Joyner, Michael J

We previously reported that epinephrine stimulates leg free fatty acid (FFA) release in men but not in women. The present studies were conducted to determine whether the same is true during exercise. Six men and six women bicycled for 90 min at 45% of peak O2 consumption, during which time systemic and leg FFA kinetics ([9,10-3H]palmitate) were measured. The catecholamine and hormonal responses to exercise were not different in men and women. The baseline systemic and leg palmitate release was 94 ± 15 vs. 114 ± 5 μmol/min and 16 ± 2 and 20 ± 3 μmol/min, respectively, in men and women [ P = nonsignificant (NS)]. Systemic and leg palmitate release increased (both P < 0.001) to 251 ± 18 vs. 212 ± 16 μmol/min and 73 ± 19 vs. 80 ± 12 μmol/min in men and women, respectively, during the last 30 min of exercise ( P = NS, men vs. women). We conclude that the systemic and leg adipose tissue lipolytic response to exercise is not different in nonobese men and women.

Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell–cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63±4 versus 73±3 cm/s; P =0.047) and during hypercapnia ( P =0.013–0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1±1.3 versus 2.9±1.1 cm·s·mm Hg; P =0.009). Globally, the association of the 7 identified principal components with preeclampsia ( P =0.107) and with baseline middle cerebral artery velocity ( P =0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR ( P =0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes ( P =0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements.

Nitric oxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase-5 (PDE-5). Whether PDE-5 limits exercise vasodilation onset kinetics is unknown. We hypothesized the time course of exercise vasodilation would be 1) accelerated during PDE-5 inhibition (sildenafil citrate, SDF) and 2) decelerated during NO synthase inhibition ( NG-monomethyl-l-arginine, l-NMMA), and 3) the effect of SDF on vasodilation onset kinetics would be attenuated with concurrent l-NMMA. Data from 29 healthy adults were analyzed. Individuals completed 5 min of moderate-intensity forearm exercise under control conditions and during 1) oral SDF ( n = 8), 2) intra-arterial l-NMMA ( n = 15), or 3) combined SDF + l-NMMA ( n = 6). Forearm blood flow (FBF; Doppler ultrasound of the brachial artery) and mean brachial artery blood pressure (MAP) were measured continuously. Forearm vascular conductance (FVC, FBF ÷ MAP) was curve-fit with a monoexponential model, and vasodilation onset kinetics were assessed by mean response time (MRT, time to achieve 63% of steady state). SDF had no effect on MRT ( P = 0.90). NOS inhibition increased MRT ( P = 0.01). MRT during SDF+l-NMMA was not different from control exercise ( P = 0.76). PDE-5 inhibition alone has no effect on rapid-onset vasodilation. Whereas NOS inhibition decelerates vasodilator kinetics, when combined with SDF, vasodilator kinetics do not differ from control. These data suggest NO-independent activation of cGMP occurs at exercise onset; thus PDE-5 inhibition may improve vasodilation in pathologies where NO bioavailability is impaired. NEW & NOTEWORTHY We show that when NO bioavailability is reduced, PDE-5 inhibition can restore vasodilation onset kinetics of exercise-mediated vasodilation via NO-independent cGMP pathways. These data suggest PDE-5 inhibition may improve exercise vasodilation onset kinetics in pathologies where NO bioavailability is impaired.

The carotid body chemoreceptors are activated during hypoglycemia and contribute to glucoregulation during prolonged exercise in dogs. Low-dose intravenous infusions of dopamine have been shown to blunt the activation of the carotid body chemoreceptors during hypoxia. Therefore, we tested the hypotheses that dopamine would blunt glucoregulatory responses and attenuate plasma glucose during prolonged aerobic exercise in healthy participants. Twelve healthy participants completed two randomized exercise sessions at 65% peak oxygen consumption for up to 120 min. Saline was infused during one exercise session, and dopamine (2 μg·kg−1·min−1) was infused during the other session. Arterial plasma glucose, growth hormone, glucagon, cortisol, norepinephrine, and epinephrine were measured every 10 min. Exercise duration during dopamine infusion was 107 ± 6 and 119 ± 0.8 min during saline infusion. Glucose area under the curve during exercise was lower during dopamine (9,821 ± 686 vs. 11,194 ± 395 arbitrary units; P = 0.016). The ratio of circulating growth hormone to glucose and the ratio of glucagon to glucose were greater during dopamine ( P = 0.045 and 0.037, respectively). These results indicate that the infusion of dopamine during aerobic exercise impairs glucoregulation. This suggests that the carotid body chemoreceptors contribute to glucoregulation during prolonged exercise in healthy exercise-trained humans.

The aim of this systematic review and meta-analysis [International Prospective Register of Systematic Reviews (PROSPERO) CRD42017055619] was to assess the effects of strict prolonged bed rest (without countermeasures) on maximal oxygen uptake (V̇o2max) and to explore sources of variation therein. Since 1949, 80 studies with a total of 949 participants (>90% men) have been published with data on strict bed rest and V̇o2max. The studies were conducted mainly in young participants [median age (interquartile range) 24.5 (22.4–34.0) yr]. The duration of bed rest ranged from 1 to 90 days. V̇o2max declined linearly across bed rest duration. No statistical difference in the decline among studies reporting V̇o2max as l/min (−0.3% per day) compared with studies reporting V̇o2max normalized to body weight (ml·kg−1·min−1; −0.43% per day) was observed. Although both total body weight and lean body mass declined in response to bed rest, we did not see any associations with the decline in V̇o2max. However, 15–26% of the variation in the decline in V̇o2max was explained by the pre-bed-rest V̇o2max levels, independent of the duration of bed rest (i.e., higher pre-bed-rest V̇o2max levels were associated with larger declines in V̇o2max). Furthermore, the systematic review revealed a gap in the knowledge about the cardiovascular response to extreme physical inactivity, particularly in older subjects and women of any age group. In addition to its relevance to spaceflight, this lack of data has significant translational implications because younger women sometimes undergo prolonged periods of bed rest associated with the complications of pregnancy and the incidence of hospitalization including prolonged periods of bed rest increases with age. NEW & NOTEWORTHY Large interindividual responses of maximal oxygen uptake (V̇o2max) to aerobic exercise training exist. However, less is known about the variability in the response of V̇o2max to prolonged bed rest. This systematic review and meta-analysis showed that pre-bed-rest V̇o2max values were inversely associated with the change in V̇o2max independent of the duration of bed rest. Moreover, we identified a large knowledge gap about the causes of decline in V̇o2max, particularly in postmenopausal women, which may have clinical implications.

Key points Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP‐mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (K IR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt α 1 ‐adrenergic vasoconstriction in resting skeletal muscle would be independent of K IR , NO, PGs and Na + /K + ‐ATPase activity. Blockade of K IR channels alone or in combination with NO, PGs and Na + /K + ‐ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate α 1 ‐adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. Abstract Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (K IR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic α‐adrenergic vasoconstriction (sympatholysis). However, K IR channels, NO, PGs and Na + /K + ‐ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of K IR channels, NO and PG synthesis, and Na + /K + ‐ATPase would not alter the ability of ATP to blunt α 1 ‐adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra‐arterial infusion of phenylephrine (PE; α 1 ‐agonist) during ATP or control vasodilatator infusion, before and after K IR channel inhibition alone (barium chloride; n = 7; Protocol 1); NO ( l ‐NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na + /K + ‐ATPase (ouabain) and K IR channel inhibition ( n = 6; Protocol 2). ATP attenuated PE‐mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE‐mediated ΔFVC: ATP: −16 ± 2; ADO: −38 ± 6; SNP: −59 ± 6%; P < 0.05 vs . ADO and SNP). Blockade of K IR channels alone or combined with NO, PGs and Na + /K + ‐ATPase, attenuated ATP‐mediated vasodilatation (∼35 and ∼60% respectively; P < 0.05 vs . control). However, ATP maintained the ability to blunt PE‐mediated vasoconstriction (PE‐mediated ΔFVC: K IR blockade alone: −6 ± 5%; combined blockade:−4 ± 14%; P > 0.05 vs . control). These findings demonstrate that intravascular ATP modulates α 1 ‐adrenergic vasoconstriction via pathways independent of K IR channels, NO, PGs and Na + /K + ‐ATPase in humans, consistent with a role for endothelium‐derived hyperpolarization in functional sympatholysis.

The vasodilatory mechanism of Nntroglycerin (NTG) is similar to sodium nitroprusside (SNP) in regard to action on guanosine 3′5′-monophosphate (cyclic GMP) via nitric oxide. However, it is unknown whether NTG can achieve the same magnitude of vasodilation in the forearm as SNP. Therefore, the purpose of the study was to evaluate the differences in forearm blood flow (FBF) and forearm vascular conductance (FVC) during escalating infusions of NTG vs. SNP at similar concentration doses and rates. We measured FBF using venous occlusion plethysmography (VOP) and Doppler ultrasound in eight young, healthy participants (mean age = 28 ± 2 yr) during four forearm volume (FAV)-specific doses (0.25, 0.5, 1, and 2 µg·100 ml FAV−1·min−1) of SNP and NTG infused via a brachial artery catheter. There was a significant difference in FVC of SNP vs. NTG only at the higher doses, as measured by VOP (14.9 ± 1.4 and 18.3 ± 1.5 vs. 11.6 ± 1.2 and 12.5 ± 1.2 ml/dl FAV−1·min−1·100 mmHg−1). FVC as measured by Doppler ultrasound unadjusted for FAV was significantly different at the lowest and the higher two doses of SNP compared with NTG (202.1 ± 25.8, 329.4 ± 46.7, and 408 ± 63.5 vs. 142.9 ± 22.4, 217.2 ± 18.8, and 247.5 ± 18.2 ml·min−1·100 mmHg−1). SNP induces significantly higher vasodilatory actions compared with NTG. However, NTG is comparable in eliciting equivalent vasodilator effects to SNP during low concentration doses when measured by VOP. Importantly, for forearm pharmacology studies, NTG can elicit marked endothelium-independent forearm vasodilation. NEW & NOTEWORTHY We compared the vasodilatory capacities of NTG vs. SNP at similar concentration doses and rates into the forearm. Based on the results of the study, it may be feasible to use intra-arterial NTG as a measure of endothelial-independent vasodilator in research studies. However, NTG dosing may need to be higher if used as an endothelial-independent vasodilator due to significant differences in the vasodilatory effects during higher doses of SNP compared with NTG.