Citations

Evidence from animal studies indicates that hyperinsulinemia, without changes in glucose, increases ventilation via a carotid body-mediated mechanism. However, whether insulin elevates ventilation in humans independently of changes in glucose remains unclear. Therefore, we tested the hypothesis that insulin increases ventilation in humans during a hyperinsulinemic-euglycemic clamp in which insulin was elevated to postprandial concentrations while glucose was maintained at fasting concentrations. First, in 16 healthy young men ( protocol 1), we retrospectively analyzed respiration rate and estimated tidal volume from a pneumobelt to calculate minute ventilation during a hyperinsulinemic-euglycemic clamp. In addition, for a direct assessment of minute ventilation during a hyperinsulinemic-euglycemic clamp, we retrospectively analyzed breath-by-breath respiration rate and tidal volume from inspired/expired gasses in an additional 23 healthy young subjects ( protocol 2). Clamp infusion elevated minute ventilation from baseline in both protocols ( protocol 1: +11.9 ± 4.6% baseline, P = 0.001; protocol 2: +9.5 ± 3.8% baseline, P = 0.020). In protocol 1, peak changes in both respiration rate (+13.9 ± 3.0% baseline, P < 0.001) and estimated tidal volume (+16.9 ± 4.1% baseline, P = 0.001) were higher than baseline during the clamp. In protocol 2, tidal volume primarily increased during the clamp (+9.7 ± 3.7% baseline, P = 0.016), as respiration rate did not change significantly (+0.2 ± 1.8% baseline, P = 0.889). Collectively, we demonstrate for the first time in humans that elevated plasma insulin increases minute ventilation independent of changes in glucose.

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5–1.2 µg·kg−1·min−1, n = 13) or PE (0.2–1.0 µg·kg−1·min−1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Abstract The carotid bodies (CBs) are multi‐modal sensory organs located bilaterally at the bifurcation of the carotid artery and innervated by the carotid sinus nerve (Hering's nerve), a branch of the IX cranial nerve. While the CBs (or embryologically analogous structures) are well known as the dominant oxygen‐sensing organ in vertebrates, in mammals there is evidence that the CBs may also sense glucose and temperature, and respond to circulating hormones and other factors. Additionally, the CBs likely participate in regulating baseline levels of sympathetic tone. In this brief review, we focus on the evolution of our efforts to understand ‘what else’ beyond oxygen sensing the CBs do in humans. image

Abstract Hot flashes have typically been classified as “symptoms of menopause” that should be tolerated or treated until they resolve. However, mounting evidence points to hot flashes as a manifestation of one or several underlying pathophysiological processes. Associations exist between the presence, timing of onset, severity, and duration of hot flashes, and the risk of several neurological (affecting sleep, mood, and cognition) and cardiovascular conditions. In addition, four consistent patterns of vasomotor disturbances have been identified across different countries, making it unlikely that these patterns are solely explained by socioeconomic or cultural factors. The changing hormonal environment of menopause may unmask differences in the autonomic neurovascular control mechanisms that put an individual woman at risk for chronic conditions of aging. These differences may have a genetic basis or may be acquired across the life span and are consistent with the variability of the clinical manifestations of aging observed in women after bilateral oophorectomy. It is time to investigate the pathophysiological mechanisms underlying the four patterns of vasomotor symptoms more closely, and to shift from describing hot flashes as symptoms to be tolerated to manifestations of an underlying autonomic neurovascular dysregulation that need to be addressed.

Blood pressure (BP) reactivity is predictive of the development of cardiovascular disease. We hypothesized that the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery compared with obese adults and that the reliance on total peripheral resistance (TPR) would be attenuated. Twenty-six individuals (7 nonobese, 11 obese, 8 postbariatric surgery) completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform, and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30 s of exercise. Obese adults exhibited a slower rise in BP and higher peak BP at exercise onset compared with nonobese controls ( P < 0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery and nonobese controls ( P > 0.05). Nonobese controls exhibited an exercise-mediated increase in CO, whereas obese adults increased TPR ( P < 0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery ( P > 0.05). In contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at exercise onset. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest that bariatric surgery improves BP reactivity via changes in the time course of hemodynamic responses. NEW & NOTEWORTHY Bariatric surgery has been shown to reduce the blood pressure (BP) response to isometric handgrip exercise. By examining the time course of the BP response to exercise, we found, in contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at exercise onset, which is associated with a fall in total peripheral resistance and results in lower peak BP at the onset of isometric exercise. These data suggest that bariatric surgery improves BP reactivity via reflex autonomic adjustments.

Phenylephrine is generally regarded as a “pure” α1-agonist. However, after treatment of the forearm with the α-adrenergic-blocking drug phentolamine, brachial artery infusion of phenylephrine can cause transient forearm vasodilation. To determine whether this response was β-receptor mediated, phenylephrine, phentolamine, and propranolol were infused into the brachial arteries of six healthy volunteers. Forearm vascular conductance (FVC) was also calculated and expressed as arbitrary units (units). Infusion of phenylephrine by itself (0.5 μg · dl forearm volume−1 · min−1) caused a sustained decrease ( P < 0.05) in FVC from 3.5 ± 0.7 to 0.9 ± 0.2 units ( P < 0.05). Infusion of the α-blocker phentolamine increased ( P < 0.05) baseline FVC to 5.7 ± 1.3 units. Subsequent infusion of phenylephrine after α-blockade caused FVC to increase ( P < 0.05) for ∼1 min from 5.7 ± 1.3 to a peak of 13.1 ± 1.8 units. Propranolol had no effect on baseline flow, and subsequent phenylephrine infusion after α- and β-blockade caused a small, but significant, sustained decrease in FVC from 5.1 ± 1.0 to 3.6 ± 0.8 units. There were no systemic effects from the infusions, and saline infusion at the same rate (1–2 ml/min) had no forearm vasoconstrictor or dilator effects. These data indicate that in humans phenylephrine can exert transient β2-vasodilator activity when its predominant α-constrictor effects are blocked.

An open-circuit (OpCirc) acetylene uptake cardiac output (Q˙t) method was modified for use during exercise. Two computational techniques were used. OpCirc1 was based on the integrated uptake vs. end-tidal change in acetylene, and OpCirc2 was based on an iterative finite difference modeling method. Six subjects [28–44 yr, peak oxygen consumption (V˙o2) = 120% predicted] performed cycle ergometry exercise to compareQ˙t using OpCirc and direct Fick methods. An incremental protocol was repeated twice, separated by a 10-min rest, and subsequently subjects exercised at 85–90% of their peak work rate. Coefficient of variation of the OpCirc methods and Fick were highest at rest (OpCirc1, 7%, OpCirc2, 12%, Fick, 10%) but were lower at moderate to high exercise intensities (OpCirc1, 3%, OpCirc2, 3%, Fick, 5%). OpCirc1 and OpCirc2 Q˙t correlated highly with Fick Q˙t( R2= 0.90 and 0.89, respectively). There were minimal differences between OpCirc1 and OpCirc2 compared with Fick up to moderate-intensity exercise (<70% peakV˙o2); however, both techniques tended to underestimate Fick at >70% peakV˙o2. These differences became significant for OpCirc1 only. Part of the differences between Fick and OpCirc methods at the higher exercise intensities are likely related to inhomogeneities in ventilation and perfusion matching ( R2= 0.36 for Fick − OpCirc1 vs. alveolar-to-arterial oxygen tension difference). In conclusion, both OpCirc methods provided reproducible, reliable measurements ofQ˙t during mild to moderate exercise. However, only OpCirc2 appeared to approximate FickQ˙t at the higher work intensities.

An acute bout of aerobic exercise results in a reduced blood pressure that lasts several hours. Animal studies suggest this response is mediated by increased production of nitric oxide. We tested the extent to which systemic nitric oxide synthase inhibition [ N G-monomethyl-l-arginine (l-NMMA)] can reverse the drop in blood pressure that occurs after exercise in humans. Eight healthy subjects underwent parallel experiments on 2 separate days. The order of the experiments was randomized between sham (60 min of seated upright rest) and exercise (60 min of upright cycling at 60% peak aerobic capacity). After both sham and exercise, subjects received, in sequence, systemic α-adrenergic blockade (phentolamine) and l-NMMA. Phentolamine was given first to isolate the contribution of nitric oxide to postexercise hypotension by preventing reflex changes in sympathetic tone that result from systemic nitric oxide synthase inhibition and to control for alterations in resting sympathetic activity after exercise. During each condition, systemic and regional hemodynamics were measured. Throughout the study, arterial pressure and vascular resistances remained lower postexercise vs. postsham despite nitric oxide synthase inhibition (e.g., mean arterial pressure afterl-NMMA was 108.0 ± 2.4 mmHg postsham vs. 102.1 ± 3.3 mmHg postexercise; P < 0.05). Thus it does not appear that postexercise hypotension is dependent on increased production of nitric oxide in humans.

The mechanisms underlying the skin blood flow (SkBF) response to local heating are complex and poorly understood. Our goal was to examine the role of axon reflexes and nitric oxide (NO) in the SkBF response to a local heating protocol. We performed 40 experiments following a standardized heating protocol with different interventions, including blockade of the axon reflex (EMLA cream), antebrachial nerve blockade (0.5% bupivacaine injection), and NO synthase (NOS) inhibition (≥10 mM NG-nitro-l-arginine methyl ester; microdialysis). Appropriate controls were performed to verify the efficacy of the various blocks. Values are expressed as a percentage of maximal SkBF (SkBFmax; 50 mM sodium nitroprusside). At the initiation of local heating, SkBF rose to an initial peak, followed by a brief nadir, and a secondary, progressive rise to a plateau. Axon reflex block decreased the initial peak from 75+3 to 32 ± 2% SkBFmax( P< 0.01 vs. control) but did not affect the plateau. NOS inhibition before and throughout local heating reduced the initial peak from 75 ± 3 to 56 ± 3% SkBFmax( P< 0.01) and the plateau from 87 ± 4 to 40 ± 5%. NOS inhibition during axon reflex block did not further reduce the initial SkBF peak compared with axon reflex block alone. Antebrachial nerve block did not affect the local heating SkBF response. The primary finding of these studies is that there are at least two independent mechanisms contributing to the rise in SkBF during nonpainful local heating: a fast-responding vasodilator system mediated by the axon reflexes and a more slowly responding vasodilator system that relies on local production of NO.