Paraventricular Nucleus Of Spontaneously Hypertensive Rats Research Articles

Macrophage migration inhibitory factor in hypothalamic paraventricular nucleus neurons decreases blood pressure in spontaneously hypertensive rats

Macrophage migration inhibitory factor (MIF) expression is increased by angiotensin II (Ang II) within paraventricular nucleus (PVN) neurons of normotensive rats and acts via its intrinsic thiol protein oxidoreductase (TPOR) to counterregulate the central nervous system-mediated pressor action of Ang II. Considering that the PVN-mediated actions of Ang II are enhanced in spontaneously hypertensive rats (SHRs) and contribute to the development of hypertension in these animals, we investigated this MIF regulatory mechanism in SHRs. Here, we have demonstrated that Ang II failed to increase MIF protein expression in the PVN of SHRs. Furthermore, although basal levels of MIF protein and mRNA were similar in the PVN of SHRs and normotensive rats, immunostaining revealed that MIF was either absent from or diminished in PVN neurons of SHRs. AAV2-mediated increases in MIF expression within PVN neurons of young (8 wk old) SHRs produced a chronic attenuation of hypertension and cardiac hypertrophy. However, similar AAV2-mediated transduction of [C60S]-MIF, which lacks TPOR activity, did not alter the development of hypertension or cardiac hypertrophy in SHRs. Collectively, these findings suggest that a lack of MIF expression within PVN neurons contributes to the development of hypertension and cardiac hypertrophy in SHRs.

Glutamatergic Inputs in the Hypothalamic Paraventricular Nucleus Maintain Sympathetic Vasomotor Tone in Hypertension

The paraventricular nucleus (PVN) of the hypothalamus is critical to the regulation of sympathetic output. The PVN hyperactivity is known to cause increased sympathetic nerve activity in spontaneously hypertensive rats (SHRs). The purpose of this study was to determine whether glutamatergic input to the PVN contributes to heightened sympathetic outflow in hypertension. Lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate were recorded from anesthetized SHRs and Wistar-Kyoto (WKY) rats. Bilateral microinjection of an N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonopentanoic acid, or a non-N-methyl-D-aspartate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, into the PVN dose-dependently decreased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in SHRs but not in WKY rats. Bilateral microinjection of kynurenic acid into the PVN also significantly decreased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in SHRs but not in WKY rats. Furthermore, microinjection of gabazine, a specific GABA(A) receptor antagonist, into the PVN increased lumbar sympathetic nerve activity, mean arterial blood pressure, and heart rate in both SHRs and WKY rats. Notably, this response was significantly attenuated in SHRs compared with that in WKY rats. In addition, kynurenic acid abolished the sympathoexcitatory and pressor responses to microinjection of gabazine into the PVN in both SHRs and WKY rats. Thus, this study provides new functional evidence that resting sympathetic vasomotor tone is maintained by tonic glutamatergic input in the PVN in SHRs. Removal of GABAergic inhibition results in augmented glutamatergic input in the PVN, which probably constitutes an important source of excitatory drive to the brain stem vasomotor neurons in hypertension.

Role of γ-Aminobutyric Acid (GABA)Aand GABABReceptors in Paraventricular Nucleus in Control of Sympathetic Vasomotor Tone in Hypertension

The paraventricular nucleus (PVN) of the hypothalamus is involved in tonic regulation of sympathetic outflow. Impaired GABAergic control of PVN neurons may contribute to the elevated sympathetic drive in hypertension. In this study, we examined the function of GABA(A) and GABA(B) receptors in the PVN in control of sympathetic nerve activity and arterial blood pressure (ABP) in normotensive and hypertensive rats. Lumbar sympathetic activity (LSNA) and ABP were recorded from anesthetized spontaneously hypertensive rats (SHRs), Sprague-Dawley (SD) rats, and Wistar-Kyoto (WKY) rats. Bilateral microinjection of bicuculline (0.01-0.15 nmol), a GABA(A) receptor antagonist, into the PVN increased LSNA and ABP in normotensive WKY and SD rats in a dose-dependent manner. This response was significantly attenuated in SHRs. Furthermore, the decrease in LSNA and ABP induced by a GABA(A) receptor agonist, muscimol (0.05-1.5 nmol), in the PVN was significantly less in SHRs than in normotensive controls. In contrast, microinjection of the GABA(B) receptor agonist baclofen (0.3-4.5 nmol) into the PVN decreased LSNA and ABP in SHRs. However, in WKY and SD rats, baclofen only decreased LSNA and ABP at the highest dose tested. In addition, blockade of GABA(B) receptors in the PVN with CGP52432 (3-[[(3,4-dichlorophenyl)methyl]amino]propyl]diethoxymethyl)phosphinic acid) (0.15-3.0 nmol) dose-dependently increased LSNA and ABP in SHRs but not in normotensive controls. Collectively, this study provides new evidence that GABA(A) receptor function is attenuated, whereas the function of GABA(B) receptors is enhanced, in the PVN of SHRs.

Hypertensive rats exhibit heightened expression of corticotropin-releasing factor in activated central neurons in response to restraint stress

To test the hypothesis that chronically elevated sympathetic drive is associated with hyperreactiveness of autonomic centers in the brain to stress, adult spontaneously hypertensive rats (SHRs) and two strains of normotensive rats (Wistar Kyoto [WKY] and Sprague Dawley [SD] rats) were acutely exposed to restraint stress; controls from each strain were not stressed. Brain sections were prepared for Fos immunohistochemistry to identify activated neurons in the paraventricular nucleus of the hypothalamus, Barrington's nucleus of the pons, nucleus of the tractus solitarius, and ventrolateral medulla, or for combined Fos immunohistochemistry and corticotropin-releasing factor (CRF) in situ hybridization in the paraventricular nucleus and Barrington's nucleus. Restraint led to increased activation of neurons in all nuclei. Strain differences were found only in the caudal and rostral paraventricular nucleus where restraint resulted in greater numbers of activated neurons in SHRs compared to either normotensive strain. Levels of CRF mRNA in Barrington's nucleus of unrestrained rats were similar among strains. After restraint, mRNA levels and double labeled neurons were increased in Barrington's nucleus of SHRs. In unstressed rats, CRF mRNA levels were elevated in some regions of the paraventricular nucleus in SHRs. After restraint, mRNA levels increased throughout the paraventricular nucleus of SHRs. Significantly greater numbers of double labeled neurons were found in the dorsolateral medial and ventral medial parvocellular paraventricular nucleus of stressed SHRs compared to WKY or SD rats. These data show that chronic elevation in sympathetic activity, present in SHRs, is associated with hyperreactiveness of the paraventricular and Barrington's nucleus including recruitment of neurons to express CRF, and may have important implications for the response of the hypothalamo–pituitary–adrenal axis during stress.

Increased brain transcription factor expression by angiotensin in genetic hypertension.

A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR). in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II-induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II-induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II-induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.

Complex activation of inducible transcription factors in the brain of normotensive and spontaneously hypertensive rats following central angiotensin II administration

The effects of intracerebroventricular (i.c.v.) injections of angiotensin II (Ang II) on the expression of inducible transcription factors (ITF) (c-Fos, FosB, c-Jun, JunB, JunD, Krox-20 and Krox-24) in the brain of conscious rats were assessed immunohistochemically using polyclonal antisera. Ang II (1, 10, 100 ng) induced after 90 min a dose-dependent expression of c-Fos, FosB, c-Jun, JunB and Krox-24, which was confined to four specific brain areas, namely the subfornical organ (SFO), median preoptic area (MnPO), paraventricular nucleus (PVN) and supraoptic nucleus (SON). In the above-mentioned regions, JunD exhibited a high basal staining which was not visibly altered by Ang II. Krox 20 was not induced by AnG II. FosB was only induced 4 h after i.c.v. injection of 100 ng Ang II in the MnPO and PVN. The Ang II-AT 1 receptor antagonist, losartan, applied i.c.v. 5 min prior to Ang II (100 ng, i.c.v.) prevented the Ang II-induced ITF expression. In spontaneously hypertensive rats (SHR) but not in Wistar rats with nephrogenic hypertension due to aortic banding (WIab), the Ang II-induced expression of c-Fos, and c-Jun was enhanced in all four areas when compared to normotensive Wistar Kyoto (WKY)- and Wistar (WI) rats. The Ang II-induced expression of Krox-24 in the SFO, MnPO and PVN in SHR was also significantly increased when compared to WKY, WI and WIab rats. Our data demonstrate that a stimulation of periventricular Ang II-AT 1 receptors induces a temporally and spatially highly differentiated expression pattern of ITFs restricted to four distinct regions of the forebrain involved in blood pressure regulation and body fluid homeostasis. This points to a strictly regulated expression of target genes in the respective regions. The enhanced Ang II-induced expression of ITFs in SHR compared to normotensive controls is not due to elevated blood pressure itself, since it was not observed in secondary hypertensive rats WIab. Thus, the increased sensitivity to Ang II in SHR appears to be genetically determined. The target genes regulated by Ang II-induced ITFs will have to be identified.