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90 million Americans suffer metabolic syndrome (MetSyn), increasing risk of diabetes and poor brain outcomes including neuropathology linked to lower cerebral blood flow (CBF)-predominantly in anterior regions. We tested the hypothesis total and regional CBF is lower in MetSyn more so in the anterior brain and explored three potential mechanisms. 34 Controls (25±5 yrs) and 19 MetSyn (30±9 yrs), with no history of cardiovascular disease/medications, underwent 4D flow magnetic resonance imaging (MRI) to quantify macrovascular CBF, while arterial spin labeling (ASL) quantified brain perfusion in a subset (n=38/53). Contributions of cyclooxygenase (COX; n=14), nitric oxide synthase (NOS, n=17), or endothelin receptor A signaling (ETA; n=13) were tested with indomethacin, L-NMMA, and Ambrisentan, respectively. Total CBF was 20±16% lower in MetSyn (725±116 vs. 582±119 mL/min, P

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 with 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. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) 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/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18–40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [N(G)-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). 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 adults with obesity (P = 0.27). 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 adults with obesity. Despite shifts in COX and NOS, β-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity. NEW & NOTEWORTHY We examined β-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, β-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

Cyclooxygenase (COX) is proposed to regulate cerebral blood flow (CBF); however, accurate regional contributions of COX are relatively unknown at baseline and particularly during hypoxia. We hypothesized that COX contributes to both basal and hypoxic cerebral vasodilation, but COX-mediated vasodilation is greater in the posterior versus anterior cerebral circulation. CBF was measured in 9 healthy adults (28 ± 4 yr) during normoxia and isocapnic hypoxia (fraction of inspired oxygen = 0.11), with COX inhibition (oral indomethacin, 100mg) or placebo. Four-dimensional flow magnetic resonance imaging measured cross-sectional area (CSA) and blood velocity to quantify CBF in 11 cerebral arteries. Cerebrovascular conductance (CVC) was calculated (CVC = CBF × 100/mean arterial blood pressure) and hypoxic reactivity was expressed as absolute and relative change in CVC [ΔCVC/Δ pulse oximetry oxygen saturation ([Formula: see text])]. At normoxic baseline, indomethacin reduced CVC by 44 ± 5% ( P < 0.001) and artery CSA ( P < 0.001), which was similar across arteries. Hypoxia ([Formula: see text] 80%–83%) increased CVC ( P < 0.01), reflected as a similar relative increase in reactivity (% ΔCVC/−Δ[Formula: see text]) across arteries ( P < 0.05), in part because of increases in CSA ( P < 0.05). Indomethacin did not alter ΔCVC or ΔCVC/Δ[Formula: see text] to hypoxia. These findings indicate that 1) COX contributes, in a largely uniform fashion, to cerebrovascular tone during normoxia and 2) COX is not obligatory for hypoxic vasodilation in any regions supplied by large extracranial or intracranial arteries.

In healthy young women, basal cerebral blood flow (CBF) and cerebrovascular reactivity may change across the menstrual cycle, but mechanisms remain untested. When compared with the early follicular phase of the menstrual cycle, we hypothesized women in late follicular phase would exhibit: 1) greater basal CBF, 2) greater hypercapnic increases in CBF, 3) greater hypoxic increases in CBF, and 4) increased cyclooxygenase (COX) signaling. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 11 healthy women (23 ± 1 yr) during rest, hypoxia, and hypercapnia. Subjects completed four visits: two during the early follicular (∼ day 3) and two during the late follicular (∼ day 14) phases of the menstrual cycle, with and without COX inhibition (oral indomethacin). Isocapnic hypoxia elicited an SPO2 = 90% and SPO2 = 80% for 5 min each. Separately, hypercapnia increased end-tidal CO2 10 mmHg above baseline. Cerebral vascular conductance index (CVCi = MCAv/MABP·100, where MABP is mean arterial blood pressure) was calculated and a positive change reflected vasodilation (ΔCVCi). Basal CVCi was greater in the late follicular phase ( P < 0.001). Indomethacin decreased basal CVCi (∼37%) and abolished the phase difference ( P < 0.001). Hypoxic ΔCVCi was similar between phases and unaffected by indomethacin. Hypercapnic ΔCVCi was similar between phases, and indomethacin decreased hypercapnic ΔCVCi (∼68%; P < 0.001) similarly between phases. In summary, while neither hypercapnic nor hypoxic vasodilation is altered by menstrual phase, increased basal CBF in the late follicular phase is fully explained by a greater contribution of COX. These data provide new mechanistic insight into anterior CBF regulation across menstrual phases and contribute to our understanding of CBF regulation in women.

The inability to quantify cerebral blood flow and changes in macrocirculation cross-sectional area in all brain regions impedes robust insight into hypoxic cerebral blood flow control. We applied four-dimensional flow magnetic resonance imaging to quantify cerebral blood flow (ml • min−1) and cross-sectional area (mm2) simultaneously in 11 arteries. In healthy adults, blood pressure, O2 Saturation (SpO2), and end-tidal CO2 were measured at baseline and steady-state hypoxia (FiO2 = 0.11). We investigated left and right: internal carotid, vertebral, middle, anterior, posterior cerebral arteries, and basilar artery. Hypoxia (SpO2 = 80±2%) increased total cerebral blood flow from 621±38 to 742±50 ml • min−1 ( p 2−1) were not different between arteries. Collectively, moderate hypoxia: (1) increased cerebral blood flow, but relative distribution remains similar to normoxia, (2) evokes similar vascular reactivity between 11 arteries, and (3) increased cross-sectional area primarily in the anterior arteries. This study provides the first wide-ranging, quantitative, functional and structural data regarding intracranial arteries during hypoxia in humans, highlighting cerebral blood flow regulation of microcirculation and macrocirculation differs between anterior and posterior circulation.

We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men ( n = 29, 26 ± 1 yr) and women ( n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [ NG-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion ( P < 0.01), and this effect was not different between men and women ( P = 0.41). l-NMMA infusion had no effect on isoproterenol-mediated dilation in men ( P > 0.99) or women ( P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men ( P < 0.01) and women ( P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). β-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.

AIM The role of reactive oxygen species (ROS) in human cerebral blood flow (CBF) during hypoxia is largely unknown. Additionally, it is unknown whether ROS interact with cyclooxygenase-derived signals during hypoxia to increase CBF. We hypothesized ROS inhibition would reduce hypoxic CBF, and combined inhibition of cyclooxygenase (COX) and ROS would decrease hypoxic CBF more than ROS suppression alone. METHODS We measured middle cerebral artery velocity with transcranial Doppler ultrasound in 12 healthy adults during normoxia and 2 isocapnic hypoxia trials. Intravenous ascorbic acid infusion during the first hypoxia trial suppressed ROS. Oral indomethacin inhibited COX between hypoxia trials. The second bout of hypoxia tested the combined effects of ROS and COX inhibition. Middle cerebral artery velocity was normalized for blood pressure as cerebrovascular conductance index. RESULTS Hypoxia increased cerebrovascular conductance index in both trials (P

We hypothesized exercise vasodilation would be greater in women due to nitric oxide synthase (NOS) and cyclooxygenase (COX) signaling.45 healthy adults (23 women, W, 22 men, M, 26 ± 1 years) completed two 10-min trials of dynamic forearm exercise at 15 % intensity. Forearm blood flow (FBF; Doppler ultrasound), arterial pressure (brachial catheter), and forearm lean mass were measured to calculate relative forearm vascular conductance (FVCrel) = FBF 100 mmHg(-1) 100 g(-1) lean mass. Local intra-arterial infusion of L-NMMA or ketorolac acutely inhibited NOS and COX, respectively. In Trial 1, the first 5 min served as control exercise (CON), followed by 5 min of L-NMMA or ketorolac over the last 5 min of exercise. In Trial 2, the remaining drug was infused during 5-10 min, to achieve combined NOS-COX inhibition (double blockade, DB).Are mean ± SE. Women exhibited 29 % greater vasodilation in CON (ΔFVCrel, 19 ± 1 vs. 15 ± 1, p = 0.01). L-NMMA reduced ΔFVCrel (p0.001) (W: Δ -2.3 ± 1.3 vs. M: Δ -3.7 ± 0.8, p = 0.25); whereas, ketorolac modestly increased ΔFVCrel (p = 0.04) similarly between sexes (W: Δ 1.6 ± 1.1 vs. M: Δ 2.0 ± 1.6, p = 0.78). DB was also found to be similar between the sexes (p = 0.85).These data clearly indicate women produce a greater exercise vasodilator response. Furthermore, contrary to experiments in animal models, these data are the first to demonstrate vascular control by NOS and COX is similar between sexes.

We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults ( n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise − rest) before and during acute AA infusion. The MRT ( P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group ( P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT ( r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion ( r = −0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA.

Older adults with cardiovascular disease exhibit microvascular dysfunction and increased levels of reactive oxygen species (ROS). We hypothesized that microvascular impairments begin early in the disease process and can be improved by scavenging ROS. Forearm blood flow (Doppler ultrasound) was measured in 45 young (32 ± 2 yr old) adults ( n = 15/group) classified as lean, obese, and metabolic syndrome (MetSyn). Vasodilation in response to endothelial (ACh) and vascular smooth muscle [nitroprusside (NTP) and epoprostenol (Epo)] agonists was tested before and after intra-arterial infusion of ascorbic acid to scavenge ROS. Vasodilation was assessed as a rise in relative vascular conductance (ml·min−1·dl−1·100 mmHg−1). ACh and NTP responses were preserved ( P = 0.825 and P = 0.924, respectively), whereas Epo responses were lower in obese and MetSyn adults ( P < 0.05) than in lean controls. Scavenging of ROS via infusion of ascorbic acid resulted in an increase in ACh-mediated ( P < 0.001) and NTP-mediated ( P < 0.001) relative vascular conductance across all groups, suggesting that oxidative stress influences vascular responsiveness in adults with and without overt cardiovascular disease risk. Ascorbic acid had no effect on Epo-mediated vasodilation ( P = 0.267). These results suggest that obese and MetSyn adults exhibit preserved endothelium-dependent vasodilation with reduced dependence on prostacyclin and are consistent with an upregulation of compensatory vascular control mechanisms.

Background: β-adrenergic receptors play an important role in mitigating the pressor effects of sympathetic nervous system activity in young women. Based on recent data showing oral contraceptive use in women abolishes the relationship between muscle sympathetic nervous system activity and blood pressure, we hypothesized forearm blood flow responses to a β-adrenergic receptor agonist would be greater in young women currently using oral contraceptives (OC+, n = 13) when compared to those not using oral contraceptives (OC–, n = 10). Methods: Women (18–35 years) were studied during the early follicular phase of the menstrual cycle (days 1–5) or placebo phase of oral contraceptive use. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured at baseline and during graded brachial artery infusion of the β-adrenergic receptor agonist, Isoproterenol (ISO), as well as Acetylcholine (ACH, endothelium-dependent vasodilation) and Nitroprusside (NTP, endothelium-independent vasodilation). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100 mmHg) and the rise in FVC from baseline during infusion quantified vasodilation (ΔFVC = FVCinfusion − FVCbaseline). Results: ISO increased FVC in both groups (p < 0.01) and ISO-mediated ΔFVC was greater in OC+ compared to OC– (Main effect of group, p = 0.02). Expressing data as FVC and FBF resulted in similar conclusions. FVC responses to both ACH and NTP were also greater in OC+ compared to OC–. Conclusions: These data are the first to demonstrate greater β-adrenergic receptor-mediated vasodilation in the forearm of women currently using oral contraceptives (placebo phase) when compared to those not using oral contraceptives (early follicular phase), and suggest oral contraceptive use influences neurovascular control.

Metabolic syndrome (MetSyn) increases the risk of cerebrovascular disease and stroke; however, its impact on human cerebral circulation remains unclear. Reduced cerebral dilation is also associated with an increased risk of stroke and may occur in MetSyn adults. We hypothesised that MetSyn adults would exhibit reduced cerebral vasodilation to hypoxia and hypercapnia. Middle cerebral artery velocity (MCAv) was insonated with Doppler ultrasound in younger (approximately 35 years) MetSyn and healthy adults. We measured mean arterial blood pressure (MABP), arterial oxygen saturation (SpO2) and end tidal carbon dioxide (PetCO2). Cerebrovascular conductance index (CVCi) was calculated as MCAv*100/MABP. Cerebral vasodilation (ΔCVCi) to hypoxia (SpO2 = 90% and 80%) and hypercapnia (+10 mm Hg PetCO2) was assessed. Baseline MCAv was similar, while adults with MetSyn had lower baseline CVCi. MetSyn adults demonstrated markedly reduced ΔCVCi compared to healthy adults in response to hypoxia (90% SpO2: 1±2 vs 6±2; 80% SpO2: 5±2 vs 15±3 cm/s/mmHg, p

Data indicate endothelium-dependent dilation (EDD) may be preserved in the skeletal muscle microcirculation of young, obese adults. Preserved EDD might be mediated by compensatory mechanisms, impeding insight into preclinical vascular dysfunction. We aimed to determine the functional roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) toward EDD in younger obese adults. We first hypothesized EDD would be preserved in young, obese adults. Further, we hypothesized a reduced contribution of NOS in young, obese adults would be replaced by increased COX signaling. Microvascular EDD was assessed with Doppler ultrasound and brachial artery infusion of acetylcholine (ACh) in younger (27±1 yr) obese (n=29) and lean (n=46) humans. Individual and combined contributions of NOS and COX were examined with intra-arterial infusions of L-NMMA and ketorolac, respectively. Vasodilation was quantified as an increase in forearm vascular conductance (ΔFVC). Arterial endothelial cell biopsies were analyzed for protein expression of endothelial nitric oxide synthase (eNOS). ΔFVC to ACh was similar between groups. After L-NMMA, ΔFVC to ACh was greater in obese adults (p

Non-invasive measurement of cerebral blood flow (CBF) in humans is fraught with technologic, anatomic, and accessibility issues, which has hindered multi-vessel hemodynamic analysis of the cranial vasculature. Recent developments in cardiovascular MRI have allowed for the measurement of cine velocity vector fields over large imaging volumes in a single acquisition with 4D flow MRI. The purpose of this study was to develop an imaging protocol to simultaneously measure pulsatile flow in the circle of Willis as well as the carotid and vertebrate arteries at rest and during increased CO 2 (hypercapnia). Methods 8 healthy adults (3 women, 26 ± 0.4 years) completed this study. Heart rate (pulse oximetry), arterial oxygen saturation (pulse oximetry), blood pressure (MAP, sphygmomanometry), and end-tidal CO 2 (capnograph) were measured at rest (baseline) and during hypercapnia. Hypercapnia was induced via breathing a mixed gas of 3% CO 2 and 21% O 2 (balance N 2 ) in the MR magnet. CBF and vessel cross-sectional area were quantified in 11 arteries using a 4D flow MRI scan, lasting 5–6 min with a radially undersampled acquisition and an isotropic spatial resolution of 0.7 mm. Results Baseline total CBF was 665 ± 54 ml • min − 1 . Hypercapnia increased total CBF 9 ± 3% to 721 ± 61 ml • min − 1 . Hypercapnic increases in CBF ranged from 7 to 36% by artery, with the largest increases in the left anterior cerebral artery. Increases in artery cross-sectional area were observed in basilar and vertebral arteries. Conclusion 4D flow MRI methods are sensitive enough to detect non-uniform changes in CBF and cross-sectional area to a mild yet clinically relevant CO 2 stimulus. 4D flow MRI is a non-invasive reliable tool providing high spatio-temporal resolution in clinically feasible scan times without contrast agent. This approach can be used to interrogate regional cerebrovascular control in health and disease.

Greater cerebral artery vasodilation mediated by cyclooxygenase (COX) in female animals is unexplored in humans. We hypothesized that young, healthy women would exhibit greater basal cerebral blood flow (CBF) and greater vasodilation during hypoxia or hypercapnia compared to men, mediated by a larger contribution of COX. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 42 adults (24 women, 18 men; 24 ± 1 years) during two visits, in a double-blind, placebo-controlled design (COX inhibition, 100 mg oral indomethacin, Indo). Women were studied early in the follicular phase of the menstrual cycle (days 1–5). Two levels of isocapnic hypoxia (SPO2 = 90% and 80%) were induced for 5-min each. Separately, hypercapnia was induced by increasing end-tidal carbon dioxide (PETCO2) 10 mmHg above baseline. A positive change in MCAv (ΔMCAv) reflected vasodilation. Basal MCAv was greater in women compared to men (P

Excess reactive oxygen species (ROS) limit hypoxia-mediated cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking ...

Metabolic Syndrome (MetSyn) increases the risk of developing cerebrovascular diseases (e.g. stroke). We tested the hypothesis that MetSyn impairs cerebral dilation to hypoxia, and the attenuation would be observed primarily in the middle cerebral arteries. Macroscopic cerebral blood flow (CBF) was measured with a novel 4D Flow MRI approach at 3T using radial undersampling to quantify regional vasodilation to isocapnic hypoxia in 10 healthy controls (Con, 29±4 yrs) and 8 MetSyn patients (38±8 yrs). Blood pressure, O2 Saturation (SaO2), end-tidal CO2 was measured and Cerebral Vascular Conductance (CVC=CBF/blood pressure*100mmHg) was calculated for five intracranial arteries: Middle [MCA] x2, Anterior [ACA] x2, and Basilar [BA] (ml/min/100mmHg). Hypoxia (5 min steady state) lowered SaO2 to ~85±2% (Fi O2 =0.1). End-tidal CO2 was maintained (36±1 mmHg). Baseline CVC was 25% lower in MetSyn (750±57 Con vs. 562±75 MetSyn, p=0.03). Hypoxia increased total CVC (p

Animal data suggest females rely more on cyclooxygenase (COX) than males to achieve increases in cerebral blood flow. Our aim was to determine the contribution of COX to hypoxia-mediated increases ...

We hypothesized exercise vasodilation in skeletal muscle differs between sexes due to nitric oxide synthase (NOS) and cyclooxygenase (COX) signalling. 39 healthy adults (19 females, F, 20 males, M,...

Poor cerebrovascular function in metabolic syndrome (MetSyn) likely contributes to elevated risk of cerebrovascular disease in this growing clinical population. Younger MetSyn adults without clinical evidence of cerebrovascular disease exhibit preserved hypercapnic vasodilation yet markedly impaired hypoxic vasodilation, but the mechanisms behind reduced hypoxic vasodilation are unknown. Based on data from rats, we tested the hypothesis that younger adults with MetSyn exhibit reduced cerebral hypoxic vasodilation due to loss of vasodilating prostaglandins. Middle cerebral artery velocity (MCAv) was measured with transcranial Doppler ultrasound in adults with MetSyn ( n = 13, 33 ± 3 yr) and healthy controls ( n = 15, 31 ± 2 yr). Isocapnic hypoxia was induced by titrating inspired oxygen to lower arterial saturation to 90% and 80% for 5 min each. Separately, hypercapnia was induced by increasing end-tidal CO2 10 mmHg above baseline levels. Cyclooxygenase inhibition (100 mg indomethacin) was conducted in a randomized double-blind, placebo controlled design. MCAv was normalized for group differences in blood pressure (healthy: 89 ± 2 mmHg vs. MetSyn: 102 ± 2 mmHg) as cerebrovascular conductance index (CVCi), and used to assess cerebral vasodilation. Hypoxia increased CVCi in both groups; however, vasodilation was ∼55% lower in MetSyn at SpO2 = 80% ( P < 0.05). Indomethacin tended to decrease hypoxic vasodilation in healthy controls, and unexpectedly increased dilation in MetSyn ( P < 0.05). In contrast to hypoxia, hypercapnia-mediated vasodilation was similar between groups, as was the decrease in vasodilation with indomethacin. These data indicate increased production of vasoconstrictor prostaglandins restrains hypoxic cerebral vasodilation in MetSyn, preventing them from responding appropriately to this important physiological stressor.

Arterial CO2 serves as a mediator of cerebral blood flow (CBF), and its relative influence on the regulation of CBF is defined as cerebral CO2 reactivity. Our previous studies have demonstrated that there are differences in CBF responses to physiological stimuli (i.e. dynamic exercise and orthostatic stress) between arteries in humans. These findings suggest that dynamic CBF regulation and cerebral CO2 reactivity may be different in the anterior and posterior cerebral circulation. The aim of this study was to identify cerebral CO2 reactivity by measuring blood flow and examine potential differences in CO2 reactivity between the internal carotid artery (ICA), external carotid artery (ECA) and vertebral artery (VA). In 10 healthy young subjects, we evaluated the ICA, ECA, and VA blood flow responses by duplex ultrasonography (Vivid-e, GE Healthcare), and mean blood flow velocity in middle cerebral artery (MCA) and basilar artery (BA) by transcranial Doppler (Vivid-7, GE healthcare) during two levels of hypercapnia (3% and 6% CO2), normocapnia and hypocapnia to estimate CO2 reactivity. To characterize cerebrovascular reactivity to CO2, we used both exponential and linear regression analysis between CBF and estimated partial pressure of arterial CO2, calculated by end-tidal partial pressure of CO2. CO2 reactivity in VA was significantly lower than in ICA (coefficient of exponential regression 0.021 ± 0.008 vs. 0.030 ± 0.008; slope of linear regression 2.11 ± 0.84 vs. 3.18 ± 1.09% mmHg−1: VA vs. ICA, P < 0.01). Lower CO2 reactivity in the posterior cerebral circulation was persistent in distal intracranial arteries (exponent 0.023 ± 0.006 vs. 0.037 ± 0.009; linear 2.29 ± 0.56 vs. 3.31 ± 0.87% mmHg−1: BA vs. MCA). In contrast, CO2 reactivity in ECA was markedly lower than in the intra-cerebral circulation (exponent 0.006 ± 0.007; linear 0.63 ± 0.64% mmHg−1, P < 0.01). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation, and that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation, which may explain different CBF responses to physiological stress.

The vast majority of research comparing skeletal muscle haemodynamics during exercise in young and older adults has been done under normoxic conditions. These studies provided novel insight into regulatory mechanisms of skeletal muscle blood flow, but leave untested circumstances when arterial oxygen saturation may be limited by environmental conditions or medical pathologies. Enhanced vasodilatation in response to hypoxia has been termed compensatory vasodilatation. Compensatory vasodilatation allows for an adequate amount of oxygen to be delivered to the working musculature and is, in part, nitric oxide (NO) dependent (Casey et al. 2010). Ageing is associated with changes in cardiovascular regulation that may alter NO-mediated dilatation (Schrage et al. 2007) and thereby reduce vasodilatory responses to hypoxia during exercise. Any alterations to the regulation of skeletal muscle blood flow may limit functional capacity and impair the ability to perform exercise with ageing. It was previously unknown whether older adults exhibit reduced compensatory vasodilatation or the regulatory mechanisms responsible for any impairment. In a recent article in The Journal of Physiology, Casey et al. (2011) explored the contribution of NO to forearm vasodilatation during exercise in ageing humans under conditions of hypoxia. To test the hypothesis that skeletal muscle compensatory vasodilatation is blunted in ageing humans, Casey et al. (2011) assessed forearm vascular conductance (FVC) in 11 healthy older subjects (55–70 years). FVC was measured under normoxic and hypoxic (80% arterial oxygen saturation) conditions during graded forearm exercise (10% and 20% of maximal effort); data were compared with findings from young adults presented previously (Casey et al. 2010). Results showed hypoxic compensatory vasodilatation (% change in ΔFVC) was maintained in older adults at 10% and absent at 20% effort. These findings suggest attenuated hypoxic vasodilatation in ageing humans presents with increasing exercise intensity. Casey et al. predicted that altered NO signalling in the ageing group contributed to the attenuated compensatory vasodilatation. To test this hypothesis, the group infused l-NMMA at rest to inhibit NO synthesis. In the young adults, l-NMMA reduced compensatory vasodilatation to hypoxic exercise at 10% and 20% effort (Casey et al. 2010); l-NMMA had no effect on compensatory vasodilatation in the older adults. This form of analysis suggests that reduced NO signalling may be responsible for attenuated compensatory vasodilatation with ageing. However, it is important to acknowledge when analysed as a change in FVC (ΔFVC), the older group showed significantly reduced hypoxic FVC with l-NMMA infusion at 10% effort (but not at 20%). Thus, a portion of the increase of FVC at 10% effort in older adults may be due to NO signaling; however, any increase in FVC at 20% cannot be attributed to NO considering l-NMMA did not alter vascular responses. The authors further explored the vasodilatory role of NO in ageing by infusing acetylcholine during l-NMMA or saline administration. l-NMMA reduced endothelial-dependent vasodilator responses to acetylcholine in the young adults compared to the response with saline (Casey et al. 2010). Conversely, l-NMMA did not significantly alter the vasodilator response in the older adults; this again suggests attenuated NO signalling with ageing, although irrespective of hypoxia. In summary, novel findings from the current study demonstrate that hypoxia-induced compensatory vasodilatation is attenuated in ageing subjects during moderate-intensity exercise (20% effort). The authors attributed the decrease in compensatory vasodilatation to diminished NO signalling. This conclusion was reinforced by the lack of significant reduction in ΔFVC with l-NMMA infusion at 20% effort. The authors provide readers with a thorough analysis of data from ageing adults, including absolute FVC measures and both delta (Δ) and per cent (%) changes from normoxic levels. The representation of hypoxia-mediated compensatory vasodilatation (per cent change in ΔFVC from respective normoxic responses) may seem convoluted. However, it is probably the most appropriate means to compare results between groups with varying absolute flows. In this way, variability in resting flow is heeded and results are presented within the context of normoxic exercise vasodilatation. However, considering the hypothesis of the current study, the authors presented few direct statistical comparisons of ageing and young subjects – leaving conclusions based solely upon compensatory (% change in ΔFVC) analysis. Providing additional between-group analyses from available data could have added key information regarding apparent differences in haemodynamic responses to hypoxia. Whereas these findings suggest the importance of NO to hypoxic vasodilatation is attenuated with ageing, the methods used do not allow for understanding of vascular control during hypoxic exercise. When nitric oxide synthase (NOS) inhibition occurs prior to the onset of hypoxia at rest, redundant signals are capable of compensating to produce a normal hyperaemic response (Markwald et al. 2011). However, when combined with exercise, Casey and colleagues suggest NOS inhibition attenuates hypoxic exercise dilatation in young adults (2010) while minimally impacting older adults (2011). Though novel, these findings cannot rule out the possibility of compensatory mechanisms capable of masking the normal contribution of NO to steady-state flow. Thus, current results may underestimate the importance of NO to hypoxic dilatation in either study population. Follow-up studies should consider local inhibition of NO synthesis during hypoxic handgrip exercise, in addition to the exploration of compensatory mechanisms. Consistent with the concept of signal redundancy, the possible contribution of β-adrenergic or prostaglandin-mediated vasodilatation remains untested. In young adults, β-receptor activation is responsible for a substantial portion of hypoxic dilatation during low-intensity forearm exercise (10% effort, Wilkins et al. 2008); a portion of this dilatation occurs through an NO-dependent pathway. As a result, the exact mechanisms behind NO-mediated compensatory vasodilatation at 10% effort may be group-specific if altered β-adrenergic sensitivity or receptor expression occur with ageing. Furthermore, prostaglandins are known to play a role in resting hypoxic vasodilatation in young adults (Markwald et al. 2011) and their contribution to normoxic exercise vasodilatation is reduced with age (Schrage et al. 2007). Future studies are necessary to fill the gap in knowledge and elucidate the individual roles of both β-adrenergic and prostaglandin-mediated mechanisms on hypoxic vasodilatation in ageing adults. Neurovascular control of hypoxia-mediated blood flow is a balance between adrenergic constriction and dilatation. Thus, it is important to acknowledge that ageing subjects presented 2-fold higher venous noradrenaline levels compared to young adults – probably due, in part, to age-related increases in sympathetic nerve activity. Given the observed increase, it is possible that enhanced adrenergic vasoconstriction contributed to blunted compensatory vasodilatation in the ageing subjects. However, the authors show similar heart rate and blood pressure responses to hypoxia between groups (Casey et al. 2011). Whereas these observations are unlikely to confound current conclusions, one should consider the potential clinical implications in disease states presenting increased sympathetic nerve activity (diabetes, heart failure, hypertension). Interestingly, the authors note significant between-group differences in baseline blood pressures. Given that both ageing and hypertension are known to increase sympathetic nerve activity and independently reduce NO-mediated dilatation, the current cohort does not allow for differentiation between these manifestations. Despite attenuated compensatory vasodilatation in ageing adults, results from the current study suggest that oxygen consumption is maintained during forearm exercise. Thus, older adults are able to meet metabolic demand through combined changes in oxygen delivery and extraction. Although vasodilatory responses to environmental stressors and the mechanisms behind vascular control are altered with ageing, reduced haemodynamics do not appear to compromise older adults’ ability to meet oxygen demand. Whether this continues to apply at higher exercise intensities or under more severe hypoxia, and the clinical implications of such changes, have yet to be assessed. In conclusion, Casey et al. (2011) provide novel insight to hypoxia-mediated dilatation during forearm exercise and the effects of ageing on mechanisms of vascular control. This, combined with their previous work, begins to describe complex interactions in vascular control. Future studies might aim to examine the relative importance of alternative vascular control mechanisms and the effect of differences in sympathetic nerve activity between groups. Clinically, this information provides further understanding of the impact of ageing and the role of NO in skeletal muscle blood flow under circumstances when local or systemic arterial oxygen saturation may be limited by exercise, environmental conditions or medical pathologies.