Joyner, Michael J.

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.

Venous occlusion plethysmography is a simple but elegant technique that has contributed to almost every major area of vascular biology in humans. The general principles of plethysmography were appreciated by the late 1800s, and the application of these principles to measure limb blood flow occurred in the early 1900s. Plethysmography has been instrumental in studying the role of the autonomic nervous system in regulating limb blood flow in humans and important in studying the vasodilator responses to exercise, reactive hyperemia, body heating, and mental stress. It has also been the technique of choice to study how human blood vessels respond to a variety of exogenously administered vasodilators and vasoconstrictors, especially those that act on various autonomic and adrenergic receptors. In recent years, plethysmography has been exploited to study the role of the vascular endothelium in health and disease. Venous occlusion plethysmography is likely to continue to play an important role as investigators seek to understand the physiological significance of newly identified vasoactive factors and how genetic polymorphisms affect the cardiovascular system in humans.

We sought to examine further the potential role of nitric oxide (NO) in the neurally mediated cutaneous vasodilation in nonacral skin during body heating in humans. Six subjects were heated with a water-perfused suit while cutaneous blood flow was measured by using laser-Doppler flowmeters placed on both forearms. The NO synthase inhibitor NG-monomethyl-l-arginine (l-NMMA) was given selectively to one forearm via a brachial artery catheter after marked cutaneous vasodilation had been established. During body heating, oral temperature increased by 1.1 ± 0.1°C while heart rate increased by 30 ± 6 beats/min. Mean arterial pressure stayed constant at 84 ± 2 mmHg. In the experimental forearm, cutaneous vascular conductance (CVC; laser-Doppler) decreased to 86 ± 5% of the peak response to heating ( P < 0.05 vs. pre-l-NMMA values) afterl-NMMA infusion. In some subjects, l-NMMA caused CVC to fall by ∼30%; in others, it had little impact on the cutaneous circulation. CVC in the control arm showed a similar increase with heating, then stayed constant whilel-NMMA was given to the contralateral side. These results demonstrate that NO contributes modestly, but not consistently, to cutaneous vasodilation during body heating in humans. They also indicate that NO is not the only factor responsible for the dilation.