Anterior Hypothalamic Area Angiotensin II-sensitive Neurons Research Articles

γ-Aminobutyric acid in the lateral septal area is involved in mediation of the inhibition of hypothalamic angiotensin II-sensitive neurons induced by blood pressure increases in rats

Previously, we have demonstrated that intravenous phenylephrine-induced increases in blood pressure inhibit angiotensin II-sensitive neurons via γ-aminobutyric acid (GABA) inputs in the anterior hypothalamic area (AHA). The lateral septal area (LSV) is also demonstrated to be involved in mediation of the baroreceptor reflex. To investigate central mechanisms involved in mediating the baroreceptor reflex, we examined whether GABA in the LSV is involved in mediation of the phenylephrine-induced inhibition of AHA angiotensin II-sensitive neurons. Microinjection of GABA into the LSV inhibited angiotensin II-sensitive neurons in the AHA of rats. The LSV GABA-induced inhibition of AHA neurons was abolished by pressure application of bicuculline onto the same AHA neurons. Intravenous injection of phenylephrine also inhibited AHA angiotensin II-sensitive neurons and the phenylephrine-induced inhibition of AHA neurons was abolished by microinjection of the GABAA receptor antagonist bicuculline into the LSV. In contrast, the LSV microinjection of bicuculline did not affect the inhibition of firing of AHA neurons induced by GABA pressure-applied in the AHA. These findings suggest that intravenous phenylephrine inhibits AHA angiotensin II-sensitive neurons via release of GABA in the LSV.

Intracerebroventricular injection of losartan inhibits angiotensin II-sensitive neurons via GABA inputs in the anterior hypothalamic area of rats

Previously, we have demonstrated that pressure-ejected application of angiotensin II and losartan, an angiotensin AT1 receptor antagonist, onto some neurons in the anterior hypothalamic area (AHA) of the rat increases and decreases, respectively, the basal firing rate of the neurons. To investigate possible participation of these AHA neurons in the brain angiotensin system, we examined whether intracerebroventricular injection of the angiotensin AT1 receptor antagonist losartan inhibits the neuronal activity of angiotensin II-sensitive neurons via GABA inputs in the AHA of rats. Intracerebroventricular injection of losartan decreased the firing rate of AHA angiotensin II-sensitive neurons. However, the intracerebroventricular injection of losartan did not affect the increase in firing rate of AHA angiotensin II-sensitive neurons induced by pressure application of angiotensin II onto the same neurons, although losartan similarly injected abolished the increase in firing rate of AHA angiotensin II-sensitive neurons induced by intracerebroventricular injection of angiotensin II. The losartan-induced decrease of unit firing in AHA neurons was abolished by pressure application of the GABAA receptor antagonist bicuculline onto the same neurons. Bicuculline itself did not affect the basal firing rate of AHA neurons. These findings suggest that intracerebroventricular injection of losartan inhibits AHA angiotensin II-sensitive neurons via GABA inputs to the neurons.

Centrally injected angiotensin II trans-synaptically activates angiotensin II-sensitive neurons in the anterior hypothalamic area of rats

Previously, we have demonstrated that pressure-ejected application of angiotensin II onto some neurons in the anterior hypothalamic area (AHA) of rats increases their firing rate. In contrast, pressure application of the angiotensin AT1 receptor antagonist losartan onto AHA neurons blocked the basal firing of the neurons. To investigate possible participation of these AHA neurons in the brain angiotensin system, we examined whether intracerebroventricular injection of angiotensin II results in an activation of angiotensin II-sensitive neurons in the AHA of rats. Intracerebroventricular injection of angiotensin II increased the firing rate of AHA angiotensin II-sensitive neurons. The angiotensin II-induced increase of unit firing in AHA neurons was abolished by pressure application of losartan onto the same neurons. In addition, the angiotensin II-induced increase of firing in AHA neurons was abolished by pressure application of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7), a calmodulin inhibitor, onto the same neurons. Pressure application of W7 onto AHA neurons affected neither the basal firing rate nor the increase in unit firing induced by pressure application of angiotensin II onto the same neurons. Intracerebroventricular injection of the cholinergic agonist carbachol did not affect the firing rate of angiotensin II-sensitive neurons in the AHA. These findings suggest that intracerebroventricular injection of angiotensin II activates AHA angiotensin II-sensitive neurons via angiotensinergic inputs to the neurons.

Mechanisms of Hypertension in the Central Nervous System

This article reviews studies by the author on central mechanisms of hypertension. Spontaneously hypertensive rats (SHR) have been developed as a rat model of genetic hypertension, and central acetylcholine has been implicated in hypertension in SHR. The rostral ventrolateral medulla (RVL), a major source of efferent sympathetic activity, has cholinergic pressor systems. The release of acetylcholine is enhanced in the RVL of SHR, leading to hypertension. The alteration of the RVL cholinergic system in SHR results from enhanced angiotensin systems in the anterior hypothalamic area (AHA). Angiotensin II-sensitive neurons are present in the AHA and they are tonically activated by endogenous angiotensins. The basal activity of AHA angiotensin II-sensitive neurons is enhanced in SHR, mainly due to enhanced sensitivity of AHA neurons to angiotensin II. The AHA angiotensin system is also responsible for hypertension induced by emotional stress and central Na(+) increases. These findings suggest that the AHA angiotensin system may play a critical role in the development of hypertension.

Evidence suggesting that angiotensins released not via synaptic inputs are involved in the basal activity of anterior hypothalamic neurons in rats

Previously, we have demonstrated that angiotensin II-sensitive neurons exist in the anterior hypothalamic area (AHA) and that these neurons are tonically activated by endogenous angiotensins in rats. Chemical stimulation of the lateral septal area (LSV) and medial amygdaloid nucleus (MeA), and intracerebroventricular injection of hypertonic saline, activated AHA angiotensin II-sensitive neurons. To investigate mechanisms of the basal activity of AHA angiotensin II-sensitive neurons, we examined the effect of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7), a calmodulin inhibitor, applied onto AHA neurons on the basal activity and the stimulus-evoked activation of these neurons. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Microinjections of carbachol into the LSV and corticotropin-releasing factor into the MeA, and intracerebroventricular injection of hypertonic saline, activated AHA angiotensin II-sensitive neurons. These three kinds of injection-induced activations of AHA neurons were abolished by pressure application of W7 onto the same neurons, while the calmodulin inhibitor did not affect the increase in firing of AHA neurons induced by pressure application of angiotensin II onto the same neurons. The pressure application of W7 did not affect the basal activity of AHA angiotensin II-sensitive neurons, whereas the angiotensin AT1 receptor antagonist losartan similarly applied inhibited it. These findings suggest that the basal activity of AHA angiotensin II-sensitive neurons is mediated by angiotensins released not via synaptic inputs.

Angiotensin II sensitivity of anterior hypothalamic area neurons is enhanced in both spontaneously hypertensive rats and Dahl salt-sensitive rats

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins. Furthermore, we have demonstrated that intracerebroventricular injection of hypertonic saline increases the firing rate of AHA angiotensin II-sensitive neurons via angiotensins and that the central sodium-induced activation of AHA neurons is enhanced in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. In this study, we examined whether sensitivities of AHA angiotensin II-sensitive neurons to angiotensin II are enhanced in SHR and Dahl S rats as compared with their respective controls. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY), and male 15- to 16-week-old Dahl S rats and Dahl R rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. In SHR, pressure application of angiotensin II (3 × 10 −9 to 3 × 10 −8 M) onto AHA angiotensin II-sensitive neurons increased their firing rate in a concentration-dependent manner. In WKY, only the highest concentration of angiotensin II increased the firing rate, while the lower concentrations of angiotensin II did not affect it. In Dahl S rats, pressure application of angiotensin II (10 −8 and 3 × 10 −8 M) onto AHA neurons increased their firing rate, while angiotensin II (3 × 10 −9 M) did not affect it. In Dahl R rats, the highest concentration of angiotensin II increased the firing rate, while the lower concentrations of angiotensin II did not affect it. These findings indicate that the sensitivity of AHA neurons to angiotenisn II is enhanced in SHR and Dahl S rats as compared with their respective controls.

Activities of hypothalamic angiotensin II-sensitive neurons are greately enhanced even in prehypertensive spontaneously hypertensive rats

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) of rats are tonically activated by endogenous angiotensins and that reactivities of these neurons to angiotensin II are enhanced in 15- to 16-week-old spontaneously hypertensive rats (SHR). To investigate whether the enhanced reactivity of SHR AHA neurons to angiotensin II is secondary to raised blood pressure, we examined whether the enhanced reactivity to angiotensin II also occurs in prehypertensive SHR. We also examined whether reactivities of AHA angiotensin II-sensitive neurons to intracerebroventricular hypertonic saline are enhanced in prehypertensive SHR, since intracerebroventricular injection of hypertonic saline increases the firing rate of AHA neurons via release of angiotensins at AHA neuron levels. Male 4-week-old SHR and age-matched Wistar Kyoto rats (WKY) were used in this study. There was no difference in systolic blood pressure between both rats. They were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Pressure application of angiotensin II onto some AHA neurons increased their firing rate. The basal firing rate of angiotensin II-sensitive neurons was increased in SHR as compared with WKY. The increase of unit firing by angiotenisn II was enhanced in SHR as compared with WKY. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The average threshold sodium concentration for the saline-induced increase of neural firing was lower in SHR than in WKY. These findings demonstrate that basal activities and responsiveness to angiotensin II in AHA angiotensin II-sensitive neurons are enhanced in prehypertensive SHR as compared with age-matched WKY. In addition, these findings indicate that central saline-induced activation of AHA angiotensin II-sensitive neurons is also enhanced in SHR. It appears that the enhanced reactivity of SHR AHA neurons to angiotensin II occurs primarily in nature but not secondarily to raised blood pressure in SHR.

Enhanced central hypertonic saline-induced activation of angiotensin II-sensitive neurons in the anterior hypothalamic area of spontaneously hypertensive and Dahl S rats

High dietary salt intake activates the brain renin–angiotensin system in spontaneously hypertensive rats (SHR) and Dahl S rats, resulting in sympathetic hyperactivity and hypertension. Increases of sodium concentration in cerebrospinal fluid (CSF) and/or enhanced responses to CSF sodium are considered to be involved in the high dietary salt-induced activation of central nervous system pathways in those rats. Previously we have demonstrated that intracerebroventricular injection of hypertonic saline increases the neural activity of angiotensin II-sensitive neurons trans-synaptically via endogenous angiotensins in the anterior hypothalamic area (AHA) of rats. In the present study, we examined whether the AHA angiotensin II-sensitive neuron response to hypertonic saline would differ in SHR and Dahl S rats from those of their controls. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY), Dahl S rats and Dahl R rats and Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The threshold sodium concentration for the central sodium-induced increase of neural firing was lower in SHR than those of WKY, Dahl S rats, Dahl R rats and Wistar rats. The increase in neural firing induced by hypertonic saline (250 mM) was greater in SHR than those of other four kinds of rats. Similarly, the threshold sodium concentration was lower in Dahl S rats than those of WKY, Dahl R rats and Wistar rats and the increase in neural firing induced by hypertonic saline (250 mM) was greater in Dahl S rats than those of WKY, Dahl R rats and Wistar rats. In SHR, intracerebroventricular injection of the amiloride-sensitive sodium channel blocker benzamil abolished the hypertonic saline (250 mM)-induced increase in neural firing, but the sodium channel blocker itself did not affect the basal firing of these neurons. These findings indicate that central sodium-induced activation of AHA angiotensin II-sensitive neurons is enhanced in SHR and Dahl S rats.

Cholinergic systems in the posterior hypothalamic nucleus are involved in blood pressure decrease-induced excitation of anterior hypothalamic area neurons in rats

Previously, we have demonstrated that decreases in blood pressure induced by intravenous nitroprusside increase the firing rate of angiotensin II-sensitive neurons in the anterior hypothalamic area (AHA) of rats and that this increase of neural firing rate is blocked by the pressure application of losartan onto the same neurons. It has been suggested that acetylcholine in the posterior hypothalamic nucleus (PHN) serves as a neurotransmitter in a pathway which can modulate baroreceptor reflexes. In the present study, we examined whether acetylcholine in the PHN is involved in the nitroprusside-induced increase of the firing of angiotensin II-sensitive neurons in the AHA of rats. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Decreases in blood pressure induced by intravenous nitroprusside (100 ug/kg) increased the firing rate of AHA angiotensin II-sensitive neurons. The nitroprusside-induced increase of firing rate of AHA neurons was inhibited by PHN microinjection of the cholinoceptor antagonist scopolamine and potentiated by PHN microinjection of the cholinesterase inhibitor physostigmine. Microinjections of carbachol and glutamate into the PHN caused increases of firing rate of AHA neurons. The carbachol-induced but not glutamate-induced increase of unit firing was abolished by the pre-microinjection of scopolamine into the same sites of the PHN. These findings suggest that the nitroprusside-induced increase of firing of AHA neurons is mediated via acetylcholine at the level of the PHN.

Cholinergic stimulation in the posterior hypothalamic nucleus activates angiotensin II-sensitive neurons in the anterior hypothalamic area of rats

We have previously reported that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins in rats and that activities of these AHA angiotensin II-sensitive neurons are enhanced in spontaneously hypertensive rats (SHR). Acetylcholine in the posterior hypothalamic nucleus (PHN) has been implicated in hypertension in SHR. It is suggested that there exist neuronal projections from the PHN to the AHA in rats. In this study, we examined whether cholinergic stimulation in the PHN activates AHA angiotensin II-sensitive neurons. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Microinjection of carbachol, physostigmine and glutamate into the PHN caused an increase in firing rate of AHA angiotensin II-sensitive neurons in anesthetized rats. The carbachol-induced increase of firing rate was inhibited by pressure application of the AT1 receptor antagonist losartan onto AHA angiotensin II-sensitive neurons. The glutamate-induced increase of firing rate was also inhibited by the pressure application of losartan. PHN microinjections of carbachol and glutamate did not affect blood pressure in these anesthetized rats. In conscious rats, PHN microinjection of carbachol produced an increase of blood pressure and the carbachol-induced pressor response was inhibited by bilateral microinjections of losartan into the AHA. These findings indicate that cholinergic stimulation in the PHN activates AHA angiotensin II-sensitive neurons. It seems likely that the activation of AHA angiotensin II-sensitive neurons induced by PHN cholinergic stimulation is partly mediated via release of angiotensins at AHA angiotensin II-sensitive neuron levels.

Cholinergic stimulation in the lateral septal area activates anterior hypothalamic area neurons via excitatory amino acid receptors in rats

We have previously reported that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins in rats and that activities of these AHA angiotensin II-sensitive neurons are enhanced in spontaneously hypertensive rats. It is suggested that there exist neuronal projections from the lateral septal area (LSV) to the AHA in rats. In this study, we examined whether neurons in the LSV are involved in activation of AHA angiotensin II-sensitive neurons. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Microinjection of carbachol into the LSV caused an increase in firing rate of AHA angiotensin II-sensitive neurons. The carbachol-induced increase of firing rate of AHA angiotensin II-sensitive neurons was inhibited by pressure application of the excitatory amino acid receptor antagonist kynurenate but not by the AT1 receptor antagonist losartan onto the same neurons. Microinjection of carbachol into the LSV also increased the firing rate of AHA ACh-sensitive neurons, and the carbachol-induced increase of firing rate of ACh-sensitive neurons was again abolished by pressure application of kynurenate but not by the muscarinic receptor antagonist scopolamine onto the same neurons. Microinjection of the muscarinic receptor antagonist 4-DAMP into the LSV did not affect the firing rate of AHA angiotensin II-sensitive neurons. These findings indicate that neurons in the LSV are involved in activation of AHA angiotensin II-sensitive neurons. It seems likely that the carbachol-induced activation of AHA angiotensin II-sensitive neurons is mainly mediated via excitatory amino acid receptors at AHA neurons.

Anterior hypothalamic neurons respond to blood pressure changes via γ-aminobutyric acid and angiotensins in rats

It has been suggested that neurons in the hypothalamus respond to baroreflex activation and deactivation. In this study, we examined whether angiotensin II-sensitive neurons in the anterior hypothalamic area (AHA) respond to baroreflex activation and deactivation, and which neurotransmitters are involved in mediating the baroreflex responses. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Increases in blood pressure induced by intravenous phenylephrine completely inhibited the firing of AHA angiotensin II-sensitive neurons. The phenylephrine-induced inhibition of neuronal firing was blocked and enhanced by the pressure application of bicuculline and nipecotic acid, respectively, onto the same neurons. In contrast, decreases in blood pressure induced by intravenous nitroprusside increased the firing of angiotensin II-sensitive neurons. The nitroprusside-induced increase of neuronal firing was blocked by the pressure application of losartan onto the same neurons. These findings suggest that angiotensin II-sensitive neurons in the AHA respond to blood pressure changes via γ-aminobutyric acid and angiotensins in rats.

The medial amygdaloid area is involved in activation of angiotensin II-sensitive neurons in the anterior hypothalamic area

We have previously reported that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins in rats and that the activities of these AHA angiotensin II-sensitive neurons are enhanced in spontaneously hypertensive rats. It is suggested that there exist neural projections from the medial amygdala to the AHA in rats. In this study, we examined whether neurons in the medial amygdaloid area (MeA) are involved in the activation of AHA angiotensin II-sensitive neurons. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Microinjection of glutamate into the MeA caused an increase in the firing rate of AHA angiotensin II-sensitive neurons. The glutamate-induced increase of firing rate was inhibited by pressure application of the AT1 receptor antagonist losartan onto AHA angiotensin II-sensitive neurons. The microinjection of glutamate into the central amygdaloid area also increased the firing rate of AHA angiotensin II-sensitive neurons, but the glutamate-induced increase of firing rate was not affected by pressure application of losartan onto AHA angiotensin II-sensitive neurons. The microinjection of corticotropin-releasing factor (CRF) into the MeA also increased the firing rate of AHA angiotensin II-sensitive neurons, but the CRF-induced increase of firing rate was not inhibited by pressure application of losartan onto AHA angiotensin II-sensitive neurons. Repeated microinjection of glutamate into the MeA caused an increase in the release of angiotensins in the AHA. These findings indicate that neurons in the MeA are involved in the activation of AHA angiotensin II-sensitive neurons. It seems likely that the activation of AHA angiotensin II-sensitive neurons induced by glutamate but not CRF is partly mediated via the release of angiotensins at AHA angiotensin II-sensitive neuron levels.