ABSTRACT
BACKGROUND: Surgeons routinely apply papaverine, lidocaine, or verapamil to produce acute vasodilation and prevent vasospasms during microvascular surgeries. There is evidence that topical vasodilators may induce postoperative endothelial and smooth muscle dysfunction, which would present after the acute vasodilatory effects of the topical drugs wear off. Therefore, the purpose of the current study was to evaluate the lasting effects of papaverine, lidocaine, and verapamil on human deep inferior epigastric perforator artery vasodilatory function after the acute effects of the topical drugs had worn off. METHODS: Deep inferior epigastric arterial samples were obtained from 12 patients during surgery. Each artery was dissected into four rings which where incubated for 1 minute in either physiological saline solution (control), papaverine (30 mg/mL), lidocaine (20 mg/mL), or verapamil (2.5 mg/mL), followed by a 2-hour washout. Endothelial-dependent and -independent vasorelaxation were then assessed by the isometric tension responses to acetylcholine or sodium nitroprusside, respectively. RESULTS: Peak acetylcholine-evoked vasorelaxation (mean ± standard deviation) was not different between control (62 ± 23%) and lidocaine (57 ± 18%, p = 0.881), but was reduced (all p < 0.002) in papaverine (22 ± 27%) and verapamil (22 ± 20%). Peak sodium nitroprusside-evoked vasorelaxation was not different (all p > 0.692) among control (132 ± 35%), lidocaine (121 ± 22%), and verapamil (127 ± 22%), but was less in papaverine (104 ± 41%; p = 0.045) than control. CONCLUSION: Surgically used doses of papaverine and verapamil, but not lidocaine, have lasting negative effects on arterial vasodilatory function despite the acute effects of the drugs having worn off. These findings, in conjunction with the spasmolytic properties of each drug, may help guide the selection of an optimal topical vasodilator for use during microvascular surgeries.
ABSTRACT
Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.
Subject(s)
Exercise , Heart Failure , Muscle, Skeletal , Stroke Volume , Humans , Male , Female , Heart Failure/physiopathology , Heart Failure/metabolism , Aged , Muscle, Skeletal/blood supply , Exercise/physiology , Middle Aged , Phentolamine/pharmacology , Regional Blood Flow , Phenylephrine/pharmacology , Oxygen Consumption , Adrenergic alpha-Antagonists/pharmacology , Leg/blood supplyABSTRACT
Maximal oxygen (O2 ) uptake ( V Ì O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ ) is an important parameter with utility in health and disease. However, the relative importance of O2 transport and utilization capacities in limiting muscle V Ì O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ before and after endurance exercise training is not well understood. Therefore, the present study aimed to identify the mechanisms determining muscle V Ì O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ pre- and post-endurance exercise training in initially sedentary participants. In five initially sedentary young males, radial arterial and femoral venous P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ (blood samples), leg blood flow (thermodilution), and myoglobin (Mb) desaturation (1 H nuclear magnetic resonance spectroscopy) were measured during maximal single-leg knee-extensor exercise (KE) breathing either 12%, 21% or 100% O2 both pre and post 8 weeks of KE training (1 h, 3 times per week). Mb desaturation was converted to intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ using an O2 half-saturation pressure of 3.2 mmHg. Pre-training muscle V Ì O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ was not significantly different across inspired O2 conditions (12%: 0.47 ± 0.10; 21%: 0.52 ± 0.13; 100%: 0.54 ± 0.01 L min-1 , all q > 0.174), despite significantly greater muscle mean capillary-intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ gradients in normoxia (34 ± 3 mmHg) and hyperoxia (40 ± 7 mmHg) than hypoxia (29 ± 5 mmHg, both q < 0.024). Post-training muscle V Ì O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ was significantly different across all inspired O2 conditions (12%: 0.59 ± 0.11; 21%: 0.68 ± 0.11; 100%: 0.76 ± 0.09 mmHg, all q < 0.035), as were the muscle mean capillary-intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ gradients (12%: 32 ± 2; 21%: 37 ± 2; 100%: 45 ± 7 mmHg, all q < 0.029). In these initially sedentary participants, endurance exercise training changed the basis of limitation on muscle V Ì O 2 max ${\dot{V}}_{{{\mathrm{O}}}_{\mathrm{2}}{\mathrm{max}}}$ in normoxia from the mitochondrial capacity to utilize O2 to the capacity to transport O2 to the mitochondria. KEY POINTS: Maximal O2 uptake is an important parameter with utility in health and disease. The relative importance of O2 transport and utilization capacities in limiting muscle maximal O2 uptake before and after endurance exercise training is not well understood. We combined the direct measurement of active muscle maximal O2 uptake with the measurement of muscle intracellular P O 2 ${P}_{{{\mathrm{O}}}_{\mathrm{2}}}$ before and after 8 weeks of endurance exercise training. We show that increasing O2 availability did not increase muscle maximal O2 uptake before training, whereas increasing O2 availability did increase muscle maximal O2 uptake after training. The results suggest that, in these initially sedentary participants, endurance exercise training changed the basis of limitation on muscle maximal O2 uptake in normoxia from the mitochondrial capacity to utilize O2 to the capacity to transport O2 to the mitochondria.
Subject(s)
Muscle, Skeletal , Oxygen Consumption , Male , Humans , Muscle, Skeletal/physiology , Oxygen Consumption/physiology , Oxygen/metabolism , Exercise/physiology , HypoxiaABSTRACT
Lifestyle modification including exercise training is often the first line of defense in the treatment of obesity and hypertension (HTN), however, little is known regarding how these potentially compounding disease states impact vasodilatory and hemodynamic responses at baseline and exercise. Therefore, this study sought to compare the impact of obesity on vascular function and hemodynamics at baseline and during handgrip (HG) exercise among individuals with HTN. Non-obese (13M/7F, 56 ± 16 yr, 25 ± 4 kg/m2) and obese (17M/4F, 50 ± 7 yr, 35 ± 4 kg/m2) middle-aged individuals with HTN forwent antihypertensive medication use for ≥2 wk before assessment of vascular function by brachial artery flow-mediated dilation (FMD) and exercise hemodynamics during progressive HG exercise at 15-30-45% maximal voluntary contraction (MVC). FMD was not different between Non-Obese (4.1 ± 1.7%) and Obese (5.2 ± 1.9%, P = 0.11). Systolic blood pressure (SBP) was elevated by â¼15% during the supine baseline and during HG exercise in the obese group. The blood flow response to HG exercise at 30% and 45% MVC was â¼20% greater (P < 0.05) in the obese group but not different after normalizing for the higher, albeit, nonsignificant differences in workloads (MVC: obese: 24 ± 5 kg, non-obese: 21 ± 5 kg, P = 0.11). Vascular conductance and the brachial artery shear-induced vasodilatory response during HG were not different between groups (P > 0.05). Taken together, despite elevated SBP during HG exercise, obesity does not lead to additional impairments in vascular function and peripheral exercising hemodynamics in patients with HTN. Obesity may not be a contraindication when prescribing exercise for the treatment of HTN among middle-aged adults, however, the elevated SBP should be appropriately monitored.NEW & NOTEWORTHY This study examined vascular function and handgrip exercise hemodynamics in obese and nonobese individuals with hypertension. Obesity, when combined with hypertension, was neither associated with additional vascular function impairments at baseline nor peripheral hemodynamics and vasodilation during exercise compared with nonobese hypertension. Interestingly, systolic blood pressure and pulse pressure were greater in the obese group during supine baseline and exercise. These findings should not be ignored and may be particularly important for rehabilitation strategies.
Subject(s)
Hypertension , Hypotension , Adult , Middle Aged , Humans , Hand Strength , Hemodynamics , Exercise/physiology , Blood Pressure , Obesity , Vasodilation/physiology , Brachial Artery , Regional Blood FlowABSTRACT
In the peripheral and cerebral vasculature, the impact of aging and sex on the endothelial-independent functional capacity of vascular smooth muscle cells (VSMCs) is not well understood, nor is it known whether such VSMC functions in these vascular beds reflect one another. Therefore, endothelium-independent dilation, at both the conduit (Δ diameter) and microvascular (Δ vascular conductance, VC) level, elicited by sublingual nitroglycerin (NTG, 0.8 mg of Nitrostat), compared with sham-delivery (control), was assessed using Doppler ultrasound in the popliteal (PA) and middle cerebral (MCA) artery of 20 young [23 ± 4 yr, 10 males (YM)/10 females (YF)] and 21 old [69 ± 5 yr, 11 males (OM)/10 females (OF)] relatively healthy adults. In the PA, compared with zero, NTG significantly increased diameter in all groups (YM: 0.29 ± 0.13, YF: 0.35 ± 0.26, OM: 0.30 ± 0.18, OF: 0.31 ± 0.14 mm), while control did not. The increase in VC only achieved significance in the OF (0.22 ± 0.31 mL/min/mmHg). In the MCA, compared with zero, NTG significantly increased diameter and VC in all groups (YM: 0.89 ± 0.30, 1.06 ± 1.28; YF: 0.97 ± 0.31, 1.84 ± 1.07; OM: 0.90 ± 0.42, 0.72 ± 0.99; OF: 0.74 ± 0.32, 1.19 ± 1.18, mm and mL/min/mmHg, respectively), while control did not. There were no age or sex differences or age-by-sex interactions for both the NTG-induced PA and MCA dilation and VC. In addition, PA and MCA dilation and VC responses to NTG were not related when grouped by age, sex, or as all subjects (r = 0.04-0.44, P > 0.05). Thus, peripheral and cerebral endothelial-independent VSMC function appears to be unaffected by age or sex, and variations in such VSMC function in one of these vascular beds are not reflected in the other.NEW & NOTEWORTHY To confidently explain peripheral and cerebral vascular dysfunction, it is essential to have a clear understanding of the endothelial-independent function of VSMCs across age and sex. By assessing endothelium-independent dilation using sublingual nitroglycerin, endothelial-independent VSMC function in the periphery (popliteal artery), and in the cerebral circulation (middle cerebral artery), was not different due to age or sex. In addition, endothelial-independent VSMC function in one of these vascular beds is not reflected in the other.
Subject(s)
Nitroglycerin , Vasodilator Agents , Female , Humans , Male , Aging , Brachial Artery/physiology , Endothelium, Vascular/physiology , Nitroglycerin/pharmacology , Vasodilation/physiology , Vasodilator Agents/pharmacology , Young Adult , Adult , AgedABSTRACT
The age-related increase in α-adrenergic tone may contribute to decreased leg vascular conductance (LVC) both at rest and during exercise in the old. However, the effect on passive leg movement (PLM)-induced LVC, a measure of vascular function, which is markedly attenuated in this population, is unknown. Thus, in eight young (25 ± 5 yr) and seven old (65 ± 7 yr) subjects, this investigation examined the impact of systemic ß-adrenergic blockade (propanalol, PROP) alone, and PROP combined with either α1-adrenergic stimulation (phenylephrine, PE) or α-adrenergic inhibition (phentolamine, PHEN), on PLM-induced vasodilation. LVC, calculated from femoral artery blood flow and pressure, was determined and PLM-induced Δ peak (LVCΔpeak) and total vasodilation (LVCAUC, area under curve) were documented. PROP decreased LVCΔpeak (PROP: 4.8 ± 1.8, Saline: 7.7 ± 2.7 mL·mmHg-1, P < 0.001) and LVCAUC (PROP: 1.1 ± 0.7, Saline: 2.4 ± 1.6 mL·mmHg-1, P = 0.002) in the young, but not in the old (LVCΔpeak, P = 0.931; LVCAUC, P = 0.999). PE reduced baseline LVC (PE: 1.6 ± 0.4, PROP: 2.3 ± 0.4 mL·min-1·mmHg-1, P < 0.01), LVCΔpeak (PE: 3.2 ± 1.3, PROP: 4.8 ± 1.8 mL·min-1·mmHg-1, P = 0.004), and LVCAUC (PE: 0.5 ± 0.4, PROP: 1.1 ± 0.7 mL·mmHg-1, P = 0.011) in the young, but not in the old (baseline LVC, P = 0.199; LVCΔpeak, P = 0.904; LVCAUC, P = 0.823). PHEN increased LVC at rest and throughout PLM in both groups (drug effect: P < 0.05), however LVCΔpeak was only improved in the young (PHEN: 6.4 ± 3.1, PROP: 4.4 ± 1.5 mL·min-1·mmHg-1, P = 0.004), and not in the old (P = 0.904). Furthermore, the magnitude of α-adrenergic modulation (PHEN - PE) of LVCΔpeak was greater in the young compared with the old (Young: 3.35 ± 2.32, Old: 0.40 ± 1.59 mL·min-1·mmHg-1, P = 0.019). Therefore, elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.NEW & NOTEWORTHY Stimulation of α1-adrenergic receptors eliminated age-related differences in passive leg movement (PLM) by decreasing PLM-induced vasodilation in the young. Systemic ß-blockade attenuated the central hemodynamic component of the PLM response in young individuals. Inhibition of α-adrenergic receptors did not improve the PLM response in older individuals, though withdrawal of α-adrenergic modulation augmented baseline and maximal vasodilation in both groups. Accordingly, α-adrenergic signaling plays a role in modulating the PLM vasodilatory response in young but not in old adults, and elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.
Subject(s)
Leg , Vasodilation , Humans , Aged , Vasodilation/physiology , Leg/blood supply , Adrenergic Agents/pharmacology , Movement/physiology , Hemodynamics , Regional Blood Flow/physiologyABSTRACT
Exaggerated blood pressure and diminished limb hemodynamics during exercise in patients with hypertension often are not resolved by antihypertensive medications. We hypothesized that, independent of antihypertensive medication status, dietary nitrate supplementation would increase limb blood flow, decrease mean arterial pressure (MAP), and increase limb vascular conductance during exercise in patients with hypertension. Patients with hypertension either abstained from (n = 14, Off-Meds) or continued (n = 12, On-Meds) antihypertensive medications. Within each group, patients consumed (crossover design) nitrate-rich or nitrate-depleted (placebo) beetroot juice for 3 days before performing handgrip (HG) and knee-extensor exercise (KE). Blood flow and MAP were measured using Doppler ultrasound and an automated monitor, respectively. Dietary nitrate increased plasma-[nitrite] Off-Meds and On-Meds. There were no significant effects of dietary nitrate on blood flow, MAP, or vascular conductance during HG in Off-Meds or On-Meds. For KE, dietary nitrate decreased MAP (means ± SD across all 3 exercise intensities, 118 ± 14 vs. 122 ± 14 mmHg, P = 0.024) and increased vascular conductance (26.2 ± 6.1 vs. 24.7 ± 7.0 mL/min/mmHg, P = 0.024), but did not affect blood flow for Off-Meds, with no effects On-Meds. Dietary nitrate-induced changes in blood flow (r = -0.67, P < 0.001), MAP (r = -0.43, P = 0.009), and vascular conductance (r = -0.64, P < 0.001) during KE, but only vascular conductance (r = -0.35, P = 0.039) during HG, were significantly related to the magnitude of placebo values, with no differentiation between groups. Thus, the effects of dietary nitrate on limb hemodynamics and MAP during exercise in patients with hypertension are dependent on the values at baseline, independent of antihypertensive medication status, and dependent on whether exercise was performed by the forearm or quadriceps.NEW & NOTEWORTHY Adverse hemodynamic responses to exercise in patients with hypertension, despite antihypertensive medication, indicate a sustained cardiovascular risk. The efficacy of dietary nitrate to improve limb vascular conductance during exercise was inversely dependent on the magnitude of exercising limb vascular conductance at baseline, rather than antihypertensive medication status. The effects of dietary nitrate on hemodynamics during exercise in patients with hypertension are dependent on the values at baseline and independent of antihypertensive medication status.
Subject(s)
Dietary Supplements , Essential Hypertension , Exercise Therapy , Nitrates , Antihypertensive Agents , Blood Pressure , Cross-Over Studies , Essential Hypertension/diet therapy , Essential Hypertension/therapy , Hand Strength/physiology , Hemodynamics , Humans , MusclesABSTRACT
BACKGROUND: Vascular dysfunction, an independent risk factor for cardiovascular disease, often persists in patients with hypertension, despite improvements in blood pressure control induced by antihypertensive medications. METHODS: As some of these medications may directly affect vascular function, this study sought to comprehensively examine the impact of reducing blood pressure, by a nonpharmacological approach (5âdays of sodium restriction), on vascular function in 22 hypertensive individuals (14 men/8 women, 50â±â10 years). Following a 2-week withdrawal of antihypertensive medications, two 5-day dietary phases, liberal sodium (liberal sodium, 200âmmol/day) followed by restricted sodium (restricted sodium, 10âmmol/day), were completed. Resting blood pressure was assessed and vascular function, at both the conduit and microvascular levels, was evaluated by brachial artery flow-mediated dilation (FMD), reactive hyperemia, progressive handgrip exercise, and passive leg movement (PLM). RESULTS: Despite a sodium restriction-induced fall in blood pressure (liberal sodium: 141â±â14/85â±â9; restricted sodium 124â±â12/79â±â9âmmHg, Pâ<â0.01 for both SBP and DBP), FMD (liberal sodium: 4.6â±â1.8%; restricted sodium: 5.1â±â2.1%, Pâ=â0.27), and reactive hyperemia (liberal sodium: 548â±â201; restricted sodium: 615â±â206âml, Pâ=â0.08) were not altered. Similarly, brachial artery vasodilation during handgrip exercise was not different between conditions (liberal sodium: Δ0.36â±â0.19âmm; restricted sodium: Δ0.42â±â0.18âmm, Pâ=â0.16). Lastly, PLM-induced changes in peak blood flow (liberal sodium: 5.3â±â2.5; restricted sodium: 5.8â±â3.6âml/min per mmHg, Pâ=â0.30) and the total vasodilatory response [liberal sodium: 2 (0.9-2.5) vs. restricted sodium: 1.7 (1.1-2.6) ml/min per mmHg; Pâ=â0.5] were also not different between conditions. CONCLUSION: Thus vascular dysfunction, at both the conduit and microvascular levels, persists in patients with hypertension even when blood pressure is acutely reduced by a nonpharmacological approach.
Subject(s)
Hyperemia , Hypertension , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Blood Pressure , Brachial Artery/physiology , Endothelium, Vascular , Female , Hand Strength , Humans , Male , Regional Blood Flow , Sodium , VasodilationABSTRACT
Intramuscular hydrogen ion (H+ ) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P-MRS) was used to continuously quantify intramuscular [H+ ] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw ) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+ ] (ß coefficient: -0.9, P < 0.0001) and [Pi] (-1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+ ] (-0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+ ] in Trial 1 vs. Trial 2. VA was related to [H+ ] (-0.3, P < 0.0001), but not [Pi] (-0.2, P = 0.243), across trials and there was no effect of trial (-0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. KEY POINTS: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee-extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+ ) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch-force (Qtw ) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P-MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+ ] did not. Qtw was strongly related to both [H+ ] and [Pi] across both trials. However, the relationship between Qtw and [H+ ] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+ ], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.
Subject(s)
Acidosis , Phosphates , Electromyography , Fatigue , Humans , Male , Muscle Contraction , Muscle Fatigue/physiology , Muscle, Skeletal/physiology , PhosphorusABSTRACT
NEW FINDINGS: What is the central question of this study? Use of the passive leg movement (PLM) test, a non-invasive assessment of microvascular function, is on the rise. However, PLM reliability in men has not been adequately investigated, nor has such reliability data, in men, been compared to the most commonly employed vascular function assessment, flow-mediated vasodilation (FMD). What is the main finding and its importance? PLM is a reliable method to assess vascular function in men, and is comparable to values previously reported for PLM in women, and for FMD. Given the importance of vascular function as a predictor of cardiovascular disease risk, these data support the utility of PLM as a clinically relevant measurement. ABSTRACT: Although vascular function is an independent predictor of cardiovascular disease risk, and therefore has significant prognostic value, there is currently not a single clinically accepted method of assessment. The passive leg movement (PLM) assessment predominantly reflects microvascular endothelium-dependent vasodilation and can identify decrements in vascular function with advancing age and pathology. Reliability of the PLM model was only recently determined in women, and has not been adequately investigated in men. Twenty healthy men (age: 27 ± 2 year) were studied on three separate experimental days, resulting in three within-day and three between-day trials. The hyperemic response to PLM was assessed with Doppler ultrasound, and expressed as the absolute peak in leg blood flow (LBFpeak ), change from baseline to peak (ΔLBFpeak ), absolute area under the curve (LBFAUC ), and change in AUC from baseline (ΔLBFAUC ). PLM-induced hyperemia yielded within-day coefficients of variation (CV) from 10.9 to 22.9%, intraclass correlation coefficients (ICC) from 0.82 to 0.90, standard error of the measurement (SEM) from 8.3 to 17.2%, and Pearson's correlation coefficients (r) from 0.56 to 0.81. Between-day assessments of PLM hyperemia resulted in CV from 14.4 to 25%, ICC from 0.75 to 0.87, SEM from 9.8 to 19.8%, and r from 0.46 to 0.75. Similar to previous reports in women, the hyperemic responses to PLM in men display moderate-to-high reliability, and are comparable to reliability data for brachial artery flow mediated vasodilation. These positive reliability findings further support the utility of PLM as a clinical measurement of vascular function and cardiovascular disease risk.
Subject(s)
Cardiovascular Diseases , Hyperemia , Adult , Brachial Artery , Endothelium, Vascular , Female , Humans , Leg/blood supply , Male , Movement/physiology , Regional Blood Flow/physiology , Reproducibility of Results , Vasodilation/physiologyABSTRACT
As a deficiency in tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase, has been implicated in the age-related decline in vascular function, this study aimed to determine the impact of acute BH4 supplementation on flow-mediated vasodilation (FMD) in old adults. Two approaches were used: 1) A multiday, double-blind, placebo-controlled, crossover design measuring, FMD [ΔFMD (mm), %FMD (%)] and shear rate area under the curve (SR AUC) in nine old subjects (73 ± 8 yr) with either placebo (placebo) or BH4 (≈10 mg/kg, post), and 2) a single experimental day measuring FMD in an additional 13 old subjects (74 ± 7 yr) prior to (pre) and 4.5 h after ingesting BH4 (≈10 mg/kg). With the first experimental approach, acute BH4 intake did not significantly alter FMD (ΔFMD: 0.17 ± 0.03 vs. 0.13 ± 0.02 mm; %FMD: 3.3 ± 0.61 vs. 2.9 ± 0.4%) or SR AUC (30,280 ± 4,428 vs. 37,877 ± 9,241 s-1) compared with placebo. Similarly, with the second approach, BH4 did not significantly alter FMD (ΔFMD: 0.09 ± 0.02 vs. 0.12 ± 0.03 mm; %FMD: 2.2 ± 0.6 vs. 2.9 ± 0.6%) or SR AUC (37,588 ± 6,753 vs. 28,996 ± 3,735 s-1) compared with pre. Moreover, when the two data sets were combined, resulting in a greater sample size, there was still no evidence of an effect of BH4 on vascular function in these old subjects. Importantly, both plasma BH4 and 7,8-dihydrobiopterin (BH2), the oxidized form of BH4, increased significantly with acute BH4 supplementation. Consequently, the ratio of BH4/BH2, recognized to impact vascular function, was unchanged. Thus, acute BH4 supplementation does not correct vascular dysfunction in the old.NEW & NOTEWORTHY Despite two different experimental approaches, acute BH4 supplementation did not affect vascular function in older adults, as measured by flow-mediated vasodilation. Plasma levels of both BH4 and BH2, the BH4 oxidized form, significantly increased after acute BH4 supplementation, resulting in an unchanged ratio of BH4/BH2, a key determining factor for endothelial nitric oxide synthase coupling. Therefore, likely due to the elevated oxidative stress with advancing age, acute BH4 supplementation does not correct vascular dysfunction in the old.
Subject(s)
Endothelium, Vascular , Nitric Oxide Synthase Type III , Aged , Biopterins/analogs & derivatives , Dietary Supplements , Humans , Nitric Oxide Synthase Type III/metabolism , Oxidative StressABSTRACT
NEW FINDINGS: What is the central question of this study? The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA): what is the impact of baseline CFA blood flow on the PLM response? What is the main finding and its importance? Although an attenuated PLM response is not an obligatory consequence of increased baseline CFA blood flow, increased blood flow through the deep femoral artery will diminish the response. Care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performing a PLM vascular function assessment. ABSTRACT: The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA). This response is primarily driven by vasodilation of the microvasculature downstream from the deep (DFA) and, to a lesser extent, the superficial (SFA) femoral artery, which facilitate blood flow to the upper and lower leg, respectively. However, the impact of baseline CFA blood flow on the PLM response is unknown. Therefore, to manipulate baseline CFA blood flow, PLM was performed with and without upper and lower leg cutaneous heating in 10 healthy subjects, with blood flow (ultrasound Doppler) and blood pressure (finometer) assessed. Baseline blood flow was significantly increased in the CFA (â¼97%), DFA (â¼109%) and SFA (â¼78%) by upper leg heating. This increase in baseline CFA blood flow significantly attenuated the PLM-induced total blood flow in the DFA (â¼62%), which was reflected by a significant fall in blood flow in the CFA (â¼49%), but not in the SFA. Conversely, lower leg heating increased blood flow in the CFA (â¼68%) and SFA (â¼160%), but not in the DFA. Interestingly, this increase in baseline CFA blood flow only significantly attenuated the PLM-induced total blood flow in the SFA (â¼60%), and not in the CFA or DFA. Thus, although an attenuated PLM response is not an obligatory consequence of an increase in baseline CFA blood flow, an increase in baseline blood flow through the DFA will diminish the PLM response. Therefore, care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performance of a PLM vascular function assessment.
Subject(s)
Hyperemia , Leg , Femoral Artery/physiology , Hemodynamics/physiology , Humans , Leg/blood supply , Movement/physiology , Regional Blood Flow/physiologyABSTRACT
The regulation of mean arterial pressure (MAP) during exercise has important physiological and clinical implications. Kinetics analysis on numerous physiological variables following the transition from unloaded-to-loaded exercise has revealed important information regarding their control. Surprisingly, the dynamic response of MAP during this transition remains to be quantified. Therefore, ten healthy participants (5/5 M/F, 24 ± 3 yr) completed repeated transitions from unloaded to moderate- and heavy-intensity dynamic single-leg knee-extensor exercise to investigate the on-kinetics of MAP. Following the transition to loaded exercise, MAP increased in a first-order dynamic manner, subsequent to a time delay (moderate: 23 ± 10; heavy: 19 ± 9 s, P > 0.05) at a speed (τ, moderate: 59 ± 30; heavy: 66 ± 19 s, P > 0.05), which did not differ between intensities, but the MAP amplitude was doubled during heavy-intensity exercise (moderate: 12 ± 5; heavy: 24 ± 8 mmHg, P < 0.001). The reproducibility [coefficient of variation (CV)] during heavy intensity for unloaded baseline, amplitude, and mean response time, when assessed as individual transitions, was 7 ± 1%, 18 ± 2%, and 25 ± 4%, respectively. Averaging two transitions improved the CVs to 4 ± 1%, 8 ± 2%, and 13 ± 3%, respectively. Preliminary findings supporting the clinical relevance of evaluating MAP kinetics in middle-aged hypertensive (n = 5) and, age-matched, normotensive (n = 5) participants revealed an exaggerated MAP response in both older groups (P < 0.05), but the MAP response was slowed only for the patients with hypertension (P < 0.05). It is concluded that kinetics modeling of MAP is practical for heavy-intensity knee-extensor exercise and may provide insight into cardiovascular health and the effect of aging.NEW & NOTEWORTHY Kinetics analysis of physiological variables following workload transitions provides important information, but this has not been performed on mean arterial pressure (MAP), despite the clear clinical importance of this variable. This investigation reveals that kinetic modeling of MAP following unloaded-to-loaded knee-extensor exercise is practical and repeatable. Additional preliminary findings in hypertensive and, age-matched, normotensive subjects suggest that MAP kinetics may provide insight into cardiovascular health and the effect of aging.
Subject(s)
Arterial Pressure , Exercise , Aging , Health Status , Humans , Middle Aged , Muscle, Skeletal/metabolism , Oxygen Consumption , Reproducibility of ResultsABSTRACT
Both convective oxygen (O2) transport to, and diffusive transport within, skeletal muscle are markedly diminished in patients with COPD. However, it is unknown how these determinants of peak muscle O2 uptake (V'mO2peak) respond to exercise training in patients with COPD. Therefore, the purpose of this study was to assess the plasticity of skeletal muscle O2 transport determinants of V'mO2peak in patients with COPD.Adaptations to 8â weeks of single-leg knee-extensor exercise training were measured in eight patients with severe COPD (mean±sem forced expiratory volume in 1â s (FEV1) 0.9±0.1 L) and eight healthy, well-matched controls. Femoral arterial and venous blood samples, and thermodilution-assessed leg blood flow were used to determine muscle O2 transport and utilisation at maximal exercise pre- and post-training.Training increased V'mO2peak in both COPD (by â¼26% from 271±29 to 342±35â mL·min-1) and controls (by â¼32% from 418±37 to 553±41â mL·min-1), restoring V'mO2peak in COPD to only â¼80% of pre-training control V'mO2peak Muscle diffusive O2 transport increased similarly in both COPD (by â¼38% from 6.6±0.9 to 9.1±0.9â mL·min-1·mmHg-1) and controls (by â¼36% from 10.4±0.7 to 14.1±0.8â mL·min-1·mmHg-1), with the patients reaching â¼90% of pre-training control values. In contrast, muscle convective O2 transport increased significantly only in controls (by â¼26% from 688±57 to 865±69â mL·min-1), leaving patients with COPD (438±45 versus 491±51â mL·min-1) at â¼70% of pre-training control values.While muscle diffusive O2 transport in COPD was largely restored by exercise training, V'mO2peak remained constrained by limited plasticity in muscle convective O2 transport.
Subject(s)
Oxygen Consumption , Pulmonary Disease, Chronic Obstructive , Exercise , Exercise Test , Humans , Muscle, Skeletal , Oxygen/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/therapyABSTRACT
Vascular function is further attenuated in patients with chronic heart failure implanted with a continuous-flow left ventricular assist device (LVAD), likely due to decreased arterial pulsatility, and this may contribute to LVAD-associated cardiovascular complications. However, the impact of increasing pulsatility on vascular function in this population is unknown. Therefore, 15 LVAD recipients and 15 well-matched controls underwent a 45-min, unilateral, arm pulsatility treatment, evoked by intermittent cuff inflation/deflation (2-s duty cycle), distal to the elbow. Vascular function was assessed by percent brachial artery flow-mediated dilation (%FMD) and reactive hyperemia (RH) (Doppler ultrasound). Pretreatment, %FMD (LVAD: 4.0 ± 1.7; controls: 4.2 ± 1.4%) and RH (LVAD: 340 ± 101; controls: 308 ± 94 mL) were not different between LVAD recipients and controls; however, %FMD/shear rate was attenuated (LVAD: 0.10 ± 0.04; controls: 0.17 ± 0.06%/s-1, P < 0.05). The LVAD recipients exhibited a significantly attenuated pulsatility index (PI) compared with controls prior to treatment (LVAD: 2 ± 2; controls: 15 ± 7 AU, P < 0.05); however, during the treatment, PI was no longer different (LVAD: 37 ± 38; controls: 36 ± 14 AU). Although time to peak dilation and RH were not altered by the pulsatility treatment, %FMD (LVAD: 7.0 ± 1.8; controls: 7.4 ± 2.6%) and %FMD/shear rate (LVAD: 0.19 ± 0.07; controls: 0.33 ± 0.15%/s-1) increased significantly in both groups, with, importantly, %FMD/shear rate in the LVAD recipients being restored to that of the controls pretreatment. This study documents that a localized pulsatility treatment in LVAD recipients and controls can recover local vascular function, an important precursor to the development of approaches to increase systemic pulsatility and reduce systemic vascular complications in LVAD recipients.
Subject(s)
Heart Failure/therapy , Heart-Assist Devices , Prosthesis Implantation/instrumentation , Pulsatile Flow , Therapeutic Occlusion/instrumentation , Upper Extremity/blood supply , Ventricular Function, Left , Aged , Case-Control Studies , Cross-Over Studies , Heart Failure/diagnostic imaging , Heart Failure/physiopathology , Humans , Male , Middle Aged , Prosthesis Design , Prosthesis Implantation/adverse effects , Recovery of Function , Regional Blood Flow , Therapeutic Occlusion/adverse effects , Treatment OutcomeABSTRACT
Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P-450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBFAUC)] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271 ± 97 mL, P > 0.05) or sPLM (LBFAUC: 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P-450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.
Subject(s)
Endothelium, Vascular/physiology , Hyperemia , Movement , Muscle Contraction , Muscle, Skeletal/blood supply , Nitric Oxide/metabolism , Vasodilation , Adult , Biological Factors/metabolism , Blood Flow Velocity , Cyclooxygenase Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Endothelium, Vascular/metabolism , Healthy Volunteers , Humans , Infusions, Intra-Arterial , Leg , Male , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Prostaglandins/metabolism , Regional Blood Flow , Signal Transduction , Time Factors , Young AdultABSTRACT
Nitric oxide synthase (NOS) inhibition with N(G)-monomethyl-l-arginine (L-NMMA) is often used to assess the role of NO in human cardiovascular function. However, the window of effect for L-NMMA on human vascular function is unknown, which is critical for designing and interpreting human-based studies. This study utilized the passive leg movement (PLM) assessment of vascular function, which is predominantly NO-mediated, in 7 young male subjects under control conditions, immediately following intra-arterial L-NMMA infusion (0.24 mgâ dl-1â min-1), and at 45-60 and 90-105 min post L-NMMA infusion. The leg blood flow (LBF) and leg vascular conductance (LVC) responses to PLM, measured with Doppler ultrasound and expressed as the change from baseline to peak (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCACU), were assessed. PLM-induced robust control ΔLBFpeak (1135 ± 324 mlâ min-1) and ΔLVCpeak (10.7 ± 3.6 mlâ min-1â mmHg-1) responses that were significantly attenuated (704 ± 196 mlâ min-1 and 6.7 ± 2 mlâ min-1â mmHg-1) immediately following L-NMMA infusion. Likewise, control condition PLM ΔLBFAUC (455 ± 202 ml) and ΔLVCAUC (4.0 ± 1.4 mlâ mmHg-1) were significantly attenuated (141 ± 130 ml and 1.3 ± 1.2 mlâ mmHg-1) immediately following L-NMMA infusion. However, by 45-60 min post L-NMMA infusion all PLM variables were not significantly different from control, and this was still the case at 90-105 min post L-NMMA infusion. These findings reveal that the potent reduction in NO bioavailability afforded by NOS inhibition with L-NMMA has a window of effect of less than 45-60 min in the human vasculature. These data are particularly important for the commonly employed approach of pharmacologically inhibiting NOS with L-NMMA in the human vasculature.
Subject(s)
Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase/antagonists & inhibitors , omega-N-Methylarginine/pharmacokinetics , Adult , Femoral Artery/physiology , Hemodynamics/drug effects , Humans , Leg/blood supply , Male , Nitric Oxide/metabolism , Regional Blood Flow/drug effects , Time Factors , Young AdultABSTRACT
Although the contribution of noncardiac complications to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) have been increasingly recognized, disease-related changes in peripheral vascular control remain poorly understood. We utilized small muscle mass handgrip exercise to concomitantly evaluate exercising muscle blood flow and conduit vessel endothelium-dependent vasodilation in individuals with HFpEF (n = 25) compared with hypertensive controls (HTN) (n = 25). Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), brachial artery blood velocity, and brachial artery diameter were assessed during progressive intermittent handgrip (HG) exercise [15-30-45% maximal voluntary contraction (MVC)]. Forearm blood flow (FBF) and vascular conductance (FVC) were determined to quantify the peripheral hemodynamic response to HG exercise, and changes in brachial artery diameter were evaluated to assess endothelium-dependent vasodilation. HR, SV, and CO were not different between groups across exercise intensities. However, although FBF was not different between groups at the lowest exercise intensity, FBF was significantly lower (20-40%) in individuals with HFpEF at the two higher exercise intensities (30% MVC: 229 ± 8 versus 274 ± 23 ml/min; 45% MVC: 283 ± 17 versus 399 ± 34 ml/min, HFpEF versus HTN). FVC was not different between groups at 15 and 30% MVC but was â¼20% lower in HFpEF at the highest exercise intensity. Brachial artery diameter increased across exercise intensities in both HFpEF and HTN, with no difference between groups. These findings demonstrate an attenuation in muscle blood flow during exercise in HFpEF in the absence of disease-related changes in central hemodynamics or endothelial function.NEW & NOTEWORTHY The current study identified, for the first time, an attenuation in exercising muscle blood flow during handgrip exercise in individuals with heart failure with preserved ejection fraction (HFpEF) compared with overweight individuals with hypertension, two of the most common comorbidities associated with HFpEF. These decrements in exercise hyperemia cannot be attributed to disease-related changes in central hemodynamics or endothelial function, providing additional evidence for disease-related vascular dysregulation, which may be a predominant contributor to exercise intolerance in individuals with HFpEF.
Subject(s)
Heart Failure , Blood Flow Velocity , Hand Strength , Humans , Muscle, Skeletal , Regional Blood Flow , Stroke VolumeABSTRACT
Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆-4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆-0.88 ± 4.7 cm/s) (P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) (P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆-5 ± 130 ml/min) (P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.