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

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 GABAA 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.

Research highlights
► Blocking AT1, AT2 or mas receptors in the PVN prevents IH-induced hypertension.
► Blocking AT1 but not mas receptors in the PVN lowered blood pressure in Sham rats.
► Mas receptors only appear to regulate blood pressure in pathological conditions.
► Angiotensin receptors in the PVN are necessary for IH to increase arterial pressure.