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Heat stress provides a potent stimulus for the activation of visceral sympathetic nerve discharge (SND) in young but not aged rats. Central mechanisms mediating attenuated SND responses to heating in aged rats have not been investigated. Because the GABAergic system in the rostral ventral lateral medulla (RVLM) is tonically inhibitory to SND, it is plausible to hypothesize that the withdrawal of RVLM GABA tone as a strategy to activate renal SND to heating is not engaged to the same degree in aged compared with young rats. The effect of bilateral RVLM disinhibition produced by bicuculline (BIC, GABA(A) receptor antagonist, 100 pmol) microinjections on renal SND in anesthetized young (3-6 months old) and aged (22-24 months old) Fischer 344 rats was determined after core body temperature (Tc) had been increased to 41.5 °C. Renal SND at 41.5 °C was significantly increased from control levels in young but not aged rats, whereas RVLM BIC microinjections at 41.5 °C produced marked renal sympathoexcitation in both groups. RVLM BIC microinjections at 38 °C in young and aged rats increased renal SND to similar levels as produced by RVLM BIC microinjections at 41.5 °C. The enhanced heating-induced renal sympathoactivation in young compared with aged rats; coupled with marked RVLM BIC-induced SND excitation under hyperthermic and normothermic conditions in both young and aged rats, suggests age-dependent changes in the withdrawal of RVLM GABA tone as a strategy to activate renal SND in response to acute heating., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hyperthermia is a potent activator of visceral sympathetic nerve discharge (SND), and the functional integrity of the rostral ventral lateral medulla (RVLM) is critically important for sustaining sympathoexcitation at peak hyperthermia. However, RVLM mechanisms mediating SND activation to acute heat stress are not well understood. Because RVLM GABA is tonically inhibitory to sympathetic nerve outflow, it is plausible to hypothesize that disinhibition of RVLM sympathetic neural circuits, via withdrawal of GABAergic tone, may affect SND regulation at peak hyperthermia. The effect of RVLM bicuculline (BIC; GABAA receptor antagonist, 100-200 pmol) microinjections on the level of renal SND in anesthetized rats was determined after internal body temperature (Tc) had been increased to 41.5°C. Temperature-control experiments involved RVLM BIC (100-200 pmol) microinjections, with Tc maintained at 38°C. As expected, acute heating significantly increased renal SND from control levels. Bilateral RVLM BIC microinjections at 41.5°C produced immediate and significant increases in renal SND above heating-induced levels of activation. Bilateral RVLM BIC microinjections at 38°C increased renal SND to similar levels as produced by RVLM BIC microinjections after Tc had been increased to 41.5°C (heating + RVLM BIC). These results demonstrate that a considerable level of RVLM GABAergic inhibition is sustained at peak hyperthermia, an interesting physiological response profile based on the significance of SND activation to cardiovascular regulation during heat stress.

Sympathetic nerve discharge (SND) responses to hyperthermia are attenuated in aged rats without heart failure (HF) and in young HF (Y(HF)) rats, demonstrating that individually aging and HF alter SND regulation. However, the combined effects of aging and HF on SND regulation to heat stress are unknown, despite the high prevalence of HF in aged individuals. We hypothesized that SND responses to heating would be additive when aging and HF are combined, demonstrated by marked reductions in SND and mean arterial pressure (MAP) responses to heating in aged HF (A(HF)) compared with aged sham HF (A(SHAM)) rats, and in A(HF) compared with Y(HF) rats. Renal and splenic SND responses to hyperthermia (colonic temperature increased to 41.5°C) were determined in anesthetized Y(HF), young sham (Y(SHAM)), A(HF), and A(SHAM) Fischer rats. HF was induced by myocardial infarction and documented using echocardiographic, invasive, and postmortem measures. The severity of HF was similar in Y(HF) and A(HF) rats. SND responses to heating were attenuated in Y(HF) compared with Y(SHAM) rats, demonstrating an effect of HF on SND regulation in young rats. In contrast, A(HF) and A(SHAM) rats demonstrated similar SND responses to heating, suggesting a prominent influence of age on SND regulation in A(HF) rats. Splenic SND and MAP responses to heating were similar in Y(HF), A(HF), and A(SHAM) rats, indicating that the imposition of HF in young rats changes the regulatory status of these variables to one consistent with aged rats. These data suggest that the effect of HF on SND regulation to hyperthermia is age dependent.

Hyperthermia is an environmental stressor that produces marked increases in visceral sympathetic nerve discharge (SND) in young rats. The brainstem in rats contains the essential neural circuitry for mediating visceral sympathetic activation; however, specific brainstem sites involved remain virtually unknown. The rostral ventral lateral medulla (RVLM) is a key central nervous system region involved in the maintenance of basal SND and in mediating sympathetic nerve responses evoked from supraspinal sites. In the present study we tested the hypothesis that inhibition of RVLM synaptic activation at peak hyperthermia (internal body temperature, Tc, increased to 41.5 degrees C) would affect heating-induced visceral sympathetic activation. Experiments were completed in chloralose-urethane anesthetized, baroreceptor-intact and sinoaortic-denervated, 3-6 month-old Sprague-Dawley rats. Bilateral inhibition of RVLM synaptic activation produced by muscimol microinjections (400 and 800 pmol) at 41.5 degrees C resulted in immediate and significant reductions in peak heating-induced renal and splenic sympathoexcitation. Interruption of RVLM synaptic activation and axonal transmission by lidocaine microinjections (40 nmol) at 41.5 degrees C produced significant reductions in hyperthermia-induced sympathetic activation to similar levels produced by RVLM muscimol microinjections. The total amount of SND inhibited by RVLM muscimol and lidocaine microinjections was significantly more during hyperthermia (41.5 degrees C) than normothermia (38 degrees C). These findings demonstrate that maintenance of sympathetic activation at peak hyperthermia is dependent on the integrity of RVLM neural circuits.

The aim of the present study was to characterize the sympathetic nerve responses to hyperthermia in chloralose-anesthetized rats. Discharges were recorded from the renal, lumbar, and splanchnic sympathetic nerves. Mean arterial pressure, heart rate, and sympathetic nerve discharge (SND) were recorded continuously during progressive increases in core body temperature (Tc) from 38.0 to 41.0 degrees C. The following observations were made: 1) significant increases in renal, lumbar, and splanchnic SND were observed during hyperthermia; 2) autospectral analysis of renal and lumbar SND revealed that the frequency distribution of SND can be altered during progressive increases in Tc; and 3) increases in splanchnic SND to acute heating were similar in baroreceptor-innervated and -denervated rats. We conclude that 1) hyperthermia is a potent stimulus to the sympathetic nervous system and increases the activity in three sympathetic nerves that innervate different regional arterial beds, 2) acute heating influences the neural circuits involved in generating SND as evidenced by changes in the basic pattern of renal and lumbar SND, and 3) the increase in splanchnic SND during hyperthermia is not opposed by the arterial and cardiopulmonary baroreceptors.