Augmented pressor and sympathetic responses to skeletal muscle metaboreflex activation in type 2 diabetes patients

Previous studies have reported exaggerated increases in arterial blood pressure during exercise in type 2 diabetes (T2D) patients. However, little is known regarding the underlying neural mechanism(s) involved. We hypothesized that T2D patients would exhibit an augmented muscle metaboreflex activation and this contributes to greater pressor and sympathetic responses during exercise. Mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were measured in 16 patients with T2D (8 normotensive and 8 hypertensive) and 10 healthy controls. Graded isolation of the muscle metaboreflex was achieved by postexercise ischemia (PEI) following static handgrip performed at 30% and 40% maximal voluntary contraction (MVC). A cold pressor test (CPT) was also performed as a generalized sympathoexcitatory stimulus. Increases in MAP and MSNA during 30 and 40% MVC handgrip were augmented in T2D patients compared with controls ( P < 0.05), and these differences were maintained during PEI (MAP: 30% MVC PEI: T2D, Δ16 ± 2 mmHg vs. controls, Δ8 ± 1 mmHg; 40% MVC PEI: T2D, Δ26 ± 3 mmHg vs. controls, Δ16 ± 2 mmHg, both P < 0.05). MAP and MSNA responses to handgrip and PEI were not different between normotensive and hypertensive T2D patients ( P > 0.05). Interestingly, MSNA responses were also greater in T2D patients compared with controls during the CPT ( P < 0.05). Collectively, these findings indicate that muscle metaboreflex activation is augmented in T2D patients and this contributes, in part, to augmented pressor and sympathetic responses to exercise in this patient group. Greater CPT responses suggest that a heightened central sympathetic reactivity may be involved.

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Augmented pressor and sympathoexcitatory responses to the onset of isometric handgrip in patients with type 2 diabetes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00109.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. R311-R319

Author(s):

Jennifer R. Vranish ◽

Seth W. Holwerda ◽

Jasdeep Kaur ◽

Paul J. Fadel

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Risk ◽

Muscle Sympathetic Nerve Activity ◽

Cold Pressor Test ◽

Cold Pressor ◽

Voluntary Contraction ◽

Isometric Handgrip ◽

Control Subjects ◽

Daytime Blood Pressure

Patients with type 2 diabetes (T2D) exhibit greater daytime blood pressure (BP) variability, increasing their cardiovascular risk. Given the number of daily activities that incorporate short-duration isometric muscle contractions (e.g., carrying groceries), herein we investigated BP and muscle sympathetic nerve activity (MSNA) responses at the onset of isometric handgrip (HG). We tested the hypothesis that, relative to control subjects, patients with T2D would exhibit exaggerated pressor and MSNA responses to the immediate onset of HG. Mean arterial pressure (MAP) and MSNA were quantified during the first 30 s of isometric HG at 30% and 40% of maximal voluntary contraction (MVC) and during a cold pressor test (CPT), a nonexercise sympathoexcitatory stimulus. The onset of 30% MVC HG evoked similar increases in MAP between groups ( P = 0.17); however, the increase in MSNA was significantly greater in patients with T2D versus control subjects with the largest group difference at 20 s ( P < 0.001). At the onset of 40% MVC HG, patients with T2D demonstrated greater increases in MAP (e.g., 10 s, T2D: 9 ± 1 mmHg, controls: 5 ± 2 mmHg; P = 0.04). MSNA was also greater in patients with T2D at 40% MVC onset but differences were only significant at the 20–30 s timepoint (T2D: 15 ± 3 bursts/min, controls: −2 ± 4 bursts/min; P < 0.001). Similarly, MAP and MSNA responses were augmented during the onset of CPT in T2D patients. These findings demonstrate exaggerated pressor and MSNA reactivity in patients with T2D, with rapid and robust responses to both isometric contractions and cold stress. This hyper-responsiveness may contribute to daily surges in BP in patients with T2D, increasing their short-term and long-term cardiovascular risk.

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A comparative study of effect of cold pressor test on heart rate between healthy offspring with and without parental history of Type 2 diabetes mellitus

National Journal of Physiology Pharmacy and Pharmacology ◽

10.5455/njppp.2018.8.0100431012018 ◽

2018 ◽

pp. 1

Author(s):

Arifuddin K ◽

Vivek P

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Heart Rate ◽

Type 2 Diabetes Mellitus ◽

Comparative Study ◽

Cold Pressor Test ◽

Cold Pressor ◽

Parental History ◽

History Of

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Transfer function characteristics of the neural and peripheral arterial baroreflex arcs at rest and during postexercise muscle ischemia in humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01223.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. H1416-H1424 ◽

Cited By ~ 21

Author(s):

Shigehiko Ogoh ◽

James P. Fisher ◽

Colin N. Young ◽

Peter B. Raven ◽

Paul J. Fadel

Keyword(s):

Transfer Function ◽

Muscle Sympathetic Nerve Activity ◽

Voluntary Contraction ◽

Arterial Baroreflex ◽

Isometric Handgrip ◽

Vascular Conductance ◽

Muscle Metaboreflex ◽

Arterial Blood ◽

Muscle Ischemia ◽

Transfer Function Gain

Previous studies have demonstrated an increase in the arterial baroreflex (ABR) control of muscle sympathetic nerve activity (MSNA) during isolated activation of the muscle metaboreflex with postexercise muscle ischemia (PEMI). However, the increased ABR-MSNA control does not appear to manifest in an enhancement in the ABR control of arterial blood pressure (BP), suggesting alterations in the transduction of MSNA into a peripheral vascular response and a subsequent ABR-mediated change in BP. Thus we examined the operating gains of the neural and peripheral arcs of the ABR and their interactive relationship at rest and during muscle metaboreflex activation. In nine healthy subjects, graded isolation of the muscle metaboreflex was achieved by PEMI following isometric handgrip performed at 15% and 30% maximal voluntary contraction (MVC). To obtain the sensitivities of the ABR neural and peripheral arcs, the transfer function gain from BP to MSNA and MSNA to femoral vascular conductance, respectively, was analyzed. No changes from rest were observed in the ABR neural or peripheral arcs during PEMI after 15% MVC handgrip. However, PEMI following 30% MVC handgrip increased the low frequency (LF) transfer function gain between BP and MSNA (ABR neural arc; +58 ± 28%, P = 0.036), whereas the LF gain between MSNA and femoral vascular conductance (ABR peripheral arc) was decreased from rest (−36 ± 8%, P = 0.017). These findings suggest that during high-intensity muscle metaboreflex activation an increased ABR gain of the neural arc appears to offset an attenuation of the peripheral arc gain to help maintain the overall ABR control of systemic BP.

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Effect of cyclooxygenase inhibition on the inspiratory muscle metaboreflex-induced cardiovascular consequences in men

Journal of Applied Physiology ◽

10.1152/japplphysiol.00165.2017 ◽

2017 ◽

Vol 123 (1) ◽

pp. 197-204 ◽

Cited By ~ 4

Author(s):

Joshua R. Smith ◽

Kaylin D. Didier ◽

Shane M. Hammer ◽

Andrew M. Alexander ◽

Stephanie P. Kurti ◽

...

Keyword(s):

Vascular Resistance ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Cold Pressor Test ◽

Cold Pressor ◽

Inspiratory Muscle ◽

Maximal Inspiratory Pressure ◽

Muscle Metaboreflex ◽

Resistive Breathing ◽

Prostaglandin F

Inspiratory muscle metaboreflex activation increases mean arterial pressure (MAP) and limb vascular resistance (LVR) and decreases limb blood flow (Q̇L). Cyclooxygenase (COX) inhibition has been found to attenuate limb skeletal muscle metaboreflex-induced increases in muscle sympathetic nerve activity. We hypothesized that compared with placebo (PLA), COX inhibition would attenuate inspiratory muscle metaboreflex-induced 1) increases in MAP and LVR and 2) decreases in Q̇L. Seven men (22 ± 1 yr) were recruited and orally consumed ibuprofen (IB; 10 mg/kg) or PLA 90 min before performing the cold pressor test (CPT) for 2 min and inspiratory resistive breathing task (IRBT) for 14.9 ± 2.0 min at 65% of maximal inspiratory pressure. Breathing frequency was 20 breaths/min with a 50% duty cycle during the IRBTs. MAP was measured via automated oscillometry, Q̇L was determined via Doppler ultrasound, and LVR was calculated as MAP divided by Q̇L. Electromyography was recorded on the leg to ensure no muscle contraction occurred. The 65% IRBT led to greater increases ( P = 0.02) in 6-keto-prostaglandin-F1α with PLA compared with IB. IB, compared with PLA, led to greater ( P < 0.01) increases in MAP (IB: 17 ± 7 mmHg vs. PLA: 8 ± 5 mmHg) and LVR (IB: 69 ± 28% vs. PLA: 52 ± 22%) at the final minute of the 65% IRBT. The decrease in Q̇L was not different ( P = 0.72) between IB (−28 ± 11%) and PLA (−27 ± 9%) at the final minute. The increase in MAP during the CPT was not different ( P = 0.87) between IB (25 ± 11 mmHg) and PLA (24 ± 6 mmHg). Contrary to our hypotheses, COX inhibition led to greater inspiratory muscle metaboreflex-induced increases in MAP and LVR. NEW & NOTEWORTHY Cyclooxygenase (COX) products play a role in activating the muscle metaboreflex. It is not known whether COX products contribute to the inspiratory muscle metaboreflex. Herein, we demonstrate that COX inhibition led to greater increases in blood pressure and limb vascular resistance compared with placebo during inspiratory muscle metaboreflex activation.

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Hyperglycemia and type 2 diabetes : impact on neural cardiovascular control

10.32469/10355/49538 ◽

2015 ◽

Author(s):

◽

Seth H. Holwerda

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Healthy Subjects ◽

Muscle Sympathetic Nerve Activity ◽

Muscle Afferents ◽

Chronic Hypertension ◽

University Of Missouri ◽

Arterial Blood

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Type 2 diabetes (T2D) is often characterized by chronic hypertension and exaggerated increases in arterial blood pressure (BP) during exercise. However, investigations of the neural mechanisms that are known to be critically involved in BP regulation at rest and during exercise in T2D have been lacking. Also, hyperglycemia decreases arterial baroreflex (ABR) control of heart rate (HR) in conditions of reduced insulin sensitivity, but whether hyperglycemia reduces ABR control of HR in healthy subjects has not been investigated. In study #1, findings demonstrated that ABR control of HR is reduced following acute hyperglycemia in healthy subjects independent of insulin sensitivity, and also during hyperinsulinemia. Study #2 focused on ABR control of HR and muscle sympathetic nerve activity (MSNA) in T2D patients, which are chronically hyperglycemic and hyperinsulinemic. No differences in ABR control of MSNA were observed; however, ABR control of HR was significantly reduced in T2D patients compared to lean controls, but not weight-matched (i.e., obese) controls. These findings suggest a potential selective impairment in ABR control of HR in T2D that may be a consequence of obesity. Finally, given the exaggerated BP responses to exercise in T2D patients, and the vital contribution of skeletal muscle neural feedback to the BP responses to exercise, study #3 focused on BP and MSNA responses to activation of skeletal muscle neural afferents in T2D patients. The findings demonstrated that BP and MSNA responses to activation of skeletal muscle afferents sensitive to muscle metabolites was augmented in T2D patients.

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Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00556.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. H1318-H1327 ◽

Cited By ~ 114

Author(s):

Erin P. Delaney ◽

Jody L. Greaney ◽

David G. Edwards ◽

William C. Rose ◽

Paul J. Fadel ◽

...

Keyword(s):

Animal Studies ◽

Muscle Sympathetic Nerve Activity ◽

Cold Pressor Test ◽

Cold Pressor ◽

Voluntary Contraction ◽

Group Differences ◽

Handgrip Exercise ◽

Burst Frequency ◽

Metabolic Component ◽

Pressor Responses

Recent animal studies have reported that exercise pressor reflex (EPR)-mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear. Mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and venous metabolites were measured in normotensive (NTN; n = 23; 60 ± 1 yr) and HTN ( n = 15; 63 ± 1 yr) subjects at baseline, and during static handgrip at 30 and 40% maximal voluntary contraction (MVC) followed by a period of postexercise ischemia (PEI) to isolate the metabolic component of the EPR. Changes in MAP from baseline were augmented in HTN subjects during both 30 and 40% MVC handgrip ( P < 0.05 for both), and these group differences were maintained during PEI (30% PEI trial: Δ15 ± 2 NTN vs. Δ19 ± 2 HTN mmHg; 40% PEI trial: Δ16 ± 1 NTN vs. Δ23 ± 2 HTN mmHg; P < 0.05 for both). Similarly, in HTN subjects, MSNA burst frequency was greater during 30 and 40% MVC handgrip ( P < 0.05 for both), and these differences were maintained during PEI [30% PEI trial: 35 ± 2 (NTN) vs. 44 ± 2 (HTN) bursts/min; 40% PEI trial: 36 ± 2 (NTN) vs. 48 ± 2 (HTN) bursts/min; P < 0.05 for both]. No group differences in metabolites were observed. MAP and MSNA responses to a cold pressor test were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with NTN subjects, HTN adults exhibit exaggerated sympathetic and pressor responses to handgrip exercise that are maintained during PEI, indicating that activation of the metabolic component of the EPR is augmented in older HTN humans.

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Metabolic and Hemodynamic Markers of Endothelial Dysfunction in Patients With Hypertension and Patients With Type 2 Diabetes During the Cold Pressor Test

American Journal of Therapeutics ◽

10.1097/mjt.0b013e318169bca8 ◽

2008 ◽

Vol 15 (4) ◽

pp. 389-396 ◽

Cited By ~ 8

Author(s):

Christian Fouillioux ◽

Freddy Contreras ◽

Mary Lares ◽

Raquel Cano ◽

Elliuz Leal ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Cold Pressor Test ◽

Cold Pressor ◽

Pressor Test

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Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz219 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1187-e1200 ◽

Cited By ~ 2

Author(s):

Sara Baqar ◽

Yee Wen Kong ◽

Angela X Chen ◽

Christopher O’Callaghan ◽

Richard J MacIsaac ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Endothelial Function ◽

Augmentation Index ◽

Sodium Intake ◽

Blood Pressure Monitoring ◽

Muscle Sympathetic Nerve Activity ◽

Burst Frequency ◽

Low Sodium

Abstract Context Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). Objective To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. Design We conducted a randomized, double-blinded, placebo-controlled crossover trial. Setting The study took place in a tertiary referral diabetes outpatient clinic. Participants Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium <150 mmol/24h) were included. Intervention Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. Main outcome measures The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. Results Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). Conclusions In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.

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Interindividual variability in muscle sympathetic responses to static handgrip in young men: evidence for sympathetic responder types?

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00266.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. R114-R121 ◽

Cited By ~ 5

Author(s):

Anthony V. Incognito ◽

Connor J. Doherty ◽

Jordan B. Lee ◽

Matthew J. Burns ◽

Philip J. Millar

Keyword(s):

Blood Pressure ◽

Diastolic Blood Pressure ◽

Interindividual Variability ◽

Muscle Sympathetic Nerve Activity ◽

Voluntary Contraction ◽

Response Patterns ◽

Arterial Baroreflex ◽

Muscle Metaboreflex ◽

Time To Peak ◽

Pressure Time

Negative and positive muscle sympathetic nerve activity (MSNA) responders have been observed during mental stress. We hypothesized that similar MSNA response patterns could be identified during the first minute of static handgrip and contribute to the interindividual variability throughout exercise. Supine measurements of multiunit MSNA (microneurography) and continuous blood pressure (Finometer) were recorded in 29 young healthy men during the first (HG1) and second (HG2) minute of static handgrip (30% maximal voluntary contraction) and subsequent postexercise circulatory occlusion (PECO). Responders were identified on the basis of differences from the typical error of baseline total MSNA: 7 negative, 12 positive, and 10 nonresponse patterns. Positive responders demonstrated larger total MSNA responses during HG1 ( P < 0.01) and HG2 ( P < 0.0001); however, the increases in blood pressure throughout handgrip exercise were similar between all groups, as were the changes in heart rate, stroke volume, cardiac output, total vascular conductance, and respiration (all P > 0.05). Comparing negative and positive responders, total MSNA responses were similar during PECO ( P = 0.17) but opposite from HG2 to PECO (∆40 ± 46 vs. ∆-21 ± 62%, P = 0.04). Negative responders also had a shorter time-to-peak diastolic blood pressure during HG1 (20 ± 20 vs. 44 ± 14 s, P < 0.001). Total MSNA responses during HG1 were associated with responses to PECO ( r = 0.39, P < 0.05), the change from HG2 to PECO ( r = −0.49, P < 0.01), and diastolic blood pressure time to peak ( r = 0.50, P < 0.01). Overall, MSNA response patterns during the first minute of static handgrip contribute to interindividual variability and appear to be influenced by differences in central command, muscle metaboreflex activation, and rate of loading of the arterial baroreflex.

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