Chronic infusion of angiotensin receptor antagonists in the hypothalamic paraventricular nucleus prevents hypertension in a rat model of sleep apnea

Abstract

Sleep apnea is characterized by increased sympathetic activity and is associated with systemic hypertension. Angiotensin (Ang) peptides have previously been shown to participate in the regulation of sympathetic tone and arterial pressure in the hypothalamic paraventricular nucleus (PVN) neurons. We investigated the role of endogenous Ang peptides within the PVN to control blood pressure in a rat model of sleep apnea-induced hypertension. Male Sprague–Dawley rats (250 g), instrumented with bilateral guide cannulae targeting the PVN, received chronic infusion of Ang antagonists (A-779, Ang-(1–7) antagonist; losartan and ZD7155, AT₁ antagonists; PD123319, AT₂ receptor antagonist, or saline vehicle). A separate group received an infusion of the GABA_A receptor agonist (muscimol) to inhibit PVN neuronal activity independent of angiotensin receptors. After cannula placement, rats were exposed during their sleep period to eucapnic intermittent hypoxia (IH; nadir 5% O₂; 5% CO₂ to peak 21% O₂; 0% CO₂) 20 cycles/h, 7 h/day, for 14 days while mean arterial pressure (MAP) was measured by telemetry. In rats receiving saline, IH exposure significantly increased MAP (+ 12 ± 2 mm Hg vs. Sham −2 ± 1 mm Hg P < 0.01). Inhibition of PVN neurons with muscimol reversed the increase in MAP in IH rats (MUS: −9 ± 4 mm Hg vs. vehicle + 12 ± 2 mm Hg; P < 0.01). Infusion of any of the Ang antagonists also prevented the rise in MAP induced by IH (A-779: −5 ± 1 mm Hg, losartan: -9 ± 4 mm Hg, ZD7155: -11 ± 4 mm Hg and PD123319: -4 ± 3 mm Hg; P < 0.01). Our results suggest that endogenous Ang peptides acting in the PVN contribute to IH-induced increases in MAP observed in this rat model of sleep apnea-induced hypertension.

Introduction

Chronic intermittent hypoxia (CIH), a characteristic of human sleep apnea, leads to sustained elevation of sympathetic nerve activity (SNA) and mean arterial pressure (AP). Although the mechanisms by which CIH augments AP are incompletely understood, activation of the sympathetic nervous system seems to be essential for the maintenance of hypertension (Sica et al., 2000, Fletcher, 2003, Prabhakar et al., 2005). Indeed, several methods of sympathetic blockade, including carotid body denervation, renal sympathectomy, adrenal demedullation and sympathetic nerve ablation prevent the rise in AP due to CIH exposure (Fletcher et al., 1999, Fletcher et al., 1992a).

The hypothalamic paraventricular nucleus (PVN) is an important site regulating arterial pressure and sympathetic activity (Dampney, 1994, Tagawa and Dampney, 1999;). Inhibition of PVN neurons with nitric oxide donor (Allen, 2002, Horn et al., 1994, Stern et al., 2003) or γ-aminobutyric acid (GABA) receptor agonist (Kannan et al., 1989, Allen, 2002, Silva et al., 2005), reduces renal SNA and systemic AP. Conversely, activation of PVN neurons by microinjection of an excitatory amino acid (Kannan et al., 1989) or GABA_A receptor antagonist, increases arterial pressure and sympathetic activity in anesthetized (Chen et al., 2003, Chen and Toney, 2003) and conscious (Kannan et al., 1989) rats. Several studies have suggested that augmented discharge of PVN neurons may be involved in the sustained sympathoexcitation in pathological conditions including congestive heart failure (Zucker et al., 2004), myocardial infarction (Zhang et al., 2001, Zhang et al., 2002), salt-sensitive hypertension (Weiss et al., 2007), and genetic hypertension (Allen, 2002).

Angiotensin (Ang) peptides act as important neuromodulators in brain sites controlling sympathetic output and arterial pressure (Dampney et al., 2002, Veerasingham and Raizada, 2003). Specifically in the PVN, iontophoretic application of Ang II and Ang-(1–7), two peptides produced by the renin–angiotensin system (RAS) cascade, increase the firing rate of neurons by acting on specific receptors (Ambuhl et al., 1994, Cato and Toney, 2005). We have previously reported that both Ang II and Ang-(1–7) contribute to the maintenance of renal SNA and that microinjections of these peptides into the PVN increase sympathetic tone (Silva et al., 2005). In this study we investigated the contribution of Ang II and Ang-(1–7) receptors in the PVN to hypertension developed during 14 days of IH exposure.