Central losartan attenuates increases in arterial pressure and expression of FosB/ΔFosB along the autonomic axis associated with chronic intermittent hypoxia

Abstract

Chronic intermittent hypoxia (CIH) increases mean arterial pressure (MAP) and FosB/ΔFosB staining in central autonomic nuclei. To test the role of the brain renin-angiotensin system (RAS) in CIH hypertension, rats were implanted with intracerebroventricular (icv) cannulae delivering losartan (1 μg/h) or vehicle (VEH) via miniosmotic pumps and telemetry devices for arterial pressure recording. A third group was given the same dose of losartan subcutaneously (sc). Two groups of losartan-treated rats served as normoxic controls. Rats were exposed to CIH or normoxia for 7 days and then euthanized for immunohistochemistry. Intracerebroventricular losartan attenuated CIH-induced increases in arterial pressure during CIH exposure (0800-1600 during the light phase) on days 1, 6, and 7 and each day during the normoxic dark phase. FosB/ΔFosB staining in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), paraventricular nucleus of the hypothalamus (PVN), the rostral ventrolateral medulla (RVLM), and the nucleus of the solitary tract (NTS) was decreased in icv losartan-treated rats. Subcutaneous losartan also reduced CIH hypertension during the last 2 days of CIH and produced bradycardia prior to the effect on blood pressure. Following sc losartan, FosB/ΔFosB staining was reduced only in the OVLT, MnPO, PVN, and NTS. These data indicate that the central and peripheral RAS contribute to CIH-induced hypertension and transcriptional activation of autonomic nuclei and that the contribution of the central RAS is greater during the normoxic dark phase of CIH hypertension.

Keywords: angiotensin; blood pressure; hypertension; sleep apnea.

Fig. 1.

Effects of 7-day (D) chronic intermittent hypoxia (CIH) on changes in mean arterial pressure (MAP) and heart rate (HR) during the light phase from 0800 to 1600 during CIH (A and B) and during the during the normoxic dark phase (C and D) in rats treated with intracerebroventricular (icv) vehicle (VEH & CIH; n = 12), icv losartan (icv LOS & CIH; n = 14), subcutaneous losartan (sc LOS & CIH; n = 11), or normoxia and icv LOS (icv LOS & Norm; n = 6) and normoxia and sc LOS (sc LOS & Norm; n = 6). For A–C: *VEH & CIH and sc LOS &+ CIH, significantly different from all other groups (Student-Newman-Keuls, P < 0.05); #P < 0.05, CIH groups significantly different from normoxia groups; +VEH & CIH significantly different from all other groups; ^icv LOS & CIH, significantly different from sc LOS CIH and normoxic groups. For D, +SC LOS & CIH, significantly different from all other groups. PRE, pre-CIH.

Fig. 2.

Mean no. of FosB/ΔFosB-positive cells following 7-day CIH in the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO) and the dorsal parvocellular (dp), medial parvocellular (mp), lateral magnocellular (lm), and lateral parvocellular (lp) of the paraventricular nucleus for VEH & CIH-, icv LOS & CIH-, and sc LOS & CIH-, icv LOS & Norm-, and sc LOS & Norm-treated rats. *P < 0.05 from all other groups; +P < 0.05 from icv LOS + CIH and the 2 normoxic groups (n = 6–11).

Fig. 3.

Representative digital images of FosB/ΔFosB staining in the OVLT (left) and the MnPO (right) in rats treated with VEH & CIH (A), LOS icv & CIH (B), and LOS sc & CIH (C), icv LOS & Norm (D), and sc LOS & Norm (E). Each image was adjusted for uniform brightness and contrast. Scale bar, 100 μm.

Fig. 4.

Representative digital images of FosB/ΔFosB staining in the medial paraventricular nucleus in rats treated with VEH & CIH (A), LOS icv & CIH (B), and LOS sc & CIH (C), icv LOS & normoxia (D), and sc LOS and Norm (E). Each image was adjusted for uniform brightness and contrast. Scale bar, 100 μm.

Fig. 5.

Mean no. of FosB/ΔFosB-positive cells in rostral ventrolateral medulla (RVLM) and the commissural (cNTS), subpostremal (spNTS), and rostral (rNTS) regions of the nucleus of the solitary tract in VEH & CIH-, icv LOS & CIH-, sc LOS & CIH-, icv LOS & Norm-, and sc LOS & Norm-treated rats. *P < 0.05 compared with all other groups; +P < 0.05 from other groups but not from groups with the same symbol (n = 6–11).

Fig. 6.

Representative digital images of FosB/ΔFosB staining in the cNTS (left) and RLVM (right) of rats exposed to VEH & CIH (A), LOS icv & CIH (B), and LOS sc & CIH (C), icv LOS & Norm (D), and sc LOS & Norm (E). Each image was adjusted for uniform brightness and contrast. Scale bar, 100 μm.