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Alteration of NMDA NR₁ Receptors Within the Paraventricular Nucleus of Hypothalamus in Rats With Heart Failure

From the Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Neb.

Correspondence to Kaushik P. Patel, PhD, Department of Physiology and Biophysics, University of Nebraska Medical Center, 984575 Nebraska Medical Center, Omaha, NE 68198-4575. E-mail kpatel{at}unmc.edu

One of the pathophysiological characteristics of chronic heart failure (HF) is elevated sympathetic drive, which is a major factor contributing to the morbidity and mortality of HF. Resent evidence points to a central mechanism that contributes to the sympathetic abnormality in HF. The paraventricular nucleus (PVN) of the hypothalamus is an important site that integrates sympathetic nerve activity. Studies have shown that glutamate elicits excitatory effects on neurons in the PVN through the NMDA receptor. The goal of the present study was to examine the role of NMDA receptors in the altered sympathetic nerve activation during HF. The left coronary ligation-induced heart failure model in the rat was used. In -chloralose and urethane anesthetized rats, microinjection of NMDA into the PVN (50 to 200 pmol) produced dose-dependent increases in renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR). This response to NMDA was significantly potentiated (27±7%) in HF compared with sham rats. On the other hand, microinjection of the NMDA receptor antagonist AP-5 (4 to 16 nmol) into the PVN caused significant decreases in RSND, BP, and HR only in rats with HF but very slight changes in sham rats. Furthermore, using microdialysis and HPLC in combination with electrochemical detection techniques, we found that the glutamate level in the PVN was not increased significantly in HF compared with sham rats. However, using RT-PCR, Western blot, and immunofluorescence techniques, it was found that NMDA NR₁ subunit mRNA expression and protein level in the PVN were significantly increased in HF compared with sham rats. These data suggest that the increased glutamatergic activity on sympathetic regulation, due to the upregulation of NMDA NR₁ receptor subunits within the PVN may contribute to the elevated sympathoexcitation during HF.

Key Words: heart failure • sympathetic nerve activity • NMDA receptor • paraventricular nucleus

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