(In)activity-dependent alterations in resting and reflex control of splanchnic sympathetic nerve activity

Abstract

The negative effects of sympathetic overactivity on long-term cardiovascular health are becoming increasingly clear. Moreover, recent work done in animal models of cardiovascular disease suggests that sympathetic tone to the splanchnic vasculature may play an important role in the development and maintenance of these disease states. Work from our laboratory and others led us to hypothesize that a lack of chronic physical activity increases resting and reflex-mediated splanchnic sympathetic nerve activity, possibly through changes occurring in a key brain stem center involved in sympathetic regulation, the rostral ventrolateral medulla (RVLM). To address this hypothesis, we recorded mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (SSNA) in a group of active and sedentary animals that had been housed for 10-13 wk with or without running wheels, respectively. In experiments performed under Inactin anesthesia, we tested responses to RVLM microinjections of glutamate, responses to baroreceptor unloading, and vascular reactivity, the latter of which was performed under conditions of autonomic blockade. Sedentary animals exhibited enhanced resting SSNA and MAP, augmented increases in SSNA to RVLM activation and baroreceptor unloading, and enhanced vascular reactivity to α(1)-receptor mediated vasoconstriction. Our results suggest that a sedentary lifestyle increases the risk of cardiovascular disease by augmenting resting and reflex-mediated sympathetic output to the splanchnic circulation and also by increasing vascular sensitivity to adrenergic stimulation. We speculate that regular physical exercise offsets or reverses the progression of these disease processes via similar or disparate mechanisms and warrant further examination into physical (in)activity-induced sympathetic nervous system plasticity.

Fig. 1.

Mean arterial pressure (MAP) and splanchnic sympathetic nerve recordings. A and B show representative examples of a 3-s window of splanchnic sympathetic nerve activity (SSNA) recorded in 1 active (A) and 1 sedentary rat (B). A raw arterial pressure (AP) tracing is shown at top with raw SSNA recording in the middle. Integrated SSNA calculated from raw activity is shown at the bottom. Post mortem noise has not been subtracted from resting SSNA in this figure. V, volts; V·s, units of rectified, integrated, and amplified SSNA.

Fig. 2.

Representative examples of glutamate microinjections (arrows, 10 mM, 30 nl) into the rostral ventrolateral medulla (RVLM) of the active (A) and sedentary (B) rat from Fig. 1. Microinjections of glutamate produced pressor and sympathoexcitatory responses in both animals. Post mortem noise has not been subtracted from resting SSNA in this figure. Abbreviations as defined in Fig. 1 legend.

Fig. 3.

Average data for pressor and sympathoexcitatory response to glutamate (1–100 mM, 30 nl, or 3–3,000 pmol) microinjected into the RVLM of sedentary (n = 14, ●, dashed line) and active (n = 13, ○, solid line) animals. There was a significant difference at 100 mM glutamate (*P < 0.05), and a trend for an enhanced response was seen at 10 mM (P = 0.064). Two-way repeated-measures ANOVA showed a significant interaction between and physical activity level and different doses of glutamate. Post hoc tests showed a significant effect of concentration for sedentary group only (#P < 0.05). There was a significant enhancement in the blood pressure response for active and sedentary groups ($P < 0.05).

Fig. 4.

Average data for SSNA responses to activation of the baroreflex produced by decreases in arterial pressure. Seven doses of sodium nitroprusside were injected intravenously in order of increasing dose and the blood pressure decrease was averaged within groups at each individual dose (SNP, 0.5–13 μg/kg iv). SSNA activation was greater in sedentary (n = 9, ●, dashed line) compared with active (n = 9, ○, solid line) animals. Average reductions in blood pressure at each dose were similar in magnitude between groups by 2-way repeated-measures ANOVA. There was an overall effect of physical activity level on SSNA responses to various levels of MAP, and there was an interaction between physical activity level and decreases in MAP. *P < 0.05 for individual points.

Fig. 5.

Average data for MAP responses to phenylephrine (PE; 0.5–13 μg/kg iv) following ganglionic blockade with hexamethonium (30 mg/kg iv) and methyl-atropine (1 mg/kg). Activation of α₁-adrenergic receptors with PE produced dose-dependent increases in MAP in both groups but the response was significantly enhanced in sedentary (n = 6, ●, dashed line) vs. active (n = 9, ○, solid line) animals. Two-way repeated-measures ANOVA showed an overall effect of physical activity level and an interaction between physical activity level and doses of PE (P < 0.05 both); *P < 0.05 specific difference between MAP responses at individual doses.

Fig. 6.

Representation of microinjection sites modified from a rat brain atlas (57). Injection sites were marked at the end of every experiment with a 30 nl of 2% Chicago Sky blue dye. ●, Injection sites from sedentary animals (n = 12); ○, injection sites from active animals (n = 13). All injection sites fell within 240 μm of the caudal pole of the facial nucleus. (SP5, spinal trigeminal tract; NA, nucleus ambiguus; FN, facial nucleus; Py, pyramidal tract; RVL, rostral ventrolateral medulla).