Reduction In Forearm Blood Flow Research Articles

The impact of obesity on the regulation of muscle blood flow during exercise in patients with heart failure with a preserved ejection fraction.

Obesity is now considered a primary comorbidity in heart failure with preserved ejection fraction (HFpEF) pathophysiology, mediated largely by systemic inflammation. Although there is accumulating evidence for a disease-related dysregulation of blood flow during exercise in this patient group, the role of obesity in the hemodynamic response to exercise remains largely unknown. Small muscle mass handgrip (HG) exercise was used to evaluate exercising muscle blood flow in nonobese (BMI < 30 kg/m2, n = 14) and obese (BMI > 30 kg/m2, n = 40) patients with HFpEF. Heart rate (HR), stroke index (SI), cardiac index (CI), mean arterial pressure (MAP), forearm blood flow (FBF), and vascular conductance (FVC) were assessed during progressive intermittent HG exercise [15%-30%-45% maximal voluntary contraction (MVC)]. Blood biomarkers of inflammation [C-reactive protein (CRP) and interleukin-6 (IL-6)] were also determined. Exercising FBF was reduced in obese patients with HFpEF at all work rates (15%: 304 ± 42 vs. 229 ± 15 mL/min; 30%: 402 ± 46 vs. 300 ± 18 mL/min; 45%: 484 ± 55 vs. 380 ± 23 mL/min, nonobese vs. obese, P = 0.025), and was negatively correlated with BMI (R = -0.47, P < 0.01). In contrast, no differences in central hemodynamics (HR, SI, CI, and MAP) were found between groups. Proinflammatory biomarkers were markedly elevated in patients with obesity (CRP: 2,133 ± 418 vs. 4,630 ± 590 ng/mL, P = 0.02; IL-6: 2.9 ± 0.3 vs. 5.2 ± 0.7 pg/mL, nonobese vs. obese, P = 0.04), and both biomarkers were positively correlated with BMI (CRP: R = 0.40, P = 0.03; IL-6: R = 0.57, P < 0.01). Together, these findings demonstrate the presence of obesity and an accompanying milieu of systemic inflammation as important factors in the dysregulation of exercising muscle blood flow in patients with HFpEF.NEW & NOTEWORTHY Obesity is the primary comorbid condition in HFpEF pathophysiology, but the role of adiposity on the peripheral circulation is not well understood. The present study identified a 30%-40% reduction in forearm blood flow during handgrip exercise, accompanied by a marked elevation in proinflammatory plasma biomarkers, in obese patients with HFpEF compared with their nonobese counterparts. These findings suggest an exaggerated dysregulation in exercising muscle blood flow associated with the obese HFpEF phenotype.

70Autonomic dysfunction in atrial fibrillation (AF) patients: absent vasomotor reflex to decreased cardiac venous return during af in comparison to sinus rhythm; implications for earlier rhythm control

Abstract Funding Acknowledgements Dr Malik is supported by an Australian Postgraduate Award Scholarship from the University of Adelaide. OnBehalf Centre for Heart Rhythm Disorders, University of Adelaide &amp; Royal Adelaide Hospital Background A bi-directional relationship exists between AF and the autonomic nervous system (ANS). Patients with AF studied in sinus rhythm (SR) have impaired vasomotor responses to decreased cardiac volume. Whether autonomic dysfunction worsens during AF itself, is unknown. Purpose We examined haemodynamic responses to lower body negative pressure (LBNP) in patients with persistent AF compared to AF studied in SR. LBNP decreases cardiac volume, deactivates atrial stretch receptors and induces a reflex to maintain blood pressure by increasing systemic vascular resistance (SVR). Methods 21 consecutive patients with paroxysmal or persistent AF were studied; during AF (n = 8) or SR (n = 13). Anti-arrhythmic and anti-hypertensives were withheld for 5 half-lives. Patients underwent LBNP using a custom-made chamber sealing both lower limbs. Negative pressure at sham (-0 mmHg), low (-20 mmHg) and high level (-40 mmHg) was applied for 5 minutes each. Finger photo plethysmography was used for beat-beat-blood pressure. Computation of SVR during AF is not feasible with this method. Therefore, the right forearm was used to perform venous occlusion plethysmography (VOP); non-invasive, well validated with LBNP and impervious to AF: to estimate forearm blood flow (FBF) and SVR (inversely proportional). Results Baseline characteristics and responses to LBNP are presented in Table 1. MAP was maintained, and HR rose slightly, in the SR group. MAP and HR decreased in the AF group. VOP demonstrates a reduction in FBF in the SR group (vasoconstriction); whereas the vasomotor response to LBNP was absent during AF. Figure 1 (Panels A-C). Conclusion The presence of AF is associated with autonomic dysfunction from impaired cardiac volume regulation. This novel finding may contribute to the known risk of falls and syncope due to AF. Further studies are needed to evaluate whether abnormal cardiac reflexes are involved in atrial remodelling and AF progression. Table 1 Baseline Characteristics During AF During SR P Value Age 65 ± 5 59 ± 3 0.4 AAD &amp; Anti-HTN medications withheld (%) 75 85 0.6 Resting mean arterial pressure (MAP) 109 ± 9 93 ± 6 0.1 Resting heart rate (HR) 94 ± 6 60 ± 4 0.0001* Haemodynamic response to LBNP % Δ MAP due to LBNP -9 ± 5 +0.5 ± 3 0.2 % Δ HR due to LBNP -6 ± 3 +5 ± 3 0.03* % Δ FBF due to LBNP +75 ± 59 -27 ± 8 0.02* AAD Anti-arrhthmic. HTN: Hypertension. Mean +/- SEM. Abstract Figure. Vasomotor response to LBNP: in AF vs SR

2380Mechanisms of myocardial ischemia during exercise in microvascular angina

Abstract Background Coronary microvascular dysfunction (MVD) is defined by impaired flow augmentation in response to a vasodilator, the pathophysiological basis of which is unclear. This study sought to address two major gaps in our understanding of MVD: firstly, whether diminished flow reserve is due to structural changes within the microvasculature or potentially reversible dysfunction and secondly to unravel the mechanism of exercise-induced ischemia in the absence of obstructive disease. Methods Simultaneous intracoronary pressure and flow velocity recordings were made in the left anterior descending artery of patients with angina and no obstructive epicardial disease (Fractional Flow Reserve &gt;0.80). Measurements were made at rest, during adenosine-mediated hyperaemia and supine bicycle exercise. Wave intensity analysis was used to quantify waves that accelerate and decelerate coronary blood flow, coronary perfusion efficiency being defined as the proportion of total wave energy that accelerates blood flow. Patients were prospectively classified into MVD (coronary flow reserve &lt;2.5) and controls with researchers blinded to the classification throughout the protocol. Myocardial perfusion and vascular function were assessed by 3T cardiac MRI and venous occlusion plethysmography with forearm blood flow (FBF) assessment during serial infusions of acetylcholine, adenosine and the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Results 78 patients were enrolled (42 patients had MVD and 36 were controls), with no differences in cardiovascular risk factors between groups. The MVD group had elevated coronary blood flow (21.3±6.4 vs. 15.1±4.5cm s–1; p&lt;0.001) and global myocardial perfusion (1.36±0.37 vs. 1.13±0.22ml/min/g; p=0.01) at rest. Maximum coronary and myocardial blood flow during hyperaemia was similar in both groups. During exercise, MVD patients achieved similar peak flow (30.5±10.0 vs. 26.3±7.7cm s–1; p=0.07) despite a higher rate-pressure product (20777±5205 vs. 17450±4710bpm.mmHg; p=0.01). Coronary perfusion efficiency, decreased with exercise in the MVD group (61±11% vs. 44±10% p&lt;0.001) but was unchanged in controls. On MRI, MVD had lower hyperaemic endo-epicardial perfusion ratio than controls (0.94±0.08 vs. 1.04±0.13; p=0.001). Augmentation of FBF with acetylcholine was attenuated in MVD patients compared to controls (p=0.02) but the response to adenosine was similar (p=0.13). Infusion of L-NMMA caused a significantly greater reduction in FBF in MVD patients compared to controls (p&lt;0.001). Exercise Physiology in MVD Conclusion Impaired flow reserve in MVD represents a dysfunctional state, characterised by inappropriately elevated resting flow due to increased nitric-oxide synthase mediated vasodilatation. There is abnormal flow distribution in the myocardium predisposing to subendocardial ischaemia, associated with and exacerbated by impaired cardiac-coronary coupling during exercise. These novel findings may represent distinct therapeutic targets. Acknowledgement/Funding British Heart Foundation

Effects of oral sodium nitrate on forearm blood flow, oxygenation and exercise performance during acute exposure to hypobaric hypoxia (4300 m)

A reduction in oxygen transport contributes to impaired exercise capacity at high altitude. Since blood flow is mediated, in part, by nitric oxide (NO), we hypothesized that sodium nitrate provided before forearm grip exercise performed at a simulated altitude of 4300 m (hypobaric hypoxia (HH)) would increase forearm blood flow and oxygenation, and decrease the decrement in grip performance. In a double-blind, randomized crossover study, 10 healthy subjects (9 males and 1 female) performed continuous (CGrip) and repeated rhythmic (RGrip) isometric forearm exercise until task failure in normobaric normoxia (NN), 2.5 h following consumption of placebo and sodium nitrate (15 mmol) in HH, and then again post-HH at sea-level pressure. Measurements included forearm blood flow (FBF) and anterior forearm tissue oxygenation (StO2), mean arterial blood pressure (MAP), arterial blood O2 saturation (SpO2), plasma NO reaction products (NOx) and nitrite, and exhaled NO (PENO). Compared to baseline testing in NN, performing CGrip and RGrip exercise in HH resulted in significant reductions in forearm blood flow, SaO2 and StO2, responses that were accompanied by significant performance decrements (∼10%) in both CGrip and RGrip exercise. In spite of a 10-fold increase in plasma NOx levels and a significant decrease in MAP during CGrip exercise following nitrate consumption, there were no significant main effects of treatment (placebo vs. sodium nitrate) for forearm blood flow, SpO2, StO2, or grip performance. PENO remained unchanged between NN, HH and post-HH conditions with placebo, but increased (∼24%) following nitrate supplementation in HH and post-HH. These data do not support a benefit in consuming a single dose of supplemental nitrate on forearm blood flow and isometric exercise in healthy adults at a simulated altitude of 4300 m.

Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol.

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P<.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension.

Blood flow restriction without sympathetic vasoconstriction in ageing skeletal muscle during exercise.

Blood flow restriction without sympathetic vasoconstriction in ageing skeletal muscle during exercise.

Histamine‐induced vasodilatation in the human forearm vasculature

To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose-response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1 - and H2 -receptor antagonists. Flare and itch were assessed in all studies. Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min(-1) ) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min(-1) 100 ml(-1) ; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2 -receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min(-1) histamine: -11.9 ml min(-1) 100 ml(-1) (-4.0, -19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: -403.7 cm(2) (-231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1 -receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2 -receptors are important in this process. Our results support further exploration of combined H1 - and H2 -receptor antagonist therapy in acute allergic syndromes.

Sympathetic activation increases NO release from eNOS but neither eNOS nor nNOS play an essential role in exercise hyperemia in the human forearm

Nitric oxide (NO) release from endothelial NO synthase (eNOS) and/or neuronal NO synthase (nNOS) could be modulated by sympathetic nerve activity and contribute to increased blood flow after exercise. We examined the effects of brachial-arterial infusion of the nNOS selective inhibitor S-methyl-l-thiocitrulline (SMTC) and the nonselective NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA) on forearm arm blood flow at rest, during sympathetic activation by lower body negative pressure, and during lower body negative pressure immediately after handgrip exercise. Reduction in forearm blood flow by lower body negative pressure during infusion of SMTC was not significantly different from that during vehicle (-28.5 ± 4.02 vs. -34.1 ± 2.96%, respectively; P = 0.32; n = 8). However, l-NMMA augmented the reduction in forearm blood flow by lower body negative pressure (-44.2 ± 3.53 vs. -23.4 ± 5.71%; n = 8; P < 0.01). When lower body negative pressure was continued after handgrip exercise, there was no significant effect of either l-NMMA or SMTC on forearm blood flow immediately after low-intensity exercise (P = 0.91 and P = 0.44 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10) or high-intensity exercise (P = 0.46 and P = 0.68 for l-NMMA vs. saline and SMTC vs. saline, respectively; each n = 10). These results suggest that sympathetic activation increases NO release from eNOS, attenuating vasoconstriction. Dysfunction of eNOS could augment vasoconstrictor and blood pressure responses to sympathetic activation. However, neither eNOS nor nNOS plays an essential role in postexercise hyperaemia, even in the presence of increased sympathetic activation.

“Functional sympatholysis” in the present concept does not exist: arteriovenous pumping, supplied by capillary pumps, explains immediate exercise hyperemia

to the editor: We read with great interest Dr. Casey and colleagues' ([1][1]) investigations aimed at discovering the causes of substantial reduction in forearm blood flow under hyperoxia. In our opinion, they concluded quite rightly that “functional sympatholysis” (one of the most cited, yet

Vasoconstrictor responsiveness during hyperbaric hyperoxia in contracting human muscle

Large increases in systemic oxygen content cause substantial reductions in exercising forearm blood flow (FBF) due to increased vascular resistance. We hypothesized that 1) functional sympatholysis (blunting of sympathetic α-adrenergic vasoconstriction) would be attenuated during hyperoxic exercise and 2) α-adrenergic blockade would limit vasoconstriction during hyperoxia and increase FBF to levels observed under normoxic conditions. Nine male subjects (age 28 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Studies were performed in a hyperbaric chamber at 1 atmosphere absolute (ATA; sea level) while breathing 21% O(2) and at 2.82 ATA while breathing 100% O(2) (estimated change in arterial O(2) content ∼6 ml O(2)/100 ml). FBF (ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC) was calculated from FBF and blood pressure (arterial catheter). Vasoconstrictor responsiveness was determined using intra-arterial tyramine. FBF and FVC were substantially lower during hyperoxic exercise than normoxic exercise (∼20-25%; P < 0.01). At rest, vasoconstriction to tyramine (% decrease from pretyramine values) did not differ between normoxia and hyperoxia (P > 0.05). During exercise, vasoconstrictor responsiveness was slightly greater during hyperoxia than normoxia (-22 ± 3 vs. -17 ± 2%; P < 0.05). However, during α-adrenergic blockade, hyperoxic exercise FBF and FVC remained lower than during normoxia (P < 0.01). Therefore, our data suggest that although the vasoconstrictor responsiveness during hyperoxic exercise was slightly greater, it likely does not explain the majority of the large reductions in FBF and FVC (∼20-25%) during hyperbaric hyperoxic exercise.

Limb-specific training affects exercise hyperemia but not sympathetic vasoconstriction

This study used cross-sectional and longitudinal training research designs to determine if (a) exercise hyperemia is enhanced in exercise-trained forearms and (b) sympathetic vasoconstriction of the trained forearm is attenuated (sympatholysis) during handgrip exercise. In the cross-sectional comparison, 10 rock climbers, 10 runners, 10 controls participated while the longitudinal training study examined vascular responsiveness in six untrained men before and after 6weeks of handgrip training. Mean blood velocity, brachial artery diameter, heart rate, and systemic blood pressure were measured at rest, during a cold pressor test (CPT), dynamic handgrip exercise at 30% MVC with and without CPT, and during reactive hyperemia. During the resting CPT, forearm blood flow (FBF) decreased less (P<0.05) in runners than in climbers, the decline being -6.30+30.05 and -34.3+20.54 during the last minute, respectively. During handgrip exercise, FBF and vascular conductance (VC) increased more (P<0.05) in climbers than in runners and controls, the latter reaching 3.98+1.11, 2.22+0.88, and 2.75+1.06 mlmin(-1)mmHg(-1), respectively. When a CPT was added during handgrip exercise, the reduction in FBF and VC was not different between the groups. Handgrip training increased (P < 0.05) forearm volume (5 + 3%) and MVC (25 + 29%), but did not affect FBF or VC during a CPT, with or without exercise. These data suggest that arm-trained athletes have greater exercise hyperemia. However, this training effect is not explained by sympatholysis and is not evident after 6weeks of handgrip training in previously untrained subjects.

Evaluation of muscle metaboreflex function through graded reduction in forearm blood flow during rhythmic handgrip exercise in humans

Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Our aim was to determine the muscle metaboreflex threshold and gain in humans by creating an open-loop relationship between active muscle blood flow and hemodynamic responses during a rhythmic handgrip exercise. Eleven healthy subjects performed the exercise at 5 or 15% of maximal voluntary contraction (MVC) in random order. During the exercise, forearm blood flow (FBF), which was continuously measured using Doppler ultrasound, was reduced in five steps by manipulating the inner pressure of an occlusion cuff on the upper arm. The FBF at each level was maintained for 3 min. The initial reductions in FBF elicited no hemodynamic changes, but once FBF fell below a threshold, mean arterial blood pressure (MAP) and heart rate (HR) increased and total vascular conductance (TVC) decreased in a linear manner. The threshold FBF during the 15% MVC trial was significantly higher than during the 5% MVC trial. The gain was then estimated as the slope of the relationship between the hemodynamic responses and FBFs below the threshold. The gains for the MAP and TVC responses did not differ between workloads, but the gain for the HR response was greater in the 15% MVC trial. Our findings thus indicate that increasing the workload shifts the threshold for the muscle metaboreflex to higher blood flows without changing the gain of the reflex for the MAP and TVC responses, whereas it enhances the gain for the HR response.

Greater Functional ET B Receptor Antagonism With Bosentan Than Sitaxsentan in Healthy Men

Endothelin (ET)-1 is implicated in the development of hypertension and a role for endothelin receptor antagonists (ETRAs) in the management of hypertension is emerging. ETRAs are classified as selective or mixed depending on their degree of ET(A):ET(B) receptor blockade. As yet, there are no comparative studies in humans that measure biochemical and functional ET(B) blockade achieved by currently licensed ETRAs. We therefore investigated the effects of bosentan, a mixed ETRA, and sitaxsentan, an ET(A) selective ETRA, on plasma ET-1 concentrations and ET(B)-mediated vasodilatation to ET-3. In a randomized, double-blind, 3-way crossover study, 10 healthy subjects received 7 days of placebo, bosentan 250 mg, and sitaxsentan 100 mg daily. Plasma ET-1 concentrations were measured at baseline and 3 hours on day 1 and predose on day 7. Subjects also underwent forearm blood flow measurements on day 7 of each period with brachial artery infusion of ET-3 (60 pmol/min for 5 minutes). Bosentan, but not placebo or sitaxsentan, significantly increased plasma ET-1 concentrations at day 7 (+0.70+/-0.20 pg/mL; P<0.005). Maximal ET-3-mediated vasodilatation was seen at 2 minutes following placebo (30+/-6%) and sitaxsentan (21+/-11%); however, this was abolished by bosentan, with a reduction in forearm blood flow of 8+/-3% (P<0.01 versus placebo and sitaxsentan). Bosentan but not sitaxsentan increases circulating plasma ET-1 levels and abolishes acute ET-3-mediated vasodilatation, confirming that the mixed ET(A/B) antagonist bosentan, but not the selective ET(A) antagonist sitaxsentan, causes functional ET(B) blockade at clinically relevant doses in healthy human subjects.

Nitric Oxide and Reactive Hyperemia: Role of Location and Duration of Ischemia

Ischemia-induced reactive hyperemia (RH) is mediated by various factors including release of nitric oxide (NO). The contribution of NO to RH equals the extent of L-NMMA-dependent reduction of forearm blood flow (FBF). Because the optimal duration and location of ischemia that provokes maximum NO activation is unknown, we analyzed which duration and location stimulates most NO release, aiming at developing a noninvasive tool to measure endothelial integrity by NO synthase activity in humans. FBF was measured by strain gauge plethysmography after ischemia applied at the upper arm and wrist during intra-arterial infusion of L-NMMA or saline. To obtain similar FBF before RH, clamping with sodium nitroprissude was performed. Twenty-eight healthy male volunteers were randomly assigned to two groups (N = 15) undergoing ischemia of 1 and 5 min or 2 and 5 min (N = 13) at both locations. Peak FBF was not affected by L-NMMA infusion. The change of FBF during L-NMMA expressed as area under the curve (AUC) of the first minute was significantly reduced after 1 (-0.70 +/- 1.63 ml, P < 0.001) and 2 min (1.67 +/- 2.65 ml, P < 0.01) of ischemia applied at wrist level compared to 5 min (7.49 +/- 7.92 ml). Ischemia applied to the upper arm showed no significant differences of FBF after L-NMMA or saline infusion, irrespective of the duration of ischemia. Our data indicate that only immediately after ischemia the vasodilatatory response is most NO-dependent. RH as a test of NO activity in the forearm microcirculation should be applied at the wrist and last 1 min.

Basal Endothelial Nitric Oxide Release Is Preserved in Overweight and Obese Adults

Impaired basal nitric oxide release is associated with a number of cardiovascular disorders including hypertension, arterial spasm, and myocardial infarction. We determined whether basal endothelial nitric oxide release is reduced in otherwise healthy overweight and obese adult humans. Seventy sedentary adults were studied: 32 normal weight (BMI <25 kg/m(2)), 24 overweight (BMI > or = 25 < 30 kg/m(2)), and 14 obese (BMI > or = 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusions of N(g)-monomethyl-L-arginine (5 mg/min), a nitric oxide synthase inhibitor, were used as an index of basal nitric oxide release. N(g)-monomethyl-L-arginine elicited significant reductions in FBF in the normal weight (from 4.1 +/- 0.2 to 2.7 +/- 0.2 mL/100 mL tissue/min), overweight (4.1 +/- 0.1 to 2.8 +/- 0.2 mL/100 mL tissue/min), and obese (3.9 +/- 0.3 to 2.7 +/- 0.2 mL/100 mL tissue/min) subjects. Importantly, the magnitude of reduction in FBF (approximately 30%) was similar among the groups. These results indicate that the capacity of the endothelium to release nitric oxide under basal conditions is not compromised in overweight and obese adults.

The contribution of nitric oxide and vasodilatory prostanoids to bradykinin‐mediated vasodilation in Type 1 diabetes

To investigate the effect of bradykinin on endothelial tone in normoalbuminuric Type 1 diabetic patients and specifically whether any changes are mediated through nitric oxide or prostaglandins. Forearm blood flow was measured using venous occlusion plethysmography at baseline and after brachial artery infusions of incremental doses of bradykinin (50, 100 and 200 ng/min) in 15 patients with Type 1 diabetes and 13 non-diabetic controls. Forearm blood flow at baseline and following bradykinin was then re-examined after local infusion of L-NMMA, a nitric oxide synthase inhibitor, and L-NMMA with indomethacin, a cyclo-oxygenase inhibitor. Baseline blood flow in the diabetic and control groups were similar (4.46 +/- 1.11 vs. 3.41 +/- 1.23 ml/min/100 ml, respectively; P = 0.07). After infusion of L-NMMA and L-NMMA with indomethacin, there was a similar reduction in blood flow responses to bradykinin in both groups. There was no significant difference between the diabetic patients and control subjects in the percentage reduction in forearm blood flow following L-NMMA (16.55 vs. 18.12%, respectively, P = 0.94) and L-NMMA with indomethacin (47.1 vs. 37.3%, respectively, P = 0.14). This study demonstrates that bradykinin-stimulated vasodilation is mediated by both nitric oxide and prostaglandin release from the endothelium in patients with Type 1 diabetes and normoalbuminuria, and in healthy control subjects. We have also shown that the relative contributions of nitric oxide and prostaglandin to bradykinin-mediated vasodilation are similar in these diabetic patients compared with non-diabetic subjects.

Role of cyclooxygenase products in the regulation of vascular tone and in the endothelial vasodilator function of normal, hypertensive, and hypercholesterolemic humans

A defective vascular activity of endothelial vasoactive substances is observed in essential hypertension and hypercholesterolemia, and is believed to participate in the vascular abnormalities characteristic of these conditions. The present study aimed to determine the role of cyclooxygenase (COX) products in the maintenance of vascular tone and in the endothelium-mediated vasodilation of healthy subjects, and to investigate their contribution to the endothelial dysfunction of essential hypertensive and hypercholesterolemic patients. The effects of intra-arterial aspirin (acetylsalicylic acid [ASA], 1, 3, and 10 mg/min) were assessed on basal forearm blood flow (strain gauge plethysmography) and on responses to acetylcholine (7.5, 15 and 30 μg/min) and sodium nitroprusside (0.8, 1.6 and 3.2 μg/min) in 24 normal, 23 hypertensive, and 24 hypercholesterolemic subjects. Basal forearm blood flow was not different among the 3 groups (p = 0.95). ASA resulted in a significant reduction of forearm blood flow from baseline in normal (p = 0.003), hypertensive (p = 0.001), and hypercholesterolemic subjects (p = 0.001), without any difference among the 3 groups (p = 0.90). ASA significantly improved the effect of acetylcholine in normal (p = 0.008), hypertensive (p = 0.008), and hypercholesterolemic subjects (p = 0.022), without significant difference among the 3 groups (p = 0.46). ASA did not significantly modify the vasodilator effect of sodium nitroprusside in any of the 3 groups. These findings suggest that in humans, vasodilator prostanoids actively contribute to the maintenance of basal vascular tone, whereas vasoconstrictor products of COX activity limit endothelium-dependent vasodilation. COX products do not appear to play a major role in the endothelial dysfunction of hypertensive or hypercholesterolemic patients.

Enhanced vasoconstrictor effect of big endothelin-1 in patients with atherosclerosis: relation to conversion to endothelin-1

The enhanced production of endothelin-1 (ET-1) in atherosclerotic arteries may be related to increased activity of the endothelin converting enzyme (ECE) which converts big ET-1 to ET-1. The purpose of the present study was to investigate whether the vasoconstrictor activity of big ET-1 is altered as a result of increased conversion to ET-1 in patients with atherosclerosis. Big ET-1 was infused into the brachial artery of nine patients with atherosclerosis and nine healthy controls. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Big ET-1 (15 and 50 pmol/min) evoked more pronounced reduction in FBF in the patients than in the controls ( P<0.01). The low dose big ET-1 elevated local venous plasma ET-1 (from 2.8±0.3 to 9.0±1.6 pmol/l; P<0.01) and the net formation of ET-1 (from −6.6±8.6 to 50.5±16.0 fmol/min; P<0.01) in the patients but not in the controls. Furthermore, histological examination revealed ECE immunoreactivity in the fibrous cap of atherosclerotic plaques in addition to the endothelium and smooth muscle cells of radial arteries. In conclusion, administration of big ET-1 results in enhanced vasoconstriction and increased formation of ET-1 in patients with atherosclerosis as compared to healthy controls which may be due to increased activity of ECE.

Effect of hypohydration on core temperature during exercise in temperate and hot environments.

The purpose of this study was to compare directly the physiological consequences of 5% hypohydration or euhydration during exercise in both temperate (23 degrees C) and hot (33 degrees C) environments. The subjects were eight male volunteers. Each performed four 1-h exercise bouts at 60% maximum oxygen uptake, one in each of the following conditions: hot-hypohydrated, hot-euhydrated, temperate-hypohydrated, and temperate-euhydrated. Heart rate (HR), rectal temperature (Tre), forearm blood flow, and oxygen uptake were measured after 20, 40, and 60 min exercise. Whole-body sweat rate was also determined for each exercise bout. Hypohydration increased Tre significantly (P<0.05) more in the hot environment (0.16 degrees C per 1% decrease in body mass) than in the temperate environment (0.08 degrees C per 1% hypohydration). Furthermore, compared with euhydration, hypohydration decreased forearm blood flow and whole-body sweat rate significantly more during exercise in the hot than in the temperate environment. The reductions in forearm blood flow and whole-body sweat rate appear to have decreased heat loss, thus accounting for the increase in Tre during exercise in the heat while hypohydrated. In conclusion, this study illustrates that the physiological consequences of hypohydration during exercise are exacerbated in the heat.

Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis

Background & Aims: The renin-angiotensin and sympathetic nervous systems are activated in cirrhosis. This study aimed to establish the role of angiotensin II (ANG II) in the regulation of basal and sympathetically stimulated vascular tone in preascitic cirrhotic patients and patients with iuretic-refractory ascites compared with age- and sex-matched healthy controls. Methods: Forearm blood flow (FBF) responses to lower body negative pressure (LBNP) and to subsystemic, intrabrachial infusions of losartan, an angiotensin II type 1 (AT 1) receptor antagonist, norepinephrine, and ANG II were measured using venous occlusion plethysmography. Results: In all groups, ANG II and norepinephrine caused dose-dependent reductions in FBF ( P < 0.001); responses to norepinephrine were similar across the 3 groups but those to ANG II were less in both cirrhotic groups than in controls ( P < 0.01). Losartan caused a dose-dependent increase in FBF only in patients with refractory ascites ( P < 0.01). LBNP caused less reduction in FBF in refractory ascites patients than in both preascitic patients and controls ( P < 0.01). Conclusions: Despite hyporesponsiveness to exogenous ANG II in both early and advanced cirrhosis, endogenous ANG II contributes to the maintenance of basal vascular tone only in advanced cirrhosis. These findings suggest a role of ANG II in the pathogenesis of ascites. Attenuated LBNP responses occurred only in advanced cirrhosis, without apparent interaction with endogenous ANG II. GASTROENTEROLOGY 2000;118:565-572