Decrease In Forearm Blood Flow Research Articles

Intra and inter‐day reproducibility of the functional sympatholysis protocol during rhythmic handgrip exercise in healthy humans

IntroductionThe effects of increased sympathetic activity on vasoconstriction are blunted in active skeletal muscle during exercise. This mechanism, termed functional sympatholysis (FSY), plays a vital role in the maintenance of blood perfusion and oxygen delivery to meet the metabolic demands of active skeletal muscle. In humans, FSY can be determined experimentally by applying low‐levels of lower‐body negative pressure (LBNP) to unload the cardiopulmonary baroreceptors and induce a reflex sympathoexcitation at rest and simultaneously during rhythmic handgrip exercise. In young healthy individuals, LBNP causes a pronounced vasoconstrictor response at rest, but not during exercise in the working forearm. Although this paradigm has been used extensively to assess the FSY in humans, to date, no studies have examined the reproducibility of this protocol. Therefore, the aim of the present study is to assess the within‐visit and between‐visit reproducibility of the FSY protocol in healthy adults.MethodsTwenty‐three (12 females) young, healthy adults (26 ± 4 years; 73 ± 13 kg [mean ± SD]) participated in the study. Forearm blood flow (Doppler ultrasound) and beat‐to‐beat BP (finger photoplethysmography) were measured continuously at rest and during 6‐min of rhythmic handgrip exercise at 30% of maximum voluntary contraction. LBNP at ‐20 mmHg was applied for 2 min at rest and from the 3rd to the 5th min of handgrip. Participants performed two visits separated by ≥48h where two FSY bouts were completed. Forearm vascular conductance (FVC) was calculated as FBF/Mean blood pressure. The FSY index (FSYi) was calculated using the following formula: FSYi = (∆%handgrip ‐ ∆%rest)/100. Intraclass correlation coefficients (ICC; two‐way mixed effects, average measures, and absolute agreement) were used as a primary reproducibility measure (ICC values >0.75 are considered very good).ResultsAt rest, LBNP induced a decrease in forearm blood flow (Visit 1 trial 1: ∆‐43±16%; Visit 1 trial 2: ∆‐38±10%; Visit 2: ∆‐39±14%) while these responses were attenuated during LBNP+handgrip (Visit 1 trial 1: ∆‐7±7%; Visit 1 trial 2: ∆‐5±8%; Visit 2: ∆‐4±7%). Each of these responses was similar across the trials (all P≥0.17). The FSYi calculated based on the forearm blood flow responses demonstrated excellent intra (ICC=0.93 [95% CI: 0.82‐0.97]; P<0.001) and inter‐day (ICC=0.94 [95% CI: 0.85‐0.97]; P<0.001) reproducibility. Similarly, FVC responses demonstrated very good intra (ICC=0.81 [95% CI: 0.55‐0.92]; P<0.001) and inter‐day (ICC=0.86 [95% CI: 0.65‐0.95]; P<0.001) reproducibility.ConclusionThis is the first study to demonstrate that Doppler ultrasound‐derived assessments of FSY using LBNP and forearm handgrip exercise possess high intra‐ and inter‐day reproducibility in young, healthy adults.

New-Onset Diabetes, Endothelial Dysfunction, and Cardiovascular Outcomes in Hypertensive Patients: An Illness-Event Model Analysis.

Background. Insulin resistance and endothelial dysfunction are common findings in hypertensives, both predisposing to a higher risk of diabetes and cardiovascular events. We designed this study to evaluate the role of endothelial dysfunction in three pathogenetic pathways: (1) from baseline to cardiovascular events, (2) from baseline to diabetes, and (3) from new-onset diabetes to cardiovascular events. Methods. We enrolled 653 Caucasian never-treated hypertensives. Endothelial dysfunction was investigated by strain-gauge plethysmography; incident diabetes and cardiovascular events were evaluated by an illness-event model analysis. Results. During the follow-up (median 113 months), we documented 191 new cardiovascular events and 92 new cases of diabetes. In a multiple Cox regression analysis, acetylcholine-stimulated forearm blood flow [100% decrease, hazard ratio: 2.42 (95% confidence interval = 1.72–3.40)] and serum high-sensitivity C-reactive protein [hazard ratio: 1.30 (95% confidence interval = 1.21–1.40)] had an independent association with cardiovascular outcomes. The incidence rate of cardiovascular outcomes in diabetes-developer patients was higher than in the diabetes-free ones (34.9 vs. 2.5 events per 100 persons-year). In an illness-event model, a 100% decrease in forearm blood flow was associated with a 55.5% hazard ratio increase (hazard ratio: 1.56, 95% confidence interval: 1.33–1.82) of transition 1 (from baseline status to cardiovascular events) and to an almost doubled increase (hazard ratio: 2.54, 95% CI: 2.00–3.25) of the risk of transition 2 (from baseline status to diabetes). No such effects were found in transition 3 (from diabetes to cardiovascular events). Conclusions. Endothelial dysfunction plays a primary role in the pathways leading to diabetes and cardiovascular events in hypertensives. When diabetes is overt, endothelial dysfunction has no predictive value for subsequent cardiovascular events.

Forearm vasodilatation to a β2 -adrenergic receptor agonist in premenopausal and postmenopausal women.

What is the central question of this study? What is the role of β2 -adrenergic receptor (β2 AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2 AR-mediated vasodilatation in both groups of women? What is the main finding and its importance? β2 AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2 AR-mediated vasodilatation in young premenopausal women. β2 -Adrenergic receptor (β2 AR)-mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2 AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β2 AR agonist terbutaline is blunted in older postmenopausal women (59±4years) compared to young premenopausal women (27±3years) and to assess NO contribution to β2 AR-mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra-arterial infusions of terbutaline at 0.1-2.0µg (100ml tissue)-1 min-1 with and without the NO synthase inhibitor l-NG -monomethylarginine (l-NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P=0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P>0.05) and rose significantly within each group during terbutaline infusion (P<0.05). There were significant group × dose interactions for FBF (P=0.01) and FVC (P=0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l-NMMA co-infusion vs. without l-NMMA (P=0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l-NMMA co-infusion (P>0.05 for all). These data suggest that β2 AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2 AR-mediated vasodilatation in young premenopausal women.

Effect of vitamin C on hyperoxia-induced vasoconstriction in exercising skeletal muscle.

Hyperoxia can cause substantial reductions in peripheral and coronary blood flow at rest and during exercise, which may be caused by reactive oxygen species (ROS) generated during hyperoxia. The aim of this study was to investigate the role of ROS in hyperoxia-induced reductions in skeletal muscle blood flow during forearm exercise. We hypothesized that infusion of vitamin C would abolish the effects of hyperoxia on the forearm blood flow (FBF) responses to exercise. Twelve young healthy adults performed rhythmic forearm handgrip exercise (10% of maximum voluntary contraction for 5 min) during normoxia and hyperoxia. For each condition, two trials were conducted with intra-arterial administration of saline or vitamin C. FBF was measured using Doppler ultrasound. During hyperoxia with saline, FBF and forearm vascular conductance (FVC) were 86.3 ± 5.1 and 86.8 ± 5.2%, respectively, of the normoxic values (100%) (P < 0.05). During vitamin C, hyperoxic FBF and FVC responses were 90.9 ± 4.2 and 90.9 ± 4.1%, respectively, of the normoxic values (P = 0.57 and 0.59). Subjects were then divided into three subgroups based on their percent decrease in FBF (>20, 10-20, and <10%) during hyperoxia. In the subgroup that demonstrated the greatest hyperoxia-induced changes (>20%), FBF and FVC during hyperoxia were 67.1 ± 4.0 and 66.8 ± 3.6%, respectively, of the normoxic values. Vitamin C abolished these effects on FBF and FVC with values that were 102.0 ± 5.2 and 100.8 ± 6.1%, respectively. However, vitamin C had no effect in the other two subgroups. This analysis is consistent with the idea that ROS generation blunts the FBF responses to exercise in the subjects most affected by hyperoxia.

Hemodynamic responses to angiotensin-(1-7) in women in their third trimester of pregnancy

Background: To understand the role of Angiotensin-(1-7) (Ang-(1-7)) in vasculature of pregnant women, we compared cardiac output (CO), total peripheral resistance (TPR) and forearm blood flow (FBF) responses to Ang-(1-7) infusion between normotensive pregnant women in their third trimester and healthy age matched non-pregnant women. The responses of skin microcirculation to Ang-(1-7) were tested in preeclamptic, normotensive pregnant and non-pregnant women. Responses to Angiotensin II (Ang II) were also determined. Methods: Non-invasive methods for systemic (bioimpedance and VascuMAP), FBF (venous occlusion strain gauge plethysmography), and skin (laser Doppler) hemodynamics assessments were used. Results: Compared to non-pregnant women, systemic infusion of Ang-(1-7) (2000 pmol/min) resulted in a greater increase in CO (9.4 ± 6.4 versus −3.3 ± 2.1%, n = 9–10) in normotensive pregnant women. Brachial local infusion of Ang-(1-7) had no effect on FBF in either group. In non-pregnant and normotensive pregnant women, local Ang II induced a dose-dependent decrease in FBF and increase in forearm resistance at 50 and 100 pmol/min (p < 0.05 versus corresponding baseline, n = 7–10). Following iontophoretic application of 5 mmol/l dose of Ang-(1-7), the change in skin flow was higher in normotensive pregnant versus preeclamptic women (182.5 ± 93 versus 15.76 ± 19.46%, n = 14–15). Skin flow was lower in normotensive pregnant versus preeclamptic women (−46.5 ± 48.7 versus 108.7 ± 49.1%, n = 14–15) following Ang II infusion at 1.0 pmol/min. Conclusion: In the third trimester of pregnancy, Ang-(1-7) induces alterations in CO and differentially regulates micro- and macro-circulations, depending on the dose. Dysregulation in skin vasculature may contribute to the development of vascular dysfunction and hypertension in preeclampsia.

B-29 Free Communication/Poster - Concussion

Hyperoxia can cause substantial reductions in the peripheral and coronary blood flow at rest and during exercise. This has been attributed to an increase in reactive oxygen species (ROS) generation during hyperoxia. Indeed, vitamin C has been shown to restore coronary flow during administration of 100% O2. However, this model has not been studied in local exercising skeletal muscle. PURPOSE: The primary aim of this study was to investigate the role of ROS in hyperoxia induced reductions in skeletal muscle blood flow during forearm exercise. METHODS: 12 young healthy adults (28±2 years) performed forearm handgrip exercise under normoxia and hyperoxia with saline or Vitamin C infusions. Forearm blood flow (FBF) was measured using Doppler ultrasound while forearm vascular conductance (FVC) was calculated from FBF and mean arterial pressure (brachial artery catheter). RESULTS: Under the control (saline) condition, the percent change of FBF and FVC during hyperoxic exercise (86.3±5.1% and 86.8±5.2%, respectively) was reduced as compared to normoxia (mean=100%) (P 20%, 10-20%, and 20%), infusion of Vitamin C substantially increased the FBF and FVC responses to hyperoxic exercise (102.0±5.2% and 100.8±6.1% respectively) compared to control (saline) conditions (67.1±4.0% and 66.8±3.6% respectively) (P<0.05). However, this was not observed with individuals in the other 2 sub-groups. CONCLUSIONS: Our data suggests that in participants with the greatest hyperoxia induced vasoconstriction during forearm exercise, ROS generation may be a contributing factor. Hence, when Vitamin C is administered during hyperoxic exercise, the FBF seems to be restored only in the individuals who have a 20% or greater decrease in FBF.

Effect of thermal stimuli on peripheral blood flow in homozygous sickle cell disease: A preliminary study

Forearm blood flow (FBF) was measured in 23 patients with homozygous sickle cell (SS) disease and 20 controls with normal hemoglobin genotype (AA) using venous occlusion air plethysmography to examine the pattern of peripheral blood flow in both groups at rest, and in response to thermal stimuli. The mean resting FBF in SS patients was more than twice that in AA controls (P<0.001). Indirect cooling (15°C) of the left forearm for 2 minutes evoked a significant increase (P<0.005) in FBF in the opposite arm in both SS patients and AA controls, with the response being greater in the controls. Indirect heating (40°C) for 2 minutes evoked a decrease in FBF of a similar magnitude in both groups. The increased FBF in response to moderate cooling in SS patients may be part of an important reflex mechanism which could support the concept of the ‘steal’ syndrome, as recently postulated, as a possible explanation for the cold-related initiation of the painful crisis of SS disease.

Endothelial function in migraine: a cross-sectional study

BackgroundMigraine has been associated with cardiovascular disorders. Endothelial dysfunction may be a mechanism underlying this association. The present study tested the hypothesis that endothelium-dependent vasodilation, basal endothelial nitric oxide release and endothelial fibrinolytic capacity are impaired in migraine patients.MethodsGraded doses of sodium nitroprusside (SNP, 0.2 to 0.8 μg.min-1.dL-1 forearm), substance P (0.2 to 0.8 pmol.min-1.dL-1 forearm) and NG-monomethyl-L-arginine (L-NMMA, 0.1 to 0.4 μmol.min-1.dL-1 forearm) were infused into the brachial artery of 16 migraine patients with or without aura during a headache-free interval and 16 age- and sex-matched subjects without a history of migraine. Forearm blood flow (FBF) was measured by strain-gauge venous occlusion plethysmography. Local forearm release of tissue plasminogen activator (t-PA) in response to substance P infusion was assessed using the arteriovenous plasma concentration gradient. Responses to infused drugs were compared between patients and matched controls by analysis of variance.ResultsIn both migraine patients and control subjects, SNP and substance P caused a dose-dependent increase, and L-NMMA a dose-dependent decrease in FBF (P < 0.001 for all responses). In both groups, substance P caused an increase in t-PA release (P < 0.001). FBF responses and t-PA release were comparable between migraine patients and control subjects.ConclusionsThe absence of differences in endothelium-dependent vasodilation, basal endothelial nitric oxide production and stimulated t-PA release between migraine patients and healthy control subjects argues against the presence of endothelial dysfunction in forearm resistance vessels of migraine patients.

Methodological Issues Related To Blood Flow Measurements In Obese Subjects

A high body mass index is being implicated in a variety of health problems such as heart disease, hypertension, diabetes, cancer and pulmonary disease. Understanding vascular hemodynamics in obese subjects is an important measurement in elucidating the untoward effects that obesity has on human health. Two major methods of measuring forearm blood flow (FBF) in humans are venous occlusion plethysmography (VOP) and Doppler ultrasound. PURPOSE: To examine if blood flow responses measured by Doppler ultrasound and VOP would elicit similar results in obese subjects. Due to the large amount of subcutaneous fat associated with obesity we hypothesized that VOP would not accurately measure forearm blood flow as compared to Doppler ultrasound in response to physical stressors. METHODS: FBF was measured in normal (n=12; BMI=23±1) and obese (n=7; BMI=40±2) subjects with VOP and Doppler ultrasound. FBF was measured at rest and during four interventions using both techniques. The interventions were reactive hyperemia (RH), mental stress, isometric handgrip, and cold pressor test. RESULTS: In the normal subjects, no differences in blood flow measurements were observed using either technique during the four interventions. However, differences between Doppler ultrasound and VOP in the obese subjects were observed during RH and mental stress. During RH changes in FBF (Δ790 ± 217% vs. Δ430±133%) and forearm vascular conductance (FVC) (Δ802±221% vs. Δ444±128%) was significantly greater using Doppler ultrasound than VOP (P<0.03). Using VOP mental stress elicited increases in FBF (Δ54±13%) and FVC (Δ35±11%) whereas using Doppler ultrasound mental stress elicited no significant changes in FBF (Δ-2±9%) or FVC (Δ-7±11%). However, VOP and Doppler ultrasound elicited comparable decreases in FBF and FVC during isometric handgrip and cold pressor test. CONCLUSION: Differences in FBF measurements occurred in obese subjects comparing VOP versus Doppler ultrasound. These observed differences manifested themselves during maneuvers that elicit forearm vasodilation. Therefore these findings indicate that interpretation of blood flow data from obese subjects must be carefully evaluated across studies in which different methods of measuring FBF have been utilized. Support: GCRC Student Research Award.

Abstract 5148: Coexistence of Functional Angiotensin II Type 2 Receptors Mediating Both Vasoconstriction and Vasodilation in the Human Forearm Circulation

Angiotensin (Ang) II type 2 (AT 2 ) receptors have been shown to mediate vasodilation in animal models, but data to support this concept in humans have failed to clearly define AT 2 receptor-dependent effects. In this study, therefore, we investigated the hemodynamic response to modulation of AT 2 receptors under different conditions in healthy humans (n=7) by use of the forearm perfusion technique. Intra-arterial infusion of graded doses of Ang II (12.5, 25 and 50 pmol/min) led to concentration-dependent vasoconstriction (−51±4% [mean±SEM] was the maximum decrease in forearm blood flow (FBF) from baseline; P&lt;0.001). The Ang II type 1 receptor antagonist telmisartan (30 μ g/min) induced a mild increase in unstimulated FBF (15±5%; P=0.10) and reversed the vasoconstrictor effect of Ang II into vasodilation (15±4%; P=0.02). The AT 2 receptor antagonist PD 123,319 (10 μ g/min) also resulted in a mild vasodilation (16±3%; P=0.08) and blunted the vasoconstrictor effect of Ang II (−8±3%; P=0.57). Most importantly, combined infusion of telmisartan and PD 123,319 was associated with a greater vasodilator effect (28±5%; P=0.02) than separate blockade of each Ang II receptor subtype; this response was unrelated to endothelial, nitric oxide (NO)-dependent mechanisms, because it was unaffected (27±5%; P=0.03) by the “NO clamp” (NO synthase inhibitor L-NMMA (4 μ mol/min) coinfused with the NO donor sodium nitroprusside (0.2 to 0.4 μ g/min) in order to simulate normal basal NO activity during complete inhibition of NO synthesis). By contrast, AT 2 receptor challenging with the ligand CGP 42112A (2 and 4 μ g/min) resulted in a vasodilator response (37±5% at the highest dose; P=0.02) that was abolished by the NO clamp (3±1%; P=0.94). In conclusion, AT 2 receptors contributing to Ang II-mediated vasoconstriction, likely located on vascular smooth muscle, coexist in the human forearm circulation with functional endothelial AT 2 receptors, mediating NO-dependent vasodilation. These results suggest that imbalance between these opposing effects in conditions with endothelial dysfunction contribute to Ang II-mediated vascular damage. Our current findings might also have implications for strategies targeting Ang II for treatment of hypertension.

Forearm vascular responses to combined muscle metaboreceptor activation in the upper and lower limbs in humans

Our previous studies showed that venous occlusion or passive stretch of the lower limb, assuming a mechanical stimulus, attenuates the vasoconstriction in the non-exercised forearm during postexercise muscle ischaemia (PEMI) of the upper limb. In this study, we investigated whether a metabolic stimulus to the lower limb induces a similar response. Eight subjects performed a 2 min static handgrip exercise at 30% maximal voluntary contraction (MVC) followed by 3 min PEMI of the upper limb, concomitant with or without 2 min static ankle dorsiflexion at 30% MVC followed by 2 min PEMI of the lower limb. During PEMI of the upper limb alone, forearm blood flow (FBF) and forearm vascular conductance (FVC) in the non-exercised arm decreased significantly, whereas during combined PEMI of the upper and lower limbs, the decreases in FBF and FVC produced by PEMI of the upper limb was attenuated. Forearm blood flow and FVC were significantly greater during combined PEMI of the upper and lower limbs than during PEMI of the upper limb alone. When PEMI of the lower limb was released after combined PEMI of the upper and lower limbs (only PEMI of the upper limb was maintained continuously), the attenuated decreases in FBF and FVC observed during combined PEMI of the upper and lower limbs was not observed. Thus, forearm vascular responses differ when muscle metaboreceptors are activated in the upper limb and when there is combined activation of muscle metaboreceptors in both the upper and lower limbs.

Systemic Endothelial Dysfunction in Adults With Cyanotic Congenital Heart Disease

Secondary erythrocytosis results in increased shear stress in cyanotic congenital heart disease (CCHD), which may modify the balance between vasodilators and vasoconstrictors and affect systemic endothelial function. Because no data are available on systemic vasomotion, systemic endothelial function and nitric oxide (NO) availability were investigated in CCHD patients. Responses to arterial endothelium-dependent (acetylcholine [Ach]) and -independent (sodium nitroprusside [SNP]) vasodilation, NO synthase blockade (NG-monomethyl-L-arginine [L-NMMA]), endothelin-1 (ET-1), and ET-1 receptor blockade by BQ-123 in 11 CCHD patients (O2 saturation <90%; mean+/-SD, 79+/-1%; mean+/-SD age, 39+/-2 years) were compared with those in 10 age-matched healthy referents by using forearm venous occlusion plethysmography. Resting forearm blood flow (FBF) was lower in CCHD patients than in referents (2.4+/-0.2 versus 3.5+/-0.4 mL.min(-1).100 mL(-1) of forearm volume [FAV], P<0.05). Although the response to SNP was similar in both groups (CCHD, 2.0+/-0.3 to 8.3+/-1.0; referents, 3.6+/-0.7 to 11.9+/-1.2 mL.min(-1).100 mL(-1) of FAV; P>0.1), the response to Ach was markedly reduced in CCHD (maximal increase in FBF, 2.8+/-0.8 versus 37.5+/-4.4 mL.min(-1).100 mL(-1) of FAV; P<0.0001). l-NMMA was less effective in CCHD (decrease in FBF, 25+/-6% versus 40+/-4%; P<0.05). ET-1 caused less vasoconstriction in the CCHD group (-25+/-9% versus -51+/-7%, P<0.05), but the response to BQ-123 was similar in both groups (32+/-9% versus 27+/-9%). Systemic endothelial dysfunction is evident in CCHD patients as shown by strikingly reduced endothelial vasodilation to Ach. The response to exogenous ET-1 is reduced, possibly because of elevated endogenous ET-1 levels, but the effects of endogenous ET-1 on arterial tone are not enhanced, as indicated by the similar response to ET-1 blockade.

Blunted Vascular Response to Endothelin-A Receptor Blockade in Cyclosporine-Treated Lung Transplant Recipients

The majority of cyclosporine-treated transplant recipients develop hypertension. Endothelin-1 (ET-1) has been suggested to mediate cyclosporine-induced vasoconstriction when binding to ET-A receptors. We hypothesized that cyclosporine-treated lung transplant recipients have an increased basal vascular resistance and an augmented response to ET-A receptor blockade. The selective ET-A receptor blocker BQ-123 (10 and 50 nmol/min) was infused into the brachial artery, alone or in combination with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (2 and 4 micromol/min) in 10 lung transplant recipients without pharmacologically treated hypertension and 8 healthy controls. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and plasma levels of ET-1 were analyzed. Baseline forearm vascular resistance did not differ between recipients and controls (32 +/- 4 vs 42 +/- 7 mmHg/ml/min, p = 0.32). BQ-123 increased FBF in controls but not in recipients (26% +/- 9% vs 5% +/- 11% at 10 nmol/min, p = 0.043 between groups). Coinfusion of BQ-123 and L-NMMA caused a comparable decrease in FBF in recipients and controls (-26% +/- 11%, vs -34% +/- 7%). Baseline ET-1 was higher in recipients (17.2 +/- 1.1 vs 14.7 +/- 0.8 pg/ml, p = 0.038). BQ-123 infusion increased plasma ET-1 in controls but not in recipients (+24% +/- 11% vs -0.4% +/- 6.2%, p = 0.029 between groups). The results demonstrate that cyclosporine-treated lung transplant recipients have increased plasma levels of ET-1 and a blunted response to ET-A receptor blockade compared with healthy subjects. In contrast, we found no evidence for an increased basal vascular resistance in transplant recipients. These alterations in endothelin handling may contribute to the development of transplant-associated hypertension.

Vasoregulatory Responses To Sudden Changes In Forearm Perfusion Pressure During Moderate Forearm Exercise

Exercising muscle blood flow is thought to be tightly regulated to metabolic demand. The time course of vasoregulatory responses to a disruption of steady state exercising muscle blood flow remains unclear. PURPOSE We tested the hypothesis that sudden changes in local forearm perfusion pressure during moderate intensity forearm handgrip exercise would alter forearm blood flow (FBF) and result in rapid compensatory changes in forearm vascular conductance (FVC, vasoregulatory responses) to restore FBF. METHODS 12 healthy young subjects (7 female,5 male) lay supine and were instrumented for brachial artery FBF (Doppler ultrasound), arterial blood pressure (ABP; arterial tonometry) and heart rate (HR;ECG). Exercise consisted of 30% MVC rhythmic isometric handgrip contractions (2 s /2 s contraction/relaxation duty cycle). Rapid changes in arm position between above (AH) and below (BH) heart level (forearm perfusion pressure difference of ∼30 mmHg) during steady state exercise occurred during a 2 s contraction period. Exercise then continued for 4 min in the new arm position. Vasoregulatory responses were examined by analysing cardiac cycles during relaxation between contractions. FVC during exercise was calculated using forearm level ABP. RESULTS AH to BH transition: an immediate increase in FBF (ml/min ±SE) (419.5±56.6 to 708.7±68.5, p < 0.05) and FVC (602.1±94.4 to 709.5±85.4, p < 0.05) was followed by rapid restoration of FVC (ml/min/100 mmHg ±SE) (609.6±88.9, P=1.00) with no further change, and incomplete restoration of FBF (597.0±72.1, p < 0.001). BH to AH transition:an immediate decrease in FBF (551.0±68.6 to 349.1±52.7, p < 0.001) and FVC (540.0±71.3 to 468.3±74.3, P=0.017) was followed by rapid restoration of FVC (511.8±68.5, P=0.970) with no further change, and incomplete restoration of FBF (409.6±54.3, p < 0.001). CONCLUSION Changes in perfusion pressure during exercise result in an immediate change in FBF and perfusion pressure-mediated changes in resistance vessel distension (altered FVC). Rapid acting vasoregulatory mechanism(s) (likely myogenic) respond to restore FVC, with no further vasoregulatory adjustments such that FBF is not restored. Supported by NSERC; Canada Foundation for Innovation; Ontario Innovation Trust

Vasoregulatory Responses To Sudden Changes In Forearm Perfusion Pressure During Moderate Forearm Exercise

Exercising muscle blood flow is thought to be tightly regulated to metabolic demand. The time course of vasoregulatory responses to a disruption of steady state exercising muscle blood flow remains unclear. PURPOSE We tested the hypothesis that sudden changes in local forearm perfusion pressure during moderate intensity forearm handgrip exercise would alter forearm blood flow (FBF) and result in rapid compensatory changes in forearm vascular conductance (FVC, vasoregulatory responses) to restore FBF. METHODS 12 healthy young subjects (7 female,5 male) lay supine and were instrumented for brachial artery FBF (Doppler ultrasound), arterial blood pressure (ABP; arterial tonometry) and heart rate (HR;ECG). Exercise consisted of 30% MVC rhythmic isometric handgrip contractions (2 s /2 s contraction/relaxation duty cycle). Rapid changes in arm position between above (AH) and below (BH) heart level (forearm perfusion pressure difference of ∼30 mmHg) during steady state exercise occurred during a 2 s contraction period. Exercise then continued for 4 min in the new arm position. Vasoregulatory responses were examined by analysing cardiac cycles during relaxation between contractions. FVC during exercise was calculated using forearm level ABP. RESULTS AH to BH transition: an immediate increase in FBF (ml/min ±SE) (419.5±56.6 to 708.7±68.5, p < 0.05) and FVC (602.1±94.4 to 709.5±85.4, p < 0.05) was followed by rapid restoration of FVC (ml/min/100 mmHg ±SE) (609.6±88.9, P=1.00) with no further change, and incomplete restoration of FBF (597.0±72.1, p < 0.001). BH to AH transition:an immediate decrease in FBF (551.0±68.6 to 349.1±52.7, p < 0.001) and FVC (540.0±71.3 to 468.3±74.3, P=0.017) was followed by rapid restoration of FVC (511.8±68.5, P=0.970) with no further change, and incomplete restoration of FBF (409.6±54.3, p < 0.001). CONCLUSION Changes in perfusion pressure during exercise result in an immediate change in FBF and perfusion pressure-mediated changes in resistance vessel distension (altered FVC). Rapid acting vasoregulatory mechanism(s) (likely myogenic) respond to restore FVC, with no further vasoregulatory adjustments such that FBF is not restored. Supported by NSERC; Canada Foundation for Innovation; Ontario Innovation Trust

Vasopressin facilitates presynaptic sympathetic nerve activity in humans

It was the objective of this study to investigate whether a facilitatory role of vasopressin (AVP) on sympathetic nerve activity can be demonstrated in humans at the peripheral level. Eight subjects (32 +/- 2.3 years) participated in this study. Forearm blood flow (FABF) was measured using the venous occlusion plethysmography model. Each session was performed in the presence of a continuous infusion (into the brachial artery) of AVP in sub-pressor dosage of 0.008 ng/kg per min, or NaCl 0.9%. Using lower-body negative pressure (LBNP) (-10, -20 and -30 mmHg) the combined pre- and postsynaptic action of AVP on the sympathetic nervous system was investigated. This was followed by a second protocol in which the possible postsynaptic effects of AVP were evaluated with intra-arterial infused norepinephrine (NE). The baseline FABF was 5.2 +/- 0.6 ml/100 ml per min. After infusion of AVP (0.008 ng/kg per min), the FABF remained unchanged at a flow of 5.5 +/- 0.6 ml/100 ml per min (P = 0.26). LBNP caused a pressure-dependent decrease in FABF (25.6 +/- 4.4, 29.0 +/- 6.1 and 38.6 +/- 6.9%, for -10, -20 and -30 mmHg, respectively). AVP significantly enhanced the FABF responses to lower-body negative pressures (38.0 +/- 8.6, 49.3 +/- 5.1 and 58.9 +/- 6.3%, respectively (P = 0.014). NE caused a dose-dependent vasoconstriction by 3.1 +/- 4.6, 17.0 +/- 4.3 and 23.2 +/- 4.9%, at dosages of 10, 20 and 40 pg/min, respectively, unaffected by AVP (P = 0.91). We conclude that AVP can facilitate vasoconstriction mediated by the peripheral sympathetic nervous system at the presynaptic level in humans.

Forearm blood flow measurements using computerized R-wave triggered strain-gauge venous occlusion plethysmography: unilateral vs. bilateral measurements.

The human forearm is a well established model to study local vascular reactivity in humans in vivo, using strain-gauge venous occlusion plethysmography to measure blood flow and changes in blood flow in the forearm. To reduce the intra-individual variability of the forearm blood flow (FBF), it has been advocated that simultaneous measurements of contralateral forearm blood flow is obligatory. Therefore, the use of the calculated forearm ratio (FR) is recommended instead of using the actual FBF. In the present study we compared the intra-individual variability of forearm blood flow measurements and the forearm ratio, by using computerized R-wave triggered strain-gauge venous occlusion plethysmography, to test if bilateral expression of measurements is better than unilateral. Results were obtained in eight volunteers. Intra-arterial infused sodium nitroprusside induced a dose dependent increase in forearm blood flow and a dose dependent increase in the calculated forearm ratio. Intra-arterial infused norepinephrine induced a dose dependent decrease in forearm blood flow and a dose dependent decrease in the calculated forearm ratio. The differences between the variation coefficients of the forearm blood flow measurements and the calculated forearm ratio were different. These results support our hypothesis that by using a computerized, R-wave triggered system for unilateral forearm blood flow measurement is a more reliable outcome than the calculated forearm ratio derived from bilateral measurements.

Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo.

Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the L-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors. Endothelin-A (ET(A)) and endothelin-B (ET(B)) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%, P<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during saline infusion). Selective ET(A) blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA during saline infusion), but selective ET(B) receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion). Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ET(B) receptors and may be relevant in conditions associated with endothelial dysfunction.

Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease

Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Endothelial cell activation is an early event in atherogenesis, and previous studies have reported correlations between indirect markers of endothelial cell activation and CRP concentration. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in nine healthy subjects (mean age 53+/-8.1 years; body mass index 27+/-3.2 kg/m(2); mean arterial blood pressure 101+/-9.0 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of N(G)-monomethyl-L-arginine (L-NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a non-specific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with (i) the percentage decrease in forearm blood flow (FBF) during L-NMMA infusion (r=0.85, P=0.004); and (ii) the serum leptin concentration (r=0.65, P=0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to L-NMMA remained significant when age and leptin (t=2.65, P=0.045), age and BMI (t=3.69, P=0.014), or age and low-density-lipoprotein-cholesterol plus high-density-lipoprotein-cholesterol (t=3.37, P=0.044), were included in regression models. In contrast, the response of FBF to noradrenaline was not significantly related to CRP concentration. These data demonstrate for the first time a relationship between low-grade chronic inflammation and basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disease.

Sympathetic nervous system activity and alpha-adrenergic responsiveness in older hypertensive humans.

We have previously demonstrated in normotensive humans an age-associated increase in sympathetic nervous system (SNS) activity combined with appropriate downregulation of alpha-adrenergic responsiveness. Impaired downregulation of alpha-adrenergic responsiveness, despite a comparable level of SNS activity, could contribute to higher blood pressure in older hypertensive humans. We measured arterial plasma norepinephrine (NE) levels and the extravascular NE release rate (NE2) derived from [3H]NE kinetics (to assess systemic SNS activity), and platelet and forearm arterial adrenergic responsiveness in 20 normotensive (N) and in 24 hypertensive (H), otherwise healthy, older subjects (60-75 yr). Although plasma NE levels were similar (N 357 +/- 27 vs. H 322 +/- 22 pg/ml; P = 0.37), NE2 tended to be greater in the hypertensive group (H 2.23 +/- 0.21 vs. N 1.64 +/- 0.20 microgram. min-1. m-2; P = 0. 11), and the NE metabolic clearance rate was greater (H 1,100 +/- 30 vs. N 900 +/- 50 ml/m2; P = 0.004). In the hypertensive group, there was a greater alpha-agonist-mediated inhibition of platelet membrane adenylyl cyclase activity and a NE- but not ANG II-mediated decrease in forearm blood flow. Compared with normotensive subjects, in older hypertensive subjects 1) NE metabolic clearance rate is increased, 2) systemic SNS activity tends to be increased, and 3) arterial and platelet alpha-adrenergic responsiveness is enhanced. These results suggest that heightened SNS activity coupled with enhanced alpha-adrenergic responsiveness may contribute to elevated blood pressure in older hypertensive humans.