Hypothalamic paraventricular nucleus inhibition decreases renal sympathetic nerve activity in hypertensive and normotensive rats

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Abstract

Activity of the hypothalamic paraventricular nucleus (PVN) is essential for the maintenance of vasomotor sympathetic nerve discharge (SND) and blood pressure even in the anesthetized rat. Inactivation of the paraventricular nucleus results in a large depressor and sympathoinhibitory response. The current study was designed to examine the regulation of renal sympathetic nerve activity by the paraventricular nucleus in both hypertensive and normotensive rats. Experiments were performed in anesthetized, artificially ventilated spontaneously hypertensive (SH) and Wistar–Kyoto (WKY) rats. Renal sympathetic nerve activity, blood pressure and heart rate were recorded. Bilateral microinjections of the GABAA receptor agonist, muscimol (1 nmol in 100 nl), were made into the paraventricular nucleus. Decreases in blood pressure (SHR: from 111±3 to 54±4 mm Hg; WKY: 84±2 to 48±3 mm Hg), heart rate (SHR: 336±8 to 289±12 bpm; WKY 309±7 to 258±13 bpm) and renal sympathetic nerve activity (to 46±11% and 33±7% of control in the WKY and SHR, respectively) were observed. The renal nerve response to inactivation of the paraventricular nucleus was not different between the strains, indicating that modulation of renal sympathetic nerve activity by the paraventricular nucleus is similar in these rat strains. This is different from the previously reported effect of paraventricular nucleus inhibition on lumbar sympathetic nerve activity [Hypertension 39 (2002) 275]. Overall, we demonstrate that the paraventricular nucleus plays a critical role in the regulation of renal SND even under basal conditions in anesthetized animals.

Introduction

The hypothalamic paraventricular nucleus (PVN) plays an integral role in the modulation of cardiovascular function via influences on the sympathetic and parasympathetic nervous systems and on neuroendocrine regulation (Coote, 1995). In addition, many studies have demonstrated that the PVN may be involved in cardiovascular diseases. For example, ablation of the PVN attenuates the progression of increased blood pressure in spontaneously hypertensive (SH) rats (Takeda et al., 1991) and increased activity in the PVN is associated with the sympathoexcitation observed in congestive heart failure (Felder et al., 2003).

It has been demonstrated that activation of neurons in parvocellular regions of the PVN can lead to increases in blood pressure through stimulation of sympathetic nerve discharge (SND) Katafuchi et al., 1988, Martin et al., 1991. Interestingly, the SND response to activation of the PVN is not uniform and can show a pattern resembling the response to volume expansion. Accompanying the pressor response is activation of SND to the splanchnic, adrenal and cardiac targets but inhibition of SND to the kidney Katafuchi et al., 1988, Deering and Coote, 2000. However, stimulation of the PVN can also elicit increases in renal SND (Tagawa and Dampney, 1999). Such complex renal SND responses to stimulation of the PVN are not necessarily surprising, given the fact that multi-unit activity recorded in the renal nerves supplies many different cell types (DiBona, 2001).

In human hypertension increased renal SND, measured by regional noradrenaline spillover techniques, is a common observation independent of the type of hypertension studied Esler et al., 1991, Esler, 2002. This, and other supporting evidence, has led to the hypothesis that increased renal SND may actually play a role in the generation of some forms of hypertension Esler, 2002, DiBona, 2002. Thus, understanding the factors involved in the generation and regulation of renal SND is an essential part of understanding the causes of hypertension.

Recently, it has been demonstrated that the PVN plays a role in the maintenance of tonic SND in anesthetized animals Zhang and Patel, 1998, Allen, 2002. Microinjection of the GABAA receptor agonist, muscimol, bilaterally into the PVN results in decreases in both renal and lumbar SND and blood pressure. Moreover, we demonstrated that the decrease in lumbar SND was exaggerated in the SH rat compared to its normotensive control—the Wistar–Kyoto (WKY) rat (Allen, 2002). These observations were surprising given the commonly held view, derived from mid-brain transection studies, that supracollicular regions do not have a significant effect on tonic SND in anesthetized animals Alexander, 1946, Koshiya and Guyenet, 1994. Together, these observations support the proposal that the PVN plays an important role in the generation of sympathetic vasomotor tone and may also be involved in the aberrant regulation of SND that occurs in several types of hypertension.

Given this background, in which renal SND is proposed to play an important role in the generation of hypertension, the aim of the current experiments was to determine whether ongoing regulation of basal renal SND by the PVN is different between SH and WKY rats.

Section snippets

Materials and methods

All experimental procedures were approved by the Howard Florey Institute of Animal Experimentation Ethics Committee and performed in accordance with the Australian National Health and Medical Research “Code of Practice for the Care and Use of Animals for Scientific Purposes”. The rats, which were obtained from the Animal Resource Center (Canning Vale, W.A., Australia), were maintained on a 12-h light/dark cycle and were given ad libitum access to standard rat chow and water.

Age-matched male SH

Results

The data discussed in this manuscript were derived from nine SH and seven WKY rats in which the histological examination showed that the injection tract aimed toward the PVN in the correct rostro-caudal plane bilaterally. The basal mean arterial pressure of the anesthetized SH rats was 111±3 mm Hg whilst that of the anesthetized WKY rats was 84±2 mm Hg (p<0.001) (Fig. 1). There was also a significantly higher resting heart rate in the SH rats compared to the WKY rats (336±8 bpm versus 309±7

Discussion

This study demonstrates that bilateral inactivation of the PVN in anesthetized rats results in dramatic inhibition of renal SND and an accompanying decrease in blood pressure and heart rate. The response shown here is very similar to that previously reported by Patel et al. in the Sprague–Dawley rat (Zhang and Patel, 1998) and also similar to observations from this laboratory on the lumbar SND (Allen, 2002). There are two new observations of note.

Firstly, the decrease in renal SND with

Acknowledgments

The authors greatly appreciate the financial support of the Australian National Heart Foundation that enabled this work to be carried out.

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Current address: Department of Knowledge Engineering and Computer Sciences, Faculty of Engineering, Doshisha University, Kyoto, Japan.

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