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INTRODUCTION Adults with obesity are at an increased risk of incident hypertension. Regular aerobic exercise is recommended for the prevention and treatment of hypertension, but whether young adults with obesity exhibit impaired postexercise blood pressure (BP) and vascular responses remains unclear. PURPOSE We tested the hypothesis that young adults with obesity exhibit attenuated postexercise hypotension (PEH) and postexercise peripheral vasodilation compared with young adults without obesity. METHODS Thirty-six normotensive adults without and with obesity (11 men and 7 women per group) underwent measurements of brachial and central BP, and leg blood flow (Doppler ultrasound) at baseline and at 30, 60, and 90 min after acute 1-h moderate-intensity cycling. Leg vascular conductance (LVC) was calculated as flow/mean arterial pressure. RESULTS Both groups exhibited similar brachial and central PEH (peak change from baseline, -2 and -4 mm Hg for brachial and central systolic BPs, respectively, for both groups; time effect, P < 0.05). Both groups also exhibited postexercise peripheral vasodilation, assessed via LVC (time effect, P < 0.05), but its overall magnitude was smaller in young adults with obesity (LVC change from baseline, +47% ± 37%, +29% ± 36%, and +20% ± 29%) compared with young adults without obesity (LVC change from baseline, +88% ± 58%, +59% ± 54%, and +42% ± 51%; group effect, P < 0.05). CONCLUSIONS Although obesity did not impair PEH after acute moderate-intensity exercise, young adults with obesity exhibited smaller postexercise peripheral vasodilation compared with young adults without obesity. Collectively, these findings have identified evidence for obesity-induced alterations in the peripheral vasculature after exercise.

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide considered to be causally implicated in hypertension and the development of cardiovascular disease. Increased ET-1 is commonly associated with reduced NO bioavailability and impaired vascular function; however, whether chronic elevation of ET-1 directly impairs endothelium-dependent relaxation (EDR) remains elusive. Herein, we report that (1) prolonged ET-1 exposure (ie, 48 hours) of naive mouse aortas or cultured endothelial cells did not impair EDR or reduce eNOS (endothelial NO synthase) activity, respectively (P>0.05); (2) mice with endothelial cell–specific ET-1 overexpression did not exhibit impaired EDR or reduced eNOS activity (P>0.05); (3) chronic (8 weeks) pharmacological blockade of ET-1 receptors in obese/hyperlipidemic mice did not improve aortic EDR or increase eNOS activity (P>0.05); and (4) vascular and plasma ET-1 did not inversely correlate with EDR in resistance arteries isolated from human subjects with a wide range of ET-1 levels (r=0.0037 and r=−0.1258, respectively). Furthermore, we report that prolonged ET-1 exposure downregulated vascular UCP-1 (uncoupling protein-1;P

Approximately 60% of patients with type 2 diabetes mellitus (T2D) develop hypertension. Recent work also indicates greater blood pressure (BP) excursions throughout the day in T2D. Collectively, these findings suggest altered BP control in T2D. Although muscle sympathetic nerve activity (MSNA) recordings in T2D have provided equivocal results, quantification of MSNA alone does not account for ensuing vasoconstriction and BP responses elicited by MSNA. Thus, we tested the hypothesis that patients with T2D exhibit enhanced sympathetic transduction to BP. MSNA (microneurography) and beat-to-beat BP (Finometer) were measured at rest in 21 T2D and 13 age-matched and body mass index–matched control subjects and, signal-averaging was performed to quantify the mean arterial pressure and total vascular conductance responses to spontaneous bursts of MSNA. The peak mean arterial pressure and total vascular conductance responses to spontaneous MSNA were similar between T2D and control (both P >0.05). However, further analysis, separating T2D into those taking statins (n=13, T2D +statin) and not taking statins (n=8, T2D −statin), indicated that T2D −statin patients (4.2±0.6 mm Hg) exhibited greater peak mean arterial pressure responses compared with both T2D +statin patients (2.5±0.3 mm Hg, P =0.01) and control (control: 2.8±0.3 mm Hg, P =0.02). Likewise, nadir total vascular conductance responses to spontaneous MSNA bursts were greater in T2D −statin patients (T2D −statin: −3.3±0.6 mL/(min·mm Hg), T2D +statin: −1.6±0.3 mL/(min·mm Hg), P =0.03; control −2.2±0.3 mL/(min·mm Hg), P =0.08). Notably, T2D +statin patients exhibited similar peak mean arterial pressure and total vascular conductance responses to MSNA compared with control. Collectively, these findings demonstrate, for the first time, that patients with T2D exhibit augmented sympathetic transduction and this effect seems to be offset by statin therapy.

Muscle sympathetic nerve activity (MSNA) influences the mechanical properties (ie, vascular smooth muscle tone and stiffness) of peripheral arteries, but it remains controversial whether MSNA contributes to stiffness of central arteries, such as the aorta and carotids. We examined whether elevated MSNA (age-related) would be independently associated with greater stiffness of central (carotid-femoral pulse wave velocity [PWV]) and peripheral (carotid-brachial PWV) arteries, in addition to lower carotid compliance coefficient, in healthy men and women (n=88, age: 19–73 years, 52% men). We also examined whether acute elevations in MSNA without increases in mean arterial pressure using graded levels of lower body negative pressure would augment central and peripheral artery stiffness in young (n=15, 60% men) and middle-age/older (MA/O, n=14, 43% men) adults. Resting MSNA burst frequency (bursts·min −1 ) was significantly correlated with carotid-femoral PWV ( R =0.44, P R =0.32, P =0.004), and carotid compliance coefficient ( R =0.28, P =0.01) after controlling for sex, mean arterial pressure, heart rate, and waist-to-hip ratio (central obesity), but these correlations were abolished after further controlling for age (all P >0.05). In young and MA/O adults, MSNA was elevated during lower body negative pressure ( P −1 , P =0.53) and carotid-brachial PWV (young: Δ+0.7±0.3 versus MA/O: Δ+0.7±0.5 m·s −1 , P =0.92), whereas carotid compliance coefficient during lower body negative pressure was significantly reduced in young but not MA/O (young: Δ−0.04±0.01 versus MA/O: Δ0.001±0.008 mm 2 ·mm Hg −1 , P

The arterial baroreflex (ABR) resets during exercise in an intensity-dependent manner to operate around a higher blood pressure with maintained sensitivity. This review provides a historical perspective of ABR resetting and the involvement of other neural reflexes in mediating exercise resetting. Furthermore, we discuss potential underlying signaling mechanisms that may contribute to exercise ABR resetting in physiological and pathophysiological conditions.

Blacks have the highest prevalence of hypertension, putting them at greater risk of cardiovascular disease and death. Previous studies have reported that, relative to whites, healthy black men have augmented pressor responses to sympathoexcitatory stressors. Although important, these studies do not inform about the resting state and the influence of spontaneous changes in resting muscle sympathetic nerve activity (MSNA). Likewise, little is known about the transduction of MSNA into a vascular response at rest on a beat-to-beat basis. Accordingly, we tested the hypothesis that relative to whites, blacks would exhibit greater vasoconstriction and pressor responses following spontaneous bursts of MSNA. Mean arterial pressure, common femoral artery blood flow, and MSNA were continuously recorded during 20 minutes of supine rest in 35 young healthy men (17 blacks and 18 whites). Signal averaging was used to characterize changes in leg vascular conductance, total vascular conductance, and mean arterial pressure following spontaneous MSNA bursts. Blacks demonstrated significantly greater decreases in leg vascular conductance (blacks: −15.0±1.0%; whites: −11.5±1.2%; P =0.042) and total vascular conductance (blacks: −8.6±0.9%; whites: −5.1±0.4%; P =0.001) following MSNA bursts, which resulted in greater mean arterial pressure increases (blacks: +5.2±0.6 mm Hg; whites: +3.9±0.3 mm Hg; P =0.04). These exaggerated responses in blacks compared with whites were present whether MSNA bursts occurred in isolation (singles) or in combination (multiples) and were graded with increases in burst height. Collectively, these findings suggest that healthy young black men exhibit augmented sympathetic vascular transduction at rest and provide novel insight into potential mechanism(s) by which this population may develop hypertension later in life.

An exaggerated pressor response to exercise is associated with increased risk of cardiovascular events. The exercise pressor reflex, comprised of metabolic and mechanically sensitive skeletal muscle afferents, contributes importantly to blood pressure control during exercise. Data in preclinical animal models suggest that estradiol (E2) attenuates the pressor responses to exercise pressor reflex activation, yet it remains unclear if these findings translate to humans. Accordingly, we tested the hypothesis that pressor responses during exercise are augmented in post-menopausal women (PMW) compared to young women (YW), and that E2 administration will attenuate these responses in PMW. Methods: Mean arterial pressure (MAP, Finometer) and heart rate (ECG) were continuously measured in 12 PMW (age 59±2 years) and 16 YW (age 22±1 years) during 2-min of isometric handgrip performed at 30% of maximal voluntary contraction (MVC). Handgrip was immediately followed by 3-min of post-exercise ischemia (PEI), which isolates the muscle metaboreflex. Separately, BP responses during isometric handgrip at 35% MVC and PEI were measured in 6 PMW (age 53±1 years) before and after 1 month of transdermal E2 administration (100 μg/day). Results: Resting MAP was similar between PMW (77±3 mmHg) and YW (80±3 mmHg; P >0.05). During handgrip, the increase in MAP was greater in PMW (Δ20±2mmHg) compared to YW (Δ12±1 mmHg; P P P P P =0.08). Conclusions: These preliminary data suggest that PMW exhibit an exaggerated BP response to isometric exercise, due in part to heightened metaboreflex activation, and that estradiol administration can attenuate such responses.

Background Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [ AB ]) and the loss of female sex hormones (ovariectomy [ OVX ]) impairs cerebrovascular control and spatial memory. Methods and Results Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB , (3) OVX , and (4) AB ‐ OVX . Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole‐board task) were lower in the OVX groups ( P AB ‐ OVX group ( P AB ‐ OVX group ( P OVX groups ( P AB ‐ OVX group ( P 2+ ‐activated potassium channel α‐subunit agonist NS ‐1619 was impaired in both AB groups ( P 2+ ‐activated potassium channel α‐subunit protein was increased in AB groups ( P Conclusions Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y–induced vasoconstriction along with reduced vasodilation associated with decreased Ca 2+ ‐activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.

See related article, pp 970–976 The importance of nitric oxide (NO) for normal cardiovascular regulation and health has been well established. However, the large majority of the focus and knowledge about NO has revolved around the endothelium and endothelial derived NO. Aside from its importance for blood flow and blood pressure via endothelium-dependent vasodilation,1,2 endothelial NO synthase (eNOS) has been shown to have numerous other vascular protective effects including, but not limited to, inhibition of platelet aggregation and adhesion, promotion of angiogenesis, anti-inflammation, and inhibition of the atherosclerotic process.3,4 In addition, eNOS has important cardiac effects. Thus, it is clear that impairments in eNOS-derived NO can have deleterious consequences and play a role in the disease process. Although the aforementioned functions of eNOS cannot be overstated, the synthesis of NO via neuronal NOS (nNOS) may also be critical for cardiovascular regulation and health. Indeed, nNOS along with eNOS is constitutively expressed in mammalian cells, and an emerging body of research, mainly performed in animals, has indicated that nNOS may also be important for the regulation of vasomotor tone and blood pressure.5 However, much less is known about nNOS in humans. In the current issue of Hypertension , Shabeeh et al6 report results from the first human study to systemically infuse the …

Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries, a hemodynamic environment that favors a proatherogenic endothelial cell phenotype. We evaluated whether nitric oxide (NO) bioavailability in resistance vessels contributes to age-related differences in shear rate patterns in upstream conduit arteries at rest and during rhythmic muscle contraction. Younger (n=11, age 26±2 years) and older (n=11, age 61±2 years) healthy subjects received intra-arterial saline (control) and the NO synthase inhibitor N G -Monomethyl- l -arginine. Brachial artery diameter and velocities were measured via Doppler ultrasound at rest and during a 5-minute bout of rhythmic forearm exercise. At rest, older subjects exhibited greater brachial artery retrograde and oscillatory shear (−13.2±3.0 s −1 and 0.11±.0.02 arbitrary units, respectively) compared with young subjects (−4.8±2.3 s −1 and 0.04±0.02 arbitrary units, respectively; both P P P >0.05). From rest to steady-state exercise, older subjects decreased retrograde and oscillatory shear (both P P >0.05). Inhibition of NO synthase in the forearm circulation did not affect retrograde and oscillatory shear during exercise in either group (all P >0.05). These data demonstrate for the first time that reduced NO bioavailability in the resistance vessels contributes, in part, to age-related discrepancies in resting shear patterns, thus identifying a potential mechanism for increased risk of atherosclerotic disease in conduit arteries.

Arterial baroreceptors originating in the carotid arteries and aorta play a pivotal role in the rapid reflex adjustments that accompany acute cardiovascular stressors. There is now ample evidence to indicate that the arterial baroreflex remains functional during exercise by resetting in direct relation to the intensity of exercise from rest to maximum. Moreover, there is convincing evidence that a properly functioning arterial baroreflex is requisite for an appropriate neural cardiovascular response to exercise. Importantly, an understanding of the underlying means by which the baroreflex responds to changes in blood pressure has been elucidated. In this regard, both at rest and during exercise, alterations in stroke volume do not appear to contribute to the maintenance of arterial blood pressure (ABP) by the carotid baroreceptors (CBR), and therefore, any reflex-induced changes in cardiac output are the result of CBR-mediated changes in heart rate (HR). More importantly, it appears that CBR-induced changes in ABP are primarily mediated by alterations in vascular conductance with only minimal contributions from cardiac output. Therefore, the capacity of the CBR to regulate ABP depends critically on its ability to alter vascular tone both at rest and during exercise. Indeed, studies have clearly indicated that active and inactive skeletal muscle vascular beds contribute to mediating CBR-induced changes in ABP. The purpose of this review is to describe the mechanisms by which the CBR responds to alterations in ABP both at rest and during exercise in humans with a particular emphasis on the importance of baroreflex-mediated vascular responses.

PURPOSE: We compared arterial, aortic, and carotid-cardiac baroreflex sensitivity in eight average fit (maximal oxygen uptake, VO2max = 42.2+/-1.9 mL x kg(-1) x min(-1)) and eight high fit (VO2max = 61.9+/-2.2 mL x kg(-1) x min(-1)) healthy young adults. METHODS: Arterial and aortic (ABR) baroreflex functions were assessed utilizing hypo- and hyper-tensive challenges induced by graded bolus injections of sodium nitroprusside (SN) and phenylephrine (PE), respectively. Carotid baroreflex (CBR) sensitivity was determined using ramped 5-s pulses of both pressure and suction delivered to the carotid sinus via a neck chamber collar, independent of drug administration. RESULTS: During vasoactive drug injection, mean arterial pressure (MAP) was similarly altered in average fit (AF) and high fit (HF) groups. However, the heart rate (HR) response range of the arterial baroreflex was significantly attenuated (P < 0.05) in HF (31+/-4 beats x min(-1)) compared with AF individuals (46+/-4 beats x min(-1)). When sustained neck suction and pressure were applied to counteract altered carotid sinus pressure during SN and PE administration, isolating the ABR response, the response range remained diminished (P < 0.05) in the HF population (24+/-3 beats x min(-1)) compared with the AF group (41+/-4 beats x min(-1)). During CBR perturbation, the HF (14+/-1 beats-min(-1)) and AF (16+/-1 beats-min(-1)) response ranges were similar. The arterial baroreflex response range was significantly less than the simple sum of the CBR and ABR (HF, 38+/-3 beats x min(-1) and AF, 57+/-4 beats x min(-1)) in both fitness groups. CONCLUSIONS: These data confirm that reductions in arterial-cardiac reflex sensitivity are mediated by diminished ABR function. More importantly, these data suggest that the integrative relationship between the ABR and CBR contributing to arterial baroreflex control of HR is inhibitory in nature and not altered by exercise training.

Understanding the neural circulatory responses to exercise in postmenopausal women (PMW) is important given their greater risk for developing hypertension. During exercise, blood pressure is controlled, in part, by the exercise pressor reflex, which is a feedback mechanism originating in skeletal muscle and compromised of mechanically and metabolically sensitive afferents. A recent study reported an enhanced blood pressure response during exercise in normotensive PMW due to greater muscle metaboreflex activation, but the mechanism(s) underlying these responses are unknown. Herein, we tested the hypothesis that metaboreflex activation elicits exaggerated sympathetic nervous system responses in PMW compared to young women, contributing to the enhanced blood pressure response during exercise. Methods: Blood pressure (BP, Finometer) and muscle sympathetic nerve activity (MSNA, peroneal microneurography) were continuously measured in 7 PMW (age 59±2 years; BMI 24±1 kg/m 2 ) and 7 young women (age 23±2 years; BMI 22±2 kg/m 2 ) during 2-minutes of isometric handgrip exercise performed at 30% of maximal voluntary contraction followed by 3-minutes of forearm ischemia (post-exercise ischemia, PEI) to isolate muscle metaboreflex activation. Results: Resting mean arterial pressure (MAP) was similar between PMW (85±3 mmHg) and young women (82±2 mmHg; P>0.05). During exercise, the increase in MAP was greater in PMW (Δ18±2mmHg) compared to young women (Δ 12±2 mmHg; P0.05), whereas during PEI, the increase in MSNA was approximately 50% greater in PMW compared to young women (Δ13±2 burst/min PMW vs. 7±2 bursts/min young women; P Conclusions: These preliminary data suggest that compared to young women, PMW exhibit an exaggerated MSNA response to isolated muscle metaboreflex activation.

Objectives— Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women. Methods and Results— In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 μg per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women. Conclusions— Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes.