Roberts, Shelly K.

Decreased vasoconstrictor responsiveness during hypoxic exercise does not explain the augmented vasodilation in exercising muscle. We tested the hypothesis that β‐mediated vasodilation contributes to a portion of the enhanced muscle blood flow during hypoxic exercise. Subjects breathed hypoxic gas to titrate arterial O 2 saturation to 80% while remaining normocapnic via a re‐breath system. Two consecutive bouts of forearm handgrip exercise (10 and 20% of maximum) were performed under normoxia and hypoxia during saline infusion, during phentolamine (α‐antagoinst) alone and during the combination of phentolamine and propranolol (β‐antagonist). Forearm blood flow (FBF) and blood pressure (MAP) were assessed and forearm vascular conductance (FVC) was calculated (FBF/MAP). Hypoxia alone increased heart rate (62±3 vs. 82±3 bpm) with no change in MAP (86±2 vs. 89±2 mmHg for normoxia and hypoxia respectively). During hypoxic exercise the rise (Δ from baseline) in FVC with phentolamine alone was 166±26 and 448±31 ml/min/100mmHg (10% and 20 % respectively). This rise in blood flow was blunted (143±36 and 279±73 ml/min/100mmHg) with combined phentolamine and propranolol infusion. Thus, preliminary data suggests that in the absence of overlying vasoconstriction, β‐mediated vasodilation may account for a modest portion of the enhanced blood flow during hypoxic exercise.

Key points Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin. We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance. The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia. Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts. High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange. AbstractThe longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P50 = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P50 = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected throughout both exercise tests. Despite no difference in end‐exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects’ oxyhaemoglobin saturation () was ∼7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake () (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change in between trials was related to the change in (r = −0.75, p < 0.0001). Compared to normoxia, the controls’ alveolar‐to‐arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH subjects for both exercise trials. We conclude that HAH attenuates the decline in maximal aerobic capacity and preserves pulmonary gas exchange during acute hypoxic exercise. Our data support the comparative biology literature indicating that HAH is a positive adaptation to acute hypoxia.

Arterial oxygen tension and oxyhemoglobin saturation ([Formula: see text]) decrease in parallel during hypoxia. Distinguishing between changes in oxygen tension and oxygen content as the relevant physiological stimulus for cardiorespiratory alterations remains challenging. To overcome this, we recruited nine individuals with hemoglobinopathy manifesting as high-affinity hemoglobin [HAH; partial pressure at 50% [Formula: see text] (P50) = 16 ± 0.4 mmHg] causing greater [Formula: see text] at a given oxygen partial pressure compared with control subjects ( n = 12, P50 = 26 ± 0.4 mmHg). We assessed ventilatory and cardiovascular responses to acute isocapnic hypoxia, iso-oxic hypercapnia, and 20 min of isocapnic hypoxia (arterial Po2 = 50 mmHg). Blood gas alterations were achieved with dynamic end-tidal forcing. When expressed as a function of the logarithm of oxygen partial pressure, ventilatory sensitivity to hypoxia was not different between groups. However, there was a significant difference when expressed as a function of [Formula: see text]. Conversely, the rise in heart rate was blunted in HAH subjects when expressed as a function of partial pressure but similar when expressed as a function of [Formula: see text]. Ventilatory sensitivity to hypercapnia was not different between groups. During sustained isocapnic hypoxia, the rise in minute ventilation was similar between groups; however, heart rate was significantly greater in the controls during 3 to 9 min of exposure. Our results support the notion that oxygen tension, not content, alters cellular Po2in the chemosensors and drives the hypoxic ventilatory response. Our study suggests that in addition to oxygen partial pressure, oxygen content may also influence the heart rate response to hypoxia.NEW & NOTEWORTHY We dissociated the effects of oxygen content and pressure of cardiorespiratory regulation studying individuals with high-affinity hemoglobin (HAH). During hypoxia, the ventilatory response, expressed as a function of oxygen tension, was similar between HAH variants and controls; however, the rise in heart rate was blunted in the variants. Our work supports the notion that the hypoxic ventilatory response is regulated by oxygen tension, whereas cardiovascular regulation may be influenced by arterial oxygen content and tension.

We hypothesized that individuals who have undergone gastric bypass have greater insulin sensitivity that obese subjects but less compared with lean. We measured free fatty acid (FFA) and glucose kinetics during a two-step, hyperinsulinemic euglycemic clamp in nondiabetic subjects who were 38 ± 5 mo post-gastric bypass surgery (GB; n = 15), in lean subjects (L; n = 15), and in obese subjects (O; n = 16). Fasting FFAa were not significantly different between the three study groups but during both doses of insulin were significantly higher in O than in either GB or L. The effective insulin concentration resulting in half-maximal suppression of FFA was similar in L and GB and significantly less in both groups compared with O. Glucose infusion rates during low-dose insulin were not significantly different in GB compared with either L or O. During high-dose insulin, glucose infusion rates were significantly greater in GB than in O but less than in L. Endogenous glucose production in GB was significantly lower than O only during low dose of insulin. We conclude that gastric bypass is associated with improvements in adipose tissue insulin sensitivity to levels similar to lean, healthy persons and also with improvements in the response of glucose metabolism to insulin. These changes may be due to preferential reduction in visceral fat and decreased FFA availability. However, some differences in insulin sensitivity in GB remain compared with L. Residual insulin resistance may be related to excess total body fat or abnormal lipolysis and requires further study.

Cutaneous sensory nerve-mediated vasodilation is an important component of normal microvascular responsiveness to thermal and nonthermal stimuli. Since both neural and microvascular function can be impaired in type 2 diabetes mellitus (T2DM), we tested the hypothesis that local sensory nerve-mediated vasodilation during nonpainful local warming of the skin is less in T2DM compared with healthy controls (C) matched for age and body size. The rapid vasodilation during the first ∼5 min of this local warming (“initial peak”) was previously shown to rely primarily on local sensory nerves. We measured skin blood flow in T2DM and C subjects ( n = 7 in each group) at baseline and during 35 min of local warming of the skin to 42°C at two sites on the ventral forearm. One site was pretreated with 4% lidocaine (LIDO) to block local sensory innervation. During local warming, cutaneous vascular conductance (CVC) during the initial peak was not different between groups, either at the untreated site [T2DM 75 ± 2 vs. C 81 ± 6% of maximum CVC (%maxCVC); P > 0.05] or at the LIDO site (T2DM 63 ± 7 vs. C 64 ± 6%maxCVC; P > 0.05). The difference between untreated and LIDO sites (sensory nerve contribution) was also similar between groups (T2DM 13 ± 5 vs. C 18 ± 5%maxCVC; P > 0.05) and was smaller with LIDO than was previously shown with other local anesthetics. Our results suggest that relatively healthy individuals with T2DM do not exhibit impairments in local sensory nerve vasodilation during thermal stimulation compared with controls of similar age and body size.