Abstract-Angiotensin within the central nervous system appears to be important for the maintenance of hypertension in spontaneously hypertensive rats. This study addresses the hypothesis that blockade of AT 1 receptors in the rostral ventrolateral medulla would decrease blood pressure in spontaneously hypertensive rats and that this tonically active AT 1 -mediated input to the rostral ventrolateral medulla arises from the hypothalamic paraventricular nucleus. Injection of the nonpeptide AT 1 receptor antagonist valsartan bilaterally into the rostral ventrolateral medulla of choralose-anesthetized adult spontaneously hypertensive rats produced a dose-related decrease in mean arterial pressure, with a maximal effect of Ϸ30 mm Hg. Inhibition of the paraventricular nucleus by local injection of muscimol elicited a similar response, which was inhibited by prior injection of valsartan into the rostral ventrolateral medulla. In contrast, in control Wistar-Kyoto rats, neither valsartan injected into the rostral ventrolateral medulla nor muscimol injected into the paraventricular nucleus had a substantial effect on arterial pressure. These data indicate that in spontaneously hypertensive rats but not in Wistar-Kyoto rats, rostral ventrolateral medulla vasomotor neurons are tonically excited by endogenous stimulation of AT 1 receptors, and this input is apparently driven from the hypothalamus. These results suggest that the rostral ventrolateral medulla is one site that the brain renin-angiotensin system acts to maintain elevated blood pressure in spontaneously hypertensive rats. The data supporting of a role of brain Ang II in hypertension in the spontaneously hypertensive rats (SHR) are particularly convincing. Specifically, pharmacological disruption of brain angiotensin signaling decreases AP in SHR. 6 -10 Furthermore, there appear to be alterations in SHR in the amount of angiotensin or its receptors in discrete brain regions. 3,4,11,12 Despite this important role of brain Ang II in hypertension, the site (or sites) within the brain at which Ang II acts in this regard is not fully worked out. Certainly, Ang II can act within the hypothalamus to influence cardiovascular regulation. 13 However, Ang II can also act in the caudal brain stem to increase AP and sympathetic outflow. 14 One region in the caudal brain stem that probably mediates some of the central cardiovascular effects of Ang II is the rostral ventrolateral medulla (RVLM). 15,16 The RVLM appears to be the brain site responsible for the maintenance of basal sympathetic vasomotor activity, and inhibition of RVLM neurons reduces AP to the same extent as total inhibition of sympathetic vasomotor activity. Conversely, stimulation of neurons in the RVLM increases AP. There is evidence that increased activity of the RVLM supports the elevated AP in SHR. [17][18][19] The RVLM also has a high density of angiotensin AT 1 receptors. 20 Furthermore, microinjection of Ang II into the RVLM increases AP and sympathetic nerve activity, [21][22][23][24] and stimulation of A...

Abstract-Injection of the excitatory amino acid (EAA) antagonist kynurenic acid (KYN) into the rostral ventrolateral medulla (RVLM) of anesthetized rats has no effect on arterial pressure. However, we recently reported that after inhibition of the caudal ventrolateral medulla, injection of KYN into the RVLM decreased arterial pressure to the same level as produced by complete inhibition of the RVLM. We have suggested that these results reflect tonically active EAA-mediated inputs to the RVLM producing both direct excitation of RVLM vasomotor neurons and indirect inhibition of these neurons. On the basis of this model, we hypothesize that the balance between these EAA-driven direct excitatory and indirect inhibitory influences on the RVLM may be altered in models of experimental hypertension. To begin to test this hypothesis, the effects of injecting KYN into the RVLM of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared. In chloralose-anesthetized WKY, bilateral injection of KYN into the RVLM did not alter arterial pressure, whereas similar injections in SHR reduced mean arterial pressure by Ϸ40 mm Hg. After inhibition of the caudal ventrolateral medulla, which similarly increased arterial pressure in both strains, injection of KYN into the RVLM reduced mean arterial pressure to the same level as produced by autonomic blockade. These results suggest that the balance of excitatory and inhibitory influences on RVLM vasomotor neurons driven by tonically active EAA-mediated inputs to the RVLM is disrupted in SHR and may contribute to the hypertension in SHR. Key Words: brain Ⅲ hypertension, experimental Ⅲ glutamate Ⅲ neurotransmitter Ⅲ amino acid Ⅲ rats, inbred SHR T he rostral ventrolateral medulla (RVLM) is critical to the tonic and reflexive regulation of arterial blood pressure (AP). Ongoing activity of RVLM-spinal neurons is responsible for the generation of baseline sympathetic vasomotor tone, and acute inhibition of this region causes a marked decrease in AP, similar to that seen in response to cervical spinal cord transection or inhibition of the autonomic nervous system. 1,2 Previous studies demonstrated that local injection into the RVLM of excitatory amino acid (EAA) receptor antagonists has no effect on resting AP, 3-5 and this has been interpreted as indicating that RVLM neuronal activity at rest is not produced by EAA-mediated inputs to the RVLM. However, we have recently reported that although injection of kynurenic acid (KYN) into the RVLM of anesthetized rats had no effect on baseline AP, after inhibition of the caudal ventrolateral medulla (CVLM), a region that tonically inhibits the RVLM, injection of KYN into the RVLM reduced AP to the same extent as total autonomic blockade. 6 On the basis of these results, it was proposed that tonically active EAAmediated inputs to the RVLM excite RVLM vasomotor neurons and also indirectly inhibit these neurons through excitation of an inhibitory input from the CVLM. 6 Thus, we suggested that blockade of EAA receptors in the RVLM re...

Abstract-The present study addresses the hypothesis that angiotensin type 1 receptors (AT 1 Rs) in the rostral ventrolateral medulla (RVLM) contribute to the elevation of mean arterial pressure (MAP) in Dahl salt-sensitive (DS) rats fed a diet with a high NaCl content. Groups of DS or Dahl salt-resistant (DR) rats were fed diets containing either 0.3% NaCl (LNa) or 8% NaCl (HNa) for 3 weeks. Rats were anesthetized with ␣-chloralose, and the effects of microinjecting the AT 1 R antagonist valsartan (Val) or angiotensin II (Ang II) into the RVLM on MAP were measured. Bilateral injection of 100 pmol Val into the RVLM reduced the elevated MAP in the DS-HNa rats by Ϸ35 mm Hg. In contrast, Val had no effect on MAP in DS-LNa rats. DR rats were normotensive on either diet; Val injection into the RVLM had no significant effect on MAP in DR-HNa rats but did evoke a small decrease in MAP in DR-LNa rats. Injection of Ang II into the RVLM increased arterial pressure in all groups, but the response was substantially larger in DS-HNa rats.Inhibition of neuronal function in the vicinity of the hypothalamic paraventricular nucleus, a possible source of innervation of the RVLM AT 1 R, by local injection with muscimol also produced a substantial decrease in MAP in DS-HNa rats but not in DS-LNa rats or DR rats. Thus, RVLM AT 1 Rs appear to contribute to salt-dependent hypertension in DS rats, and the paraventricular nucleus may be a source of this tonic activation. Key Words: brain Ⅲ hypertension, essential Ⅲ hypothalamus Ⅲ angiotensin Ⅲ angiotensin antagonist A ngiotensin acting within the brain has repeatedly been implicated in the pathogenesis of hypertension. In many forms of experimental hypertension, interference with components of the renin-angiotensin system in the brain decreases arterial pressure (AP). For example, in spontaneously hypertensive rats (SHR), intracerebroventricular injection of antagonists of either angiotensin-converting enzyme or angiotensin type 1 receptors (AT 1 Rs) decreases AP. [1][2][3] Furthermore, central injection with AT 1 R or angiotensinogen antisense oligonucleotides also decreases AP in SHR but not in control normotensive rats. 4,5 These observations are not unique to the SHR model of hypertension, because similar findings of decreased AP after blockade of brain AT 1 Rs have been reported for numerous models of hypertension, 6 -8 including the Dahl-salt sensitive (DS) rat. 9 -12 The DS model is particularly interesting in this regard because salt-dependent hypertension can be studied in comparison with normotensive rats with a similar genetic make-up. 13 The site (or sites) at which angiotensin acts to maintain increased AP in hypertensive rats is not presently known. However, increasing evidence has focused attention on the rostral ventrolateral medulla (RVLM), a brain stem region essential for the maintenance of sympathetic vasomotor tone and the mediation of many neurally mediated cardiovascular reflexes. 14,15 Among areas of the brain thought to be involved in the control of AP, the RVLM...

Abstract-The goal of the present study was to test the hypothesis that the balance of tonic excitation and inhibition of vasomotor neurons in the rostral ventrolateral medulla (RVLM) driven by excitatory amino acid (EAA)-mediated inputs to the RVLM is shifted toward excitation in Dahl salt-sensitive (DS) rats compared with Dahl salt-resistant (DR) rats. Glutamate and the EAA antagonist kynurenic acid were microinjected into the RVLM of chloralose-anesthetized DS and DR rats maintained on diets containing either 0.3% NaCl or 8.0% NaCl. DS rats had a higher arterial pressure than DR rats, and this difference was greatly exaggerated by high dietary salt intake. Bilateral injection of kynurenic acid (2.7 nmol) into the RVLM decreased mean arterial pressure by 16Ϯ2 mm Hg in DS rats fed a diet containing 0.3% NaCl, and this effect was significantly larger in DS rats fed the high-salt diet (40Ϯ2 mm Hg). In contrast, injections of kynurenic acid into the RVLM did not significantly decrease arterial pressure in DR rats fed either diet. In DR rats, the pressor response elicited by the injection of glutamate into the RVLM was potentiated in rats fed the high-salt diet. The glutamate-evoked pressor response was greater in DS rats compared with DR rats, and the response in DS rats was not influenced by the salt content of the diet. These data suggest that tonically active EAA inputs to the RVLM may contribute to salt-sensitive hypertension in the Dahl model. Despite the importance of the tonic activity of RVLM neurons to the maintenance of baseline AP, the mechanisms maintaining the activity of RVLM vasomotor neurons are incompletely understood. Injections of excitatory amino acid (EAA) receptor antagonists into the RVLM fail to alter baseline AP, 2-4 suggesting that inputs to the RVLM using EAA neurotransmitters are not involved in generating the tonic activity of RVLM vasomotor neurons. However, on the basis of our observation that after the removal of inhibitory inputs to the RVLM, injection of the EAA receptor antagonist kynurenic acid (KYN) into the RVLM greatly reduces AP, 4 we suggested that tonically active EAA inputs to the RVLM do contribute to the activity of RVLM vasomotor neurons, although this excitatory influence is normally balanced by EAA-mediated inputs that drive an inhibitory influence on RVLM vasomotor neurons.On the basis of our model of tonically active EAAmediated excitatory and inhibitory influences on RVLM vasomotor neurons, we proposed that shifts in the balance of these excitatory and inhibitory influences would affect baseline AP and that a shift toward excitation could result in increased activity of RVLM neurons and a sustained increase in AP. In support of this notion, we recently reported that injecting KYN into the RVLM of spontaneously hypertensive rats restores AP to normotensive levels. 5 Similarly, KYN injected into the RVLM reportedly decreases AP in renal hypertensive rats. 6 Thus, hypertension in these animal models may result from an imbalance of the EAA-driven excitatory and inhibit...