Minson, Christopher T.

Histamine appears to be intimately involved with skeletal muscle responses during and following exercise. Blocking histamine’s actions during endurance exercise training by taking common over-the-counter antihistamines resulted in diminished gains in fitness. These results indicate that exercise-induced histamine release is important in generating many of the positive adaptations to exercise training.

Some studies report an increase of resting muscle sympathetic nerve activity (MSNA) during the midluteal (ML) phase of the menstrual cycle when compared to the early follicular phase (EF), while others do not. The inconsistent findings may be due, in part, to variable surges in estradiol and progesterone. We tested the hypothesis that the degree of sympathoexcitation during the ML phase (ΔMSNA) is associated with changes in estradiol (ΔE 2 ) and progesterone (ΔP). Retrospective analysis of previous studies with recordings of mean arterial pressure (MAP), MSNA, E 2 , and P during both EF and ML phases yielded 30 eumenorrheic women (age, 18–51 yrs). ML phase increased E 2 (37±2 to 117±9 pg/ml; p<.001), P (1±0 to 11±1 ng/ml; p<.001), and MSNA (12±1 to 15±1 bursts/min; p=.02), but did not alter MAP (83±2 to 83±2 mmHg; p=.91). ΔMSNA was correlated to ΔE 2 (r=−.50, p=.005) and ΔE 2 /ΔP (r=−.52, p=.004), but not ΔP (r=.21, p=.26). There was no association between ΔMAP and ΔE 2 (r=−.13, p=.49), ΔP (r=−.04, p=.83), or ΔE 2 /ΔP (r<.01, p=.98). In conclusion, sympathoexcitatory responses to the ML phase appear to be associated with the degree of sex steroid surges. While E 2 had a stronger influence on MSNA than P, it is worthy to note that a strong association with ΔMSNA persisted when both ΔE 2 and ΔP were considered. This dynamic interaction between E 2 , P, and MSNA likely explains previously reported inconsistencies in the field. Supported by NIH.

The relationship between mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and total peripheral resistance (TPR) is altered in young women versus men and postmenopausal women due to endogenous sex hormone differences. Exogenous sex hormones in the form of oral contraceptive pills (OCPs) may further affect this relationship. We performed a retrospective review of 136 premenopausal women in whom MSNA and arterial pressure were measured, including 78 women with natural menstrual cycles in the early follicular phase (26±1 yr) and 58 women in the placebo phase of OCPs (24±1 yr). TPR and cardiac output (CO) were measured in a subset of women in whom continuous intra‐arterial blood pressure was recorded. Compared to those with natural menstrual cycles, women on OCPs had greater MAP (89±1 vs. 84±1 mmHg, p<0.01) and tended to have lower MSNA (15±1 vs. 18±1 bursts/100 heart beats, p=0.06). MAP and MSNA were positively correlated (r=0.22, p<0.05), TPR and MSNA were positively associated (r=0.41, p<0.05) and CO and MSNA (r=‐0.44, p<0.05) were inversely associated in naturally cycling women (n=26) but not in women on OCPs (r=0.15, r=0.11, r=‐0.01, respectively; p>0.05; n=38). In contrast to naturally cycling women, there appears to be no relationship between MSNA and hemodynamics in women on OCPs, suggesting that these women may regulate their blood pressure differently than women. Grant Funding Source : Supported by NIH

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 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.

This study evaluated the hypothesis that active muscle blood flow is lower during exercise at a given submaximal power output after aerobic conditioning as a result of unchanged cardiac output and blunted splanchnic vasoconstriction. Eight untrained subjects (4 men, 4 women, 23–31 yr) performed high-intensity aerobic training for 9–12 wk. Leg blood flow (femoral vein thermodilution), splanchnic blood flow (indocyanine green clearance), cardiac output (acetylene rebreathing), whole body O2 uptake (V˙o 2), and arterial-venous blood gases were measured before and after training at identical submaximal power outputs (70 and 140 W; upright 2-leg cycling). Training increased ( P < 0.05) peak V˙o 2(12–36%) but did not significantly change submaximalV˙o 2 or cardiac output. Leg blood flow during both submaximal power outputs averaged 18% lower after training ( P = 0.001; n = 7), but these reductions were not correlated with changes in splanchnic vasoconstriction. Submaximal leg V˙o 2 was also lower after training. These findings support the hypothesis that aerobic training reduces active muscle blood flow at a given submaximal power output. However, changes in leg and splanchnic blood flow resulting from high-intensity training may not be causally linked.

We conducted a series of studies to develop and test a rapid, noninvasive method to measure limb venous compliance in humans. First, we measured forearm volume (mercury-in-Silastic strain gauges) and antecubital intravenous pressure during inflation of a venous collecting cuff around the upper arm. Intravenous pressure fit the regression line, −0.3 ± 0.7 + 0.95 ± 0.02 ⋅ cuff pressure ( r = 0.99 ± 0.00), indicating cuff pressure is a good index of intravenous pressure. In subsequent studies, we measured forearm and calf venous compliance by inflating the venous collecting cuff to 60 mmHg for 4 min, then decreasing cuff pressure at 1 mmHg/s (over 1 min) to 0 mmHg, using cuff pressure as an estimate of venous pressure. This method produced pressure-volume curves fitting the quadratic regression (Δlimb volume) = β0 + β1 ⋅ (cuff pressure) + β2 ⋅ (cuff pressure)2, where Δ is change. Curves generated with this method were reproducible from day to day (coefficient of variation: 4.9%). In 11 subjects we measured venous compliance via this method under two conditions: with and without (in random order) superimposed sympathetic activation (ischemic handgrip exercise to fatigue followed by postexercise ischemia). Calf and forearm compliance did not differ between control and sympathetic activation ( P > 0.05); however, the data suggest that unstressed volume was reduced by the maneuver. These studies demonstrate that venous pressure-volume curves can be generated both rapidly and noninvasively with this technique. Furthermore, the results suggest that although whole-limb venous compliance is under negligible sympathetic control in humans, unstressed volume can be affected by the sympathetic nervous system.

We sought to investigate further the roles of sweating, ACh spillover, and nitric oxide (NO) in the neurally mediated cutaneous vasodilation during body heating in humans. Six subjects were heated with a water-perfused suit while cutaneous blood flow was measured with a laser-Doppler flowmeter. After a rise in core temperature (1.0 ± 0.1°C) and the establishment of cutaneous vasodilation, atropine and subsequently the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) were given to the forearm via a brachial artery catheter. After atropine infusion, cutaneous vascular conductance (CVC) remained constant in five of six subjects, whereasl-NAME administration blunted the rise in CVC in three of six subjects. A subsequent set of studies using intradermal microdialysis probes to selectively deliver drugs into forearm skin confirmed that atropine did not affect CVC. However, perfusion ofl-NAME resulted in a significant decrease in CVC (37 ± 4%, P < 0.05). The results indicate that neither sweating nor NO release via muscarinic receptor activation is essential to sustain cutaneous dilation during heating in humans.