Preserved β-adrenergic mediated vasodilation in skeletal muscle of young obese adults despite shifts in cyclooxygenase and nitric oxide synthase

Central adiposity is associated with greater sympathetic support of blood pressure. β-adrenergic receptors (β-AR) buffer sympathetically-mediated vasoconstriction and β-AR mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized β-AR vasodilation would be lower in obese compared to normal weight adults. Because β-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to β-AR vasodilation in this cohort. Methods: Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance was calculated (FVC=FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of Isoproterenol (ISO, 1-12 ng/100g/min) in normal weight (n=36) and obese (n=22) adults (18-40 years old). In a subset of participants, ISO-mediated vasodilation was examined prior to and during inhibition of NOS (L-NMMA), COX (Ketorolac), and NOS + COX (L-NMMA + Ketorolac). Results: ISO-mediated increases in FVC did not differ between groups (p=0.57). L-NMMA attenuated ISO-mediated ΔFVC in normal weight (p=0.03) but not obese (p=0.27) adults. In normal weight adults, Ketorolac increased ISO-mediated ΔFVC (p<0.01) and this response was lost with concurrent L-NMMA (p=0.67). In contrast, neither Ketorolac (p=0.81) nor Ketorolac + L-NMMA (p=0.40) altered ISO-mediated ΔFVC in obese adults. Conclusion: Despite shifts in COX and NOS, β-AR vasodilation is preserved in young obese adults. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger obese humans.

ATP and acetylcholine interact to modulate vascular tone and α1-adrenergic vasoconstriction in humans

The vascular endothelium senses and integrates numerous inputs to regulate vascular tone. Recent evidence reveals complex signal processing within the endothelium, yet little is known about how endothelium-dependent stimuli interact to regulate blood flow. We tested the hypothesis that combined stimulation of the endothelium with adenosine triphosphate (ATP) and acetylcholine (ACh) elicits greater vasodilation and attenuates α1‑adrenergic vasoconstriction compared to combination of ATP or ACh with the endothelium-independent dilator sodium nitroprusside (SNP). We assessed forearm vascular conductance (FVC) in young adults (6F, 7M) during local intra-arterial infusion of ATP, ACh, or SNP alone and in the following combinations: ATP+ACh, SNP+ACh, and ATP+SNP wherein the second dilator was co-infused after attaining steady-state with the first dilator. By design, each dilator evoked a similar response when infused separately (ΔFVC, ATP: 48±4; ACh: 57±6; SNP: 53±6 ml·min-1·100 mmHg-1; P≥0.62). Combined infusion of the endothelium-dependent dilators evoked greater vasodilation than combination of either dilator with SNP (ΔFVC from first dilator, ATP+ACh: 45±9 vs. SNP+ACh: 18±7 and ATP+SNP: 26±4 ml·min-1·100 mmHg-1, P<0.05). Phenylephrine was subsequently infused to evaluate α1‑adrenergic vasoconstriction. Phenylephrine elicited less vasoconstriction during infusion of ATP or ACh vs. SNP (ΔFVC, -25±3 and -29±4 vs. -48±3%; P<0.05). The vasoconstrictor response to phenylephrine was further diminished during combined infusion of ATP+ACh (-13±3%; P<0.05 vs. ATP or ACh alone) and was less than that observed when either dilator was combined with SNP (SNP+ACh: -26±3%; ATP+SNP: -31±4%; both P<0.05 vs. ATP+ACh). We conclude that endothelium-dependent agonists interact to elicit vasodilation and limit α1‑adrenergic vasoconstriction in humans.

Abstract P172: Endothelial Function In The Early Years After Delivery: Effect Of Adverse Pregnancy Outcomes And Activity Behaviors

Introduction: Adverse pregnancy outcomes (APOs) are independently associated with cardiovascular disease (CVD). Endothelial dysfunction may indicate early CVD and can be influenced by physical activity (PA) and sedentary behavior (SED). Hypothesis: We hypothesized women with a past APO would have worse endothelial function versus controls and that mid-pregnancy and current PA would be directly related while SED would be inversely related to endothelial function in the years soon after delivery. Methods: We used venous occlusion plethysmography to measure baseline forearm blood flow, reactive hyperemia, and vascular conductance (forearm blood flow/mean arterial pressure) in a case control study of 53 women 6 mo to 3 yrs after a singleton birth; 26% with past APO, 21% African American, mean age=33±1 yrs, mean BMI=27.4±0.9 kg/m 2 . Current and mid-pregnancy leisure time PA and weekday SED were assessed with validated questionnaires. We evaluated differences in endothelial function by APO exposure with t-tests and relations of endothelial function with PA and SED with Spearman correlations. Results: Baseline forearm blood flow (APO: 1.6±0.2; non-APO: 1.8±0.1 ml*min -1 *100 ml -1 tissue, p=0.3) and reactive hyperemia (APO: 13.2±2; non-APO: 11.4±1 ml*min -1 *100 ml -1 , p=0.8) were similar between groups. Vascular conductance was non-significantly lower in women with a past APO: 1.7x10 -2 versus 2.1x10 -2 ml*min -1 *100 ml -1 mmHg -1 in women without a past APO, p<0.10. Vascular conductance was related to current and mid-pregnancy SED (figure) but not PA (r=0.2 and r=0.06, p>0.05 for mid-pregnancy and current PA). Associations of mid-pregnancy and current SED with vascular conductance after delivery persisted after adjustment for age and BMI. Conclusions: Forearm vascular conductance tended to be lower soon after delivery in women with an APO. Mid-pregnancy and current SED were inversely related to forearm vascular conductance and may represent targets for interventions aimed at improving endothelial function after delivery.

Sex-Related Differences in Rapid-Onset Vasodilation: Impact of Aging

Rapid-onset vasodilation (ROV) in response to a single muscle contraction is attenuated with aging. Moreover, sex-related differences in muscle blood flow and vasodilation during dynamic exercise have been observed in young and older adults. The purpose of the present study was to explore if sex-related differences in ROV exist in young (n=36, 25±1 yr) and older (n=32, 66±1 yr) adults. Subjects performed single forearm contractions at 10%, 20%, and 40% maximal voluntary contraction. Brachial artery blood velocity and diameter were measured with Doppler ultrasound, and forearm vascular conductance (ml·min-1·100 mmHg-1) was calculated from blood flow (ml·min-1) and mean arterial pressure (mmHg) and used as a measure of ROV. Peak ROV was attenuated in women across all relative intensities in the young and older groups (P<0.05). In a subset of subjects with similar absolute workloads (~5 kg and ~11kg), age-related differences in ROV were observed among both women and men (P<0.05). However, only older women demonstrated an attenuated peak ROV compared to men (91±6 vs. 121±11 ml·min-1·100 mmHg-1, P<0.05), a difference not observed in the young group (134±8 vs. 154±11 ml·min-1·100 mmHg-1, P=0.15). Additionally, examining the slope of peak ROV across contraction intensities indicated a blunted response in older women compared to their young counterparts (P<0.05), with no differences observed between older and young men (P=0.38). Our data suggest that sex-related differences in the rapid vasodilatory response to single muscle contractions exist in older but not young adults, such that older women have a blunted response compared to older men.

Functional sympatholysis is preserved in healthy young Black men during rhythmic handgrip exercise

Black men have attenuated increases in forearm vascular conductance (FVC) and forearm blood flow (FBF) during moderate- and high-intensity rhythmic handgrip exercise compared with White men, but the underlying mechanisms are unclear. Here, we tested for the first time the hypothesis that functional sympatholysis (i.e., attenuation of sympathetic vasoconstriction in the exercising muscles) is impaired in Black men compared with White men. Thirteen White and 14 Black healthy young men were studied. FBF (duplex Doppler ultrasound) and mean arterial pressure (MAP; Finometer) were measured at rest and during rhythmic handgrip exercise at 30% maximal voluntary contraction. FVC was calculated as FBF/MAP. Sympathetic activation was induced via lower body negative pressure (LBNP) at −20 Torr for 2 min at rest and from the 3rd to the 5th min of handgrip. Sympathetic vasoconstriction was assessed as percent reductions in FVC during LBNP. The groups presented similar resting FVC, FBF, and MAP. During LBNP at rest, reductions in FVC were not different between White (−35 ± 10%) and Black men (−32 ± 14%, P = 0.616), indicating similar reflex-induced sympathetic vasoconstriction. During handgrip exercise, there were minimal reductions in FVC with LBNP in either group (White: −1 ± 7%; Black: +1 ± 8%; P = 0.523), indicating functional sympatholysis in both groups. Thus, contrary to our hypothesis, our findings indicate a preserved functional sympatholysis in healthy young Black men compared with White men, suggesting that this mechanism does not appear to contribute to reduced exercise hyperemia during moderate-intensity rhythmic handgrip in this population.

Attenuated forearm vascular conductance responses to rhythmic handgrip in young African-American compared with Caucasian-American men

Previous studies have demonstrated that African-American (AA) individuals have heightened vasoconstrictor and reduced vasodilator responses under resting conditions compared with Caucasian-American (CA) individuals. However, potential differences in vascular responses to exercise remain unclear. Therefore, we tested the hypothesis that, compared with CA subjects, AA subjects would present an attenuated increase in forearm vascular conductance (FVC) during rhythmic handgrip exercise. Forearm blood flow (FBF; duplex Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured in healthy young CA ( n = 10) and AA ( n = 10) men during six trials of rhythmic handgrip performed at workloads of 4, 8, 12, 16, 20, and 24 kg. FVC (calculated as FBF/MAP), FBF, and MAP were similar between groups at rest (FVC: 63 ± 7 ml·min−1·100 mmHg−1 in CA subjects vs. 62 ± 7 ml·min−1·100 mmHg−1 in AA subjects, P = 0.862). There was an intensity-dependent increase in FVC during exercise in both groups; however, AA subjects presented lower FVC (interaction P < 0.001) at 8-, 12-, 16-, 20-, and 24-kg workloads (e.g., 24 kg: 324 ± 20 ml·min−1·100 mmHg−1 in CA subjects vs. 241 ± 21 ml·min−1·100 mmHg−1 in AA subjects, P < 0.001). FBF responses to exercise were also lower in AA subjects (interaction P < 0.001), whereas MAP responses did not differ between groups (e.g., ∆MAP at 24 kg: +19 ± 2 mmHg in CA subjects vs. +19 ± 2 mmHg in AA subjects, interaction P = 0.950). These findings indicate lower hyperemic responses to rhythmic handgrip exercise in AA men compared with CA men. NEW & NOTEWORTHY It is known that African-American individuals have heightened vasoconstriction and reduced vasodilation under resting conditions compared with Caucasian-American individuals. Here, we identified that the hyperemic response to moderate and high-intensity rhythmic handgrip exercise was lower in healthy young African-American men.

Elevated extracellular potassium prior to muscle contraction reduces onset and steady-state exercise hyperemia in humans

The increase in interstitial potassium (K+) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K+ in exercise hyperemia, we perfused skeletal muscle with K+ before contractions, such that the effect of any endogenously-released K+ would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF) (Doppler ultrasound) and forearm vascular conductance (FVC) (FBF/mean arterial pressure) during 4 min of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions, 2) infusion of KCl before the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly before the onset of exercise (control: 39 ± 6 vs. KCl: 81 ± 12 and SNP: 82 ± 13 ml·min−1·100 mmHg−1; both P < 0.05 vs. control). Infusion of KCl at rest diminished the hyperemic (ΔFBF) and vasodilatory (ΔFVC) response to subsequent exercise by 22 ± 5% and 30 ± 5%, respectively (both P < 0.05 vs. control), whereas SNP did not affect the change in FBF ( P = 0.74 vs. control) or FVC ( P = 0.61 vs. control) from rest to steady-state exercise. These findings implicate the K+ ion as an essential vasodilator substance contributing to exercise hyperemia in humans. NEW & NOTEWORTHY Our findings support a significant and obligatory role for potassium signaling in the local vasodilatory and hyperemic response to exercise in humans.

Forearm vasodilator responses to environmental stress and reactive hyperaemia are impaired in young South Asian men

Purpose Prevalence of cardiovascular disease (CVD) is greater in South Asians (SAs) than White Europeans (WEs). Endothelial dysfunction and blunted forearm vasodilatation to environmental stressors have been implicated in CVD. We investigated whether these features are present in young SA men. Methods In 15 SA and 16 WE men (19–23 years), we compared changes in forearm blood flow, arterial blood pressure (ABP), forearm vascular conductance (FVC), heart rate, and electrodermal resistance (EDR; sweating) following release of arterial occlusion (reactive hyperaemia endothelium-dependent) and 5 single sounds at 5–10 min intervals (stressors). Results All were normotensive. Peak reactive hyperaemia was smaller in SAs than WEs (FVC increase: 0.36 ± 0.038 vs 0.44 ± 0.038 units; P < 0.05). Furthermore, in WEs, mean FVC increased at 5, 15, and 20 s of each sound (vasodilatation), but increased at 5 s only in SAs, decreasing by 20 s (vasoconstriction). This reflected a smaller proportion of SAs showing forearm vasodilatation at 15 s (5/15 SAs vs 11/16 WEs: P < 0.01), the remainder showing vasoconstriction. Concomitantly, WEs showed greater bradycardia and EDR changes. Intra-class correlation analyses showed that all responses were highly reproducible over five sounds in both WEs and SAs. Moreover, sound-evoked changes in ABP and FVC were negatively correlated in each ethnicity (P < 0.01). However, WEs showed preponderance of forearm vasodilatation and depressor responses; SAs showed preponderance of vasoconstriction and pressor responses. Conclusions Endothelium-dependent vasodilatation is blunted in young SA men. This could explain their impaired forearm vasodilatation and greater pressor responses to repeated environmental stressors, so predisposing SAs to hypertension and CVD.

Comparison of the vasodilatory effects of sodium nitroprusside vs. nitroglycerin

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.