontaneously hypertensive rat, on the spontaneous activity of the cardiovascular neurons in the rostral ventrolateral medulla of the spontaneously hypertensive rat. Both the spontaneous activity of the spinal projecting rostral ventrolateral medulla cardiovascular neurons and the arterial blood pressure were simultaneously measured in the pentobarbital-anesthetized spontaneously hypertensive rat and its normotensive control, the Wistar Kyoto rat, following microinjection to rostral ventrolateral medulla of an angiotensin II antagonist, [Sar1, Ile8]-angiotensin II (sarile). A microinjection method was developed that enabled us to perform extracellular recording of the rostral ventrolateral medulla cardiovascular neuron during the microinjection of drug to the vicinity of the neuron. It was found that sarile reduced both the arterial blood pressure and firing rate of some rostral ventrolateral medulla cardiovascular neurons dose-dependently. The effects of sarile were significantly greater in spontaneously hypertensive rat than in the Wistar Kyoto rat. The present findings indicate that the rostral ventrolateral medulla cardiovascular neurons of spontaneously hypertensive rat exhibit an augmented sensitivity to endogenous brain angiotensin II. Such an increase in sensitivity to brain angiotensin II in the spontaneously hypertensive rat may contribute to the enhanced spontaneous activities of rostral ventrolateral medulla cardiovascular neurons, as in the sarile responsive single discharge units, even in the resting or prestimulation state. This interaction of brain angiotensin II and rostral ventrolateral medulla cardiovascular neurons is likely to be contributory to the genesis of hypertension in this strain of rats.link_to_subscribed_fulltex