Early life stress sensitizes the renal and systemic sympathetic system in rats

Abstract

We hypothesized that maternal separation (MS), an early life stress model, induces a sensitization of the sympathetic system. To test this hypothesis, we evaluated the renal and systemic sympathetic system in 12- to 14-wk-old male control or MS rats with the following parameters: 1) effect of renal denervation on conscious renal filtration capacity, 2) norepinephrine (NE) content in key organs involved in blood pressure control, and 3) acute systemic pressor responses to adrenergic stimulation or ganglion blockade. MS was performed by separating pups from their mothers for 3 h/day from day 2 to 14; controls were nonhandled littermates. Glomerular filtration rate (GFR) was examined in renal denervated (DnX; within 2 wk) or sham rats using I¹²⁵-iothalamate plasma clearance. MS-DnX rats showed significantly increased GFR compared with MS-SHAM rats (3.8 ± 0.4 vs. 2.4 ± 0.2 ml/min, respectively, P < 0.05), whereas DnX had no effect in controls, indicating that renal nerves regulate GFR in MS rats. NE content was significantly increased in organ tissues from MS rats (P < 0.05, n = 6-8), suggesting a sensitization of the renal and systemic sympathetic system. Conscious MS rats displayed a significantly greater increase in mean arterial pressure (MAP) in response to NE (2 μg/kg ip) and a greater reduction in MAP in response to mecamylamine (2 mg/kg ip, P < 0.05, n = 4) monitored by telemetry, indicating that MS rats exhibit exaggerated responses to sympathetic stimulation. In conclusion, these data indicate that MS sensitizes the renal and systemic sympathetic system ultimately impairing blood pressure regulation.

Keywords: denervation; early life stress; glomerular filtration rate; maternal separation.

Fig. 1.

Chronic measurements in conscious rats. A: mean arterial pressure (MAP) was similar in control-SHAM and maternal separation (MS)-SHAM rats. Renal denervation (DnX) reduced MAP in control and MS rats. B: glomerular filtration rate (GFR) was significantly reduced in MS-SHAM rats. Denervation restored GFR in MS rats. *P < 0.05 vs. control. #P < 0.05 vs. SHAM, n = 4–5.

Fig. 2.

Norepinephrine (NE) content in large vessels and kidney tissue. A: levels of NE in renal cortex, inner medulla, and outer medulla were increased in MS rats, n = 6. B: levels of NE in several organs, n = 6–8. C: levels of NE in vascular tissue; T=thoracic, A=abdominal, n = 4–6. *P < 0.05.

Fig. 3.

Acute bolus of a nonselective adrenergic agonist (NE, 2 mg/kg ip) in telemetry-implanted rats. A: MAP showed a greater MAP in MS rats. B: heart rate (HR) was similar in MS and control rats. C: no significant changes in MAP were observed in response to a saline injection. *P < 0.05, n = 3.

Fig. 4.

Acute bolus of a ganglion blockade (2 mg/kg ip) induced a greater drop in MAP in MS telemetry-implanted rats compared with control rats. *P < 0.05, n = 4.