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Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

The evaluation of lumbar interbody fusion status is generally subjective and may differ among raters. The authors examined whether the assessment of position change of screw-rod constructs could be an alternative method for the evaluation of fusion status.Sixty-three patients undergoing lumbar interbody single-level fusion were retrospectively reviewed. Three-dimensional images of screw-rod constructs were created from baseline CT examination on the day after surgery and follow-up CT examinations (3-5 months, 6-11 months, and ≥ 12 months) and superposed, with position change of screw-rod constructs being evaluated by the distance between the 3-dimensional images at baseline and follow-up. The evaluation was repeated twice to confirm the reproducibility. Fusion status on follow-up CT examinations was assessed by three raters, where inter-rater reliability was evaluated with Fleiss' kappa. The results of the fusion status were classified into fusion and incomplete fusion groups in each timing of follow-up CT examinations, where the amount of position change was compared between the two groups.The evaluation of position change was completely reproducible. The Fleiss' kappa (agreements) was 0.481 (69.4%). The medians of the amount of position change in fusion and incomplete fusion groups were 0.134 mm and 0.158 mm at 3-5 months (p = 0.21), 0.160 mm and 0.190 mm at 6-11 months (p = 0.02), and 0.156 mm and 0.314 mm at ≥ 12 months (p = 0.004).The assessment of position change of screw-rod constructs at 6 months or more after surgery can be an alternative method for evaluating lumbar interbody fusion status.• Lumbar interbody fusion status (satisfactory, incomplete, or failed) is associated with the quantification of position change of screw-rod in this study. • Reference values for the evaluation of position change in identifying interbody fusion status are provided. • Position change of screw-rod could be a supportive method for evaluating interbody fusion status.

A mechanical stimulus to skeletal muscle during exercise activates the sympathetic nervous system via the skeletal muscle mechanoreflex. However, to date, the receptor mechanisms responsible for mechanotransduction in skeletal muscle afferents have not been fully identified. Transient receptor potential vanilloid 4 (TRPV4), a multimodally activated, nonselective cation channel, is sensitive to mechanical stimuli such as shear stress, osmotic pressure and stretch in various organs. Therefore, it is hypothesized that TRPV4 contributes to mechanotransduction in thin-fiber primary afferents innervating skeletal muscle. Purpose: The aim of this investigation was to determine 1) the extent to which TRPV4 and the afferent marker peripherin are co-localized in dorsal root ganglion (DRG) neurons subserving thin-fiber skeletal muscle afferents using a retrograde tracing technique, and 2) the impact of a selective TRPV4 antagonist, HC067047 on mechanotransduction in small DRG neurons. Methods: To label muscle afferent DRG neurons, dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate, (Dil, 60 mg/mL, 3 μL total) was injected into the white portion of the gastrocnemius muscle. Five days after the injection, L4-L6 DRGs were harvested from rats (Sprague-Dawley (SD), n = 3, body weight: 318.0 ± 8.7 g). The number of positively stained small-diameter DRG neurons (i.e. less than 30 μm in diameter) were counted and the percentage of peripherin- or DiI-positive neurons in TRPV4-positive neurons was calculated. In vitro whole-cell patch clamp recordings from cultured rat DRG neurons (SD, n = 10, body weight: 352.1 ± 52.4 g), mechanically-activated (MA) current amplitude and mechanical threshold were measured before and 5 min after the application of either HEPES-buffered solution as a control or 1 μM HC067047 solution. Results: Fluorescence immunostaining demonstrated that 20.1 ± 10.1% of TRPV4 positive neurons were expressed with Dil-labeled small DRG neurons. Of these, 9.5 ± 6.1% and 10.6 ± 7.2% were peripherin-positive and -negative neurons, respectively. In in vitro whole-cell patch clamp recordings, MA current amplitude was significantly decreased 5 min after the application of HC067047 ( P < 0.01), while mechanical threshold did not change. Conclusion: The data demonstrates that 1) TRPV4 is expressed in DRGs innervating group IV muscle afferent C-fibers, and 2) HC067047 suppresses the response to mechanical stimulation in DRG neurons. These findings suggest that TRPV4 channels play an important role as mechanoreceptors contributing to mechanotransduction in thin muscle afferents. Supported by NIH HL-151632, JSPS 21J20070 & 22KK0154, and UMF 202131013 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Type 2 diabetes mellitus (T2D) leads to alterations in insulin signaling and autonomic function, including abnormal cardiovascular response to exercise. Cardiovascular control during exercise is in part mediated by the exercise pressor reflex (EPR). The EPR transmits information from primary sensory neurons in working skeletal muscle to cardiovascular control centers in the brain, resulting in reflexively increased blood pressure (BP). Insulin receptors are expressed on neurons in these cardiovascular control centers. Thus, it is logical to suggest that insulin signaling could be disrupted in these neurons in T2D. We hypothesized that the augmented cardiovascular and sympathetic responses to exercise in T2D may be attenuated by administration of insulin into the brain. Purpose: This study was conducted to demonstrate that insulin administration into the central nervous system of rats acutely attenuates the augmented BP and sympathetic responses to muscle contraction in rats with T2D. Methods: T2D and control rats were generated by feeding Sprague-Dawley rats either a high fat diet (T2D, n=10) or normal diet (control, n=7) for 12-16 wks. Before beginning the diet, either two low doses of i.p. streptozotocin (T2D, 35mg/kg week 1, 25mg/kg week 2) or two i.p. saline injections (control) were administered. A precollicular decerebration was performed, and the left L4 and L5 ventral roots were electrically stimulated to evoke hindlimb skeletal muscle contractions. Renal sympathetic nerve activity (RSNA) and BP responses to activation of the EPR were assessed before, and post 1 and 2hr intracerebroventricular (ICV) insulin injection (500mU, 50nL). Fasting blood glucose was measured before experiments. Data were evaluated by Two-way Repeated Measures ANOVA or Student’s t-test. Results: Fasting blood glucose was significantly higher in T2D as compared to control rats (T2D 150±55 mg/dL vs 100±16 mg/dL, P=0.0353). In the T2D group, the BP and RSNA responses to contraction were significantly attenuated at 1hr post-ICV insulin (ΔMAP Pre [36±14 mmHg] vs 1hr post [21±14 mmHg], P=0.0002; ΔRSNA Pre [107.5±40%], vs 1hr post [75.4±46%], P=0.0043), and then further attenuated at 2hr post (ΔMAP 1hr [21±14 mmHg] vs 2hr [11±6 mmHg], P= 0.0155; ΔRSNA 1hr [75.4±46%] vs 2hr [51±35%], P=0.0363). There were no differences in pressor or sympathetic responses observed in the control group post-ICV insulin. Conclusion: The data demonstrate that brain insulin normalizes the potentiated BP and RSNA responses to muscle contraction in T2D rats. Thus, impaired insulin signaling within cardiovascular control centers of the brain may underlie the augmented EPR in T2D rats. Central insulin treatment may potentially restore normal autonomic function in part by decreasing neuronal excitability in T2D. Supported by NIH-NHLBI, Lawson & Rogers Lacy Research Fund This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skeletal muscle reflexes play a crucial role in determining the magnitude of the cardiovascular response to exercise. However, evidence supporting an association between the magnitude of the pressor response and velocity of muscle deformation has remained to be elucidated. Thus, we investigated the impact of different muscle deformation rates on the neural discharge of muscle afferents as well as pressor and sympathetic responses in Sprague-Dawley rats. In an ex vivo muscle-nerve preparation, action potentials elicited by sinusoidal mechanical stimuli (137 mN) at different frequencies (0.01, 0.05, 0.1, 0.2, and 0.25 Hz) were recorded in mechanosensitive group III and IV fibers. The afferent response magnitude to sine-wave stimulation significantly varied at different frequencies (ANOVA, P=0.025). Specifically, as compared to 0.01 Hz (0.83±0.96 spikes/s), the response magnitudes were significantly greater at 0.20 Hz (4.07±5.04 spikes/s, P=0.031) and 0.25 Hz (4.91±5.30 spikes/s, P=0.014). In an in vivo decerebrated rat preparation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch (1kg) of hindlimb skeletal muscle at different velocities of loading (slow, medium, fast) was measured. Pressor responses to passive stretch were significantly associated with velocity of muscle deformation (ANOVA, P

運動時には活動筋の酸素需要を満たすために循環応答が増大する.特定の疾患や病態による運動時循環応答の過剰亢進は心血管イベントの発生リスクを高めるため,その機序解明は運動実施の安全性を高めるために重要である.運動時の神経性循環調節の機序の一つに,骨格筋に対する機械刺激や代謝刺激によって反射的に昇圧応答が起こる運動昇圧反射がある.運動昇圧反射のうち,活動筋の伸長や短縮などの機械刺激による昇圧応答は筋機械受容器反射と呼ばれている.この筋機械受容器反射は,骨格筋における機械イベントが感覚神経にて電気信号に変換されるメカノトランスダクションが反射の始まりであるが,その働きを担う分子の特定や感作のメカニズムの全容解明には至っていない.つまり,運動時の神経性循環調節におけるメカノバイオロジーは発展途上である.本ミニレビューでは,運動昇圧反射におけるメカノバイオロジー機構の現在までの知見ならびに今後の課題について整理することを目的とする.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor, and develops infrequently in the central nervous system. To our knowledge, this is the first case of EHE of the spinal cord. An 85-year-old man presented with about 6-month progressive myelopathy. Magnetic resonance imaging (MRI) demonstrated an oval-shaped intradural extramedullary mass at T10 level with extensive intramedullary edema. A reddish tumor was removed via a total laminectomy of T9−T10. Histologically, the tumor cells with nuclear atypia and active mitoses were immunopositive for vascular tumor markers, and formed a lobular architecture associated with capillary-sized vessels lined with edematous endothelial cells. Although very rare, EHE should be considered in the differential diagnosis of a spinal intradural extramedullary tumor.

The blood pressure response to exercise is exaggerated in type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2DM is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2DM rats. Additionally, TRPV1 and protein kinase C (PKC) protein levels in dorsal root ganglia (DRG) subserving skeletal muscle were assessed. For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or high fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2DM). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic neve activity in decerebrated T2DM than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2DM was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high glucose environment. T2DM showed significantly increased phospholyrated-TRPV1 and −PKCα levels in DRG neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early-stage T2DM with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

Dorsal arachnoid web (DAW) is a rare entity, which has been reported only in the thoracic spine. The authors report the first case of DAW developing in the cervical spine. A 78-year-old man with several-year progressive gait disturbance and bilateral lower-extremity numbness was referred to our hospital on the suspicion of a non-enhancing cystic cervical spinal tumor. Magnetic resonance imaging (MRI) showed a focal indentation along the dorsal surface of the spinal cord at C7 associated with widened cerebrospinal fluid (CSF) space and increased T2-weighted signals in the cord at C5–C7. DAW was suspected, but because of the atypical location for DAW, computed tomography (CT) myelogram was performed and demonstrated an incomplete blockage of the CSF flow at C7 with neither visible abnormal membranes nor a cyst formation. Intraoperative ultrasonography and operative findings revealed that two fluttering membranes disturbed the CSF flow. The pathology of the excised membranes was arachnoid tissues. DAW should be suspected based on the characteristic MRI findings even if the location is in the lower cervical spine. This case seems to support the theory that DAW may be an incomplete or disrupted formation of an arachnoid cyst.

Background: SGLT2i (sodium-glucose cotransporter 2 inhibitor), a class of anti-diabetic medications, is shown to reduce blood pressure (BP) in hypertensive patients with type 2 diabetes. Mechanisms underlying this action are unknown but SGLT2i-induced sympathoinhibition is thought to play a role. Whether SGLT2i reduces BP and sympathetic nerve activity (SNA) in a nondiabetic prehypertension model is unknown. Methods: Accordingly, we assessed changes in conscious BP using radiotelemetry and alterations in mean arterial pressure and renal SNA during simulated exercise in nondiabetic spontaneously hypertensive rats during chronic administration of a diet containing dapagliflozin (0.5 mg/kg per day) versus a control diet. Results: We found that dapagliflozin had no effect on fasting blood glucose, insulin, or hemoglobin A 1C levels. However, dapagliflozin reduced BP in young (8-week old) spontaneously hypertensive rats as well as attenuated the age-related rise in BP in adult spontaneously hypertensive rat up to 17-weeks of age. The rises in mean arterial pressure and renal SNA during simulated exercise (exercise pressor reflex activation by hindlimb muscle contraction) were significantly reduced after 4 weeks of dapagliflozin (Δmean arterial pressure: 10±7 versus 25±14 mm Hg, Δrenal SNA: 31±17% versus 68±39%, P Conclusions: These data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of glycemic control. Our study may have important clinical implications for preventing hypertension and hypertensive heart disease in young prehypertensive individuals.

Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men (n = 23) and women (n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex (r = 0.44, P = 0.02) and higher HbA1c (r = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) (r = 0.45, P < 0.01), and resting systolic BP (SBP) (r = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions. NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

Systemic insulin administration evokes sympathoexcitatory actions, but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserves them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole-cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n = 13) was significantly (P 0.05) higher than with a vehicle control (n = 14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n = 9 per group, P 0.05). Furthermore, insulin receptor blockade with GSK1838705 significantly suppressed the insulin-induced augmentation in CAP-activated currents (n = 13) as well as the response magnitude of CAP-induced action potentials (n = 9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n = 8) was significantly (P 0.05) greater compared to vehicle (n = 9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. KEY POINTS: Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical-sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, it is demonstrated that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, it is demonstrated that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggest that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.

Ischemic skeletal muscle conditions are known to augment exercise‐induced increases in blood pressure (BP). Aging is also a factor that enhances the pressor response to exercise. However, the effects of aging on the BP response to ischemic exercise remain unclear. We, therefore, tested the hypothesis that aging enhances the BP response to rhythmic handgrip (RHG) exercise during postexercise muscle ischemia (PEMI). We divided the normotensive participants without cardiovascular diseases into three age groups: young (n = 26; age, 18–28 years), middle‐aged (n = 23; age, 35–59 years), and older adults (n = 23; age, 60–80 years). The participants performed RHG exercise with minimal effort for 1 min after rest with and without PEMI, which was induced by inflating a cuff on the upper arm just before the isometric handgrip exercise ended; the intensity was 30% of maximal voluntary contraction force. Under PEMI, the increase in diastolic BP (DBP) from rest to RHG exercise in the older adult group (Δ13 ± 2 mmHg) was significantly higher than that in the young (Δ5 ± 2 mmHg) and middle‐aged groups (Δ6 ± 1 mmHg), despite there being no significant difference between the groups in the DBP response from rest to RHG exercise without PEMI. Importantly, based on multiple regression analysis, age remained a significant independent determinant of both the SBP and DBP responses to RHG exercise during PEMI (p, The systolic and diastolic blood pressure responses to low‐intensity rhythmic handgrip exercise with postexercise muscle ischemia in older adults were demonstrated to be higher than that of young, and young and middle‐aged groups, respectively. Additionally, aging persisted as a significant determinant explaining the variance in the blood pressure response to low‐intensity rhythmic handgrip exercise during postexercise muscle ischemia. These finding suggests that aging enhances pressor response to ischemic exercise.

A radiologic assessment method to measure position change of screw-rod constructs over time by superposing the 3‑dimensional images assists in quantitative evaluation of screw loosening. We investigated the association between position change and radiolucent zone that was commonly used for diagnosing screw loosening.In this study 101 patients who underwent lumbar fusion were reviewed. Patient characteristics included age, sex, indications for surgery, number of fused levels, surgical procedures, and timing of follow-up computed tomography (CT, 1-5 months, 6-11 months, and ≥ 12 months). The Hounsfield unit values of L1 vertebra on preoperative CT were measured, and the radiolucent zone on each follow-up CT was evaluated. Using baseline CT on the day after surgery and follow-up CT, 3‑dimensional images of screw-rod constructs were generated and superposed. Position change was assessed by the median of the distances between the 3‑dimensional images at baseline and follow-up using the automated measurement method. Patient characteristics, the Hounsfield unit values of L1, and the amount of position change were categorized into the radiolucent zone presence and absence groups and compared.The medians of position change were 0.281 mm and 0.136 mm in the radiolucent zone presence and absence groups, respectively (P 0.001 by Mann-Whitney U-test). The area under the curve for position change in identifying radiolucent zone was 0.846; the cut-off value was 1.76 mm. In multivariable analysis, position change was independently associated with radiolucent zone (adjusted odds ratio per 0.1 mm, 2.80, 95% confidence interval 1.70-4.61).Radiolucent zone was associated with position change of screw-rod constructs.

Patients with diabetes display heightened blood pressure response to exercise but the underlying mechanism are remains to be elucidated. There is no direct evidence that insulin resistance (hyperinsulinemia or hyperglycemia) impact neural cardiovascular control during exercise. We propose a novel paradigm in which hyperinsulinemia or hyperglycemia significantly influence neural regulatory pathways controlling the circulation during exercise in diabetes.

The treatment for large central disk herniation (LCDH) at upper lumbar spine is often challenging. Previous reports showed various surgical strategies, such as microdiscectomy with posterior fixation, endoscopic surgery, and microdiscectomy through transdural approach. However, there is no consensus regarding which surgical option is better for LCDH at upper lumbar spine. In this report, we describe the novel transdural epiarachnoid approach (TDEA), which uses the corridor of epiarachnoid space for microdiscectomy. Compared with classical transdural approaches, this novel approach may reduce risks of postoperative cerebrospinal fluid leakage and the development of arachnoiditis.A 69-yr-old man presented with progressive bilateral radiating leg pain, intermittent claudication, and low back pain. Magnetic resonance images and computed tomography scans revealed LCDH at L2/3 level. We performed microdiscectomy using the TDEA. Postoperative course was uneventful, and his symptoms were relieved after surgery.The novel TDEA for LCDH at upper lumbar spine is illustrated with a video. This novel approach has an advantage of the preservation of subarachnoid components compared with classical transdural approaches.

KEY POINTS Insulin is known to activate the sympathetic nervous system centrally. A mechanical stimulus to tissues activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, we report the novel finding that insulin augments the mechanical responsiveness of thin fibre afferents not only at dorsal root ganglion, but also at muscle tissue levels. Our data suggest that sympathoexcitation is mediated via the insulin-induced mechanical sensitization peripherally. The present study proposes a novel physiological role of insulin in the regulation of mechanical sensitivity in somatosensory thin fibre afferents. ABSTRACT Insulin activates the sympathetic nervous system, although the mechanism underlying insulin-induced sympathoexcitation remains to be determined. A mechanical stimulus to tissues such as skin and/or skeletal muscle, no matter whether the stimulation is noxious or not, activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion (DRG) neurons of these afferents. Accordingly, we investigated whether insulin augments whole-cell current responses to mechanical stimuli in small DRG neurons of normal healthy mice. We performed whole-cell patch clamp recordings using cultured DRG neurons and observed mechanically-activated (MA) currents induced by mechanical stimuli applied to the cell surface. Local application of vehicle solution did not change MA currents or mechanical threshold in cultured DRG neurons. Insulin (500 mU mL-1 ) significantly augmented the amplitude of MA currents (P

The cardiovascular responses to exercise are potentiated in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms causing this abnormality remain unknown. Central command (CC) and the exercise pressor reflex (EPR) are known to contribute significantly to cardiovascular control during exercise. Thus these neural signals are viable candidates for the generation of the abnormal circulatory regulation in this disease. We hypothesized that augmentations in CC as well as EPR function contribute to the heightened cardiovascular responses during exercise in T2DM. To test this hypothesis, changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to electrical stimulation of mesencephalic locomotor region (MLR), a putative component of the central command pathway, and activation of the EPR, evoked by electrically induced hindlimb muscle contraction, were examined in decerebrate animals. Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet (14–16 wk) in combination with two low doses (35 mg/kg week 1, 25 mg/kg week 2) of streptozotocin (T2DM). The changes in MAP and RSNA responses to MLR stimulation were significantly greater in T2DM compared with control (2,739 ± 123 vs. 1,298 ± 371 mmHg/s, 6,326 ± 1,621 vs. 1,390 ± 277%/s, respectively, P < 0.05). Similarly, pressor and sympathetic responses to activation of the EPR in diabetic animals were significantly augmented compared with control animals (436 ± 74 vs. 134 ± 44 mmHg/s, 645 ± 135 vs. 139 ± 65%/s, respectively, P < 0.05). These findings provide the first evidence that CC and the EPR may generate the exaggerated rise in sympathetic activity and blood pressure during exercise in T2DM.