Prostaglandins contribute to the vasodilation induced by nicotinic acid

The significance of endogenously formed prostaglandins in the vasodilation induced by nicotinic acid (NIC) was investigated. The forearm venous plasma level of radioimmunoassayed PGE (R-PGE) and the forearm blood flow (FBF) were measured in 13 healthy male volunteers at rest and during infusion of NIC. Each subject was subsequently re-studied after pretreatment with the PG synthesis inhibitor, naproxen. In the absence of naproxen, NIC infusion resulted in an almost four-fold rise in the release of R-PGE and a 60% increase in FBF. Pretreatment with naproxen did not affect the basal release of R-PGE or the basal FBF but inhibited both the release of R-PGE and the increase in FBF following NIC. The data support the hypothesis that the vasodilating effect of NIC is largely dependent upon an increased vascular formation of PG.     

Impact of combined NO and PG blockade on rapid vasodilation in a forearm mild-to-moderate exercise transition in humans

We tested the hypothesis that nitric oxide (NO) and prostaglandins (PGs) contribute to the rapid vasodilation that accompanies a transition from mild to moderate exercise. Nine healthy volunteers (2 women and 7 men) lay supine with forearm at heart level. Subjects were instrumented for continuous brachial artery infusion of saline (control condition) or combined infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) and ketorolac (drug condition) to inhibit NO synthase and cyclooxygenase, respectively. A step increase from 5 min of steady-state mild (5.4 kg) rhythmic, dynamic forearm handgrip exercise (1 s of contraction followed by 2 s of relaxation) to moderate (10.9 kg) exercise for 30 s was performed. Steady-state forearm blood flow (FBF; Doppler ultrasound) and forearm vascular conductance (FVC) were attenuated in drug compared with saline (control) treatment: FBF = 196.8 +/- 30.8 vs. 281.4 +/- 34.3 ml/min and FVC = 179.3 +/- 29.4 vs. 277.8 +/- 34.8 ml.min(-1).100 mmHg(-1) (both P < 0.01). FBF and FVC increased from steady state after release of the initial contraction at the higher workload in saline and drug conditions: DeltaFBF = 72.4 +/- 8.7 and 52.9 +/- 7.8 ml/min, respectively, and DeltaFVC = 66.3 +/- 7.3 and 44.1 +/- 7.0 ml.min(-1).100 mmHg(-1), respectively (all P < 0.05). The percent DeltaFBF and DeltaFVC were not different during saline infusion or combined inhibition of NO and PGs: DeltaFBF = 27.2 +/- 3.1 and 28.1 +/- 3.8%, respectively (P = 0.78) and DeltaFVC = 25.7 +/- 3.2 and 26.0 +/- 4.0%, respectively (P = 0.94). The data suggest that NO and vasodilatory PGs are not obligatory for rapid vasodilation at the onset of a step increase from mild- to moderate-intensity forearm exercise. Additional vasodilatory mechanisms not dependent on NO and PG release contribute to the immediate and early increase in blood flow in an exercise-to-exercise transition.     

Effect of different prostaglandin synthesis inhibitors on post-occlusive blood flow in human forearm

The vascular relaxation response in the human forearm that follows a short period of arterial occlusion (reactive hyperemia) was investigated with respect to its dependance on an intact PG synthesis. In 10 healthy subjects, five men and five women, forearm blood flow was measured, using venous occlusion plethysmography, in the basal state and during the recovery phase following 5 min of obstructed arterial flow. The subjects were studied at nine different occasions. At six of these they were pre-treated with the highest recommended doses of either of the PG synthesis inhibitors acetyl-salicylic acid, diclofenac, ibuprofen, indomethacin, naproxen or piroxicam; the remaining occasions were controls, performed in the absence of drugs in the beginning, middle, and end of the series.All the drugs significantly decreased the total reactive hyperemia following 5 min of arterial occlusion. Ibuprofen was the most efficient agent, inhibiting the total reactive hyperemia by more than 70%, and naproxen was least active, producing about 35% inhibition. The rest of the drugs diminished the total reactive hyperemia by 55–65%. Basal forearm blood flow was not affected by either of the agents.From these data we conclude that drugs which inhibit PG synthesis in man have in common the capacity to decrease post-occlusive reactive hyperemia. This indicates that an activation of the local release of arachidonic acid, leading to formation of vasodilator PG, is one of the main factors behind the vascular smooth muscle relaxation response to arterial occlusion.     

Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n = 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthase [N(G)-monomethyl-L-arginine (L-NMMA)] and cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P = 0.22-0.99). In protocol 2 (n = 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n = 8)- and high-dose (n = 8) ATP for 5 min evoked a significant increase in FVC above baseline (low = 198 ± 24%; high = 706 ± 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low- and high-dose ATP (P < 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (ΔFVC = -31 ± 11%)- and high-dose ATP (ΔFVC -25 ± 11%; P = 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular responses. Importantly, the majority of ATP-mediated vasodilation is independent of these putative endothelium-dependent pathways in humans.     

Direct effect of ethanol on human vascular function

Epidemiological studies indicate that moderate ethanol consumption reduces cardiovascular mortality. Cellular and animal data suggest that ethanol confers beneficial effects on the vascular endothelium and increases the bioavailability of nitric oxide. The purpose of this study was to assess the effect of ethanol on endothelium-dependent, nitric oxide-mediated vasodilation in healthy human subjects. Forearm blood flow (FBF) was determined by venous occlusion plethysmography in healthy human subjects during intra-arterial infusions of either methacholine (0.3, 1.0, 3.0, and 10.0 mcg/min, n = 9), nitroprusside (0.3, 1.0, 3.0, and 10.0 mcg/min, n = 9), or verapamil (10, 30, 100, and 300 mcg/min, n = 8) before and during the concomitant intra-arterial infusions of ethanol (10% ethanol in 5% dextrose). Additionally, a time control experiment was conducted, during which the methacholine dose-response curve was measured twice during vehicle infusions (n = 5). During ethanol infusion, mean forearm and systemic alcohol levels were 227 +/- 30 and 6 +/- 0 mg/dl, respectively. Ethanol infusion alone reduced FBF (2.5 +/- 0.1 to 1.9 +/- 0.1 ml.dl(-1).min(-1), P < 0.05). Despite initial vasoconstriction, ethanol augmented the FBF dose-response curves to methacholine, nitroprusside, and verapamil (P < 0.01 by ANOVA for each). To determine whether this augmented FBF response was related to shear-stress-induced release of nitric oxide, FBF was measured during the coinfusion of ethanol and N(G)-nitro-L-arginine (L-NAME; n = 8) at rest and during verapamil-induced vasodilation. The addition of L-NAME did not block the ability of ethanol to augment verapamil-induced vasodilation. Ethanol has complex direct vascular effects, which include basal vasoconstriction as well as potentiation of both endothelium-dependent and -independent vasodilation. None of these effects appear to be mediated by an increase in nitric oxide bioavailability, thus disputing findings from preclinical models.     

Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs.

Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.     

Effect of saline infusion during exercise on thermal and circulatory regulations

To quantify the effect of an acute increase in plasma volume (PV) on forearm blood flow (FBF), heart rate (HR), and esophageal temperature (Tes) during exercise, we studied six male volunteers who exercised on a cycle ergometer at 60% of maximal aerobic power for 50 min in a warm [(W), 30 degrees C, less than 30% relative humidity (rh)] or cool environment [(C), 22 degrees C, less than 30% rh] with isotonic saline infusion [Inf(+)] or without infusion [Inf(-)]. The infusion was performed at a constant rate of 0.29 ml.kg body wt-1.min-1 for 20-50 min of exercise to mimic fluid intake during exercise. PV decreased by approximately 5 ml/kg body wt within the first 10 min of exercise in all protocols. Therefore, PV in Inf(-) was maintained at the same reduced level by 50 min of exercise in both ambient temperatures, whereas PV in Inf(+) increased toward the preexercise level and recovered approximately 4.5 ml/kg body wt by 50 min in both temperatures. The restoration of PV during exercise suppressed the HR increase by 6 beats/min at 50 min of exercise in W; however, infusion had no effect on HR in C. In W, FBF in Inf(+) continued to increase linearly as Tes rose to 38.1 degrees C by the end of exercise, whereas FBF in Inf(-) plateaued when Tes reached approximately 37.7 degrees C. The infusion in C had only a minor effect on FBF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Forearm vascular control during acute hyperglycemia in healthy humans

The vascular endothelium is a site of pathological changes in patients with diabetes mellitus that may be related to severe chronic hyperglycemia. However, it is unclear whether transient hyperglycemia alters vascular function in an otherwise healthy human forearm. To test the hypothesis that acute, moderate hyperglycemia impairs endothelium-dependent forearm vasodilation, we measured vasodilator responses in 25 healthy volunteers (11 F, 14 M) assigned to one of three protocols. In protocol 1, glucose was varied to mimic a postprandial pattern (i.e., peak glucose approximately 11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance. Protocol 2 involved 6 h of mild hyperglycemia (approximately 7 mmol/l). Protocol 3 involved 6 h of euglycemia. Glucose concentration was maintained with a variable systemic glucose infusion. Insulin concentrations were maintained at approximately 65 pmol/l by means of a somatostatin and "basal" insulin infusion. Glucagon and growth hormone were replaced at basal concentrations. Forearm blood flow (FBF) was calculated from Doppler ultrasound measurements at the brachial artery. In each protocol, FBF dose responses to intrabrachial acetylcholine (ACh) and sodium nitroprusside (NTP) were assessed at baseline and at 60, 180, and 360 min of glucose infusion. Peak endothelium-dependent vasodilator responses to ACh were not diminished by hyperglycemia in any trial. For example, peak responses to ACh during protocol 2 were 307 +/- 47 ml/min at euglycemic baseline and 325 +/- 52, 353 +/- 65, and 370 +/- 70 ml/min during three subsequent hyperglycemic trials (P = 0.46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm.     

Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise.

ATP-sensitive potassium (KATP) channels have been suggested to contribute to coronary and skeletal muscle vasodilation during exercise, either alone or interacting in a parallel or redundant process with nitric oxide (NO), prostaglandins (PGs), and adenosine. We tested the hypothesis that KATP channels, alone or in combination with NO and PGs, regulate exercise hyperemia in forearm muscle. Eighteen healthy young adults performed 20 min of moderate dynamic forearm exercise, with forearm blood flow (FBF) measured via Doppler ultrasound. After steady-state FBF was achieved for 5 min (saline control), the KATP inhibitor glibenclamide (Glib) was infused into the brachial artery for 5 min (10 microg.dl(-1).min(-1)), followed by saline infusion during the final 10 min of exercise (n = 9). Exercise increased FBF from 71 +/- 11 to 239 +/- 24 ml/min, and FBF was not altered by 5 min of Glib. Systemic plasma Glib levels were above the therapeutic range, and Glib increased insulin levels by approximately 50%, whereas blood glucose was unchanged (88 +/- 2 vs. 90 +/- 2 mg/dl). In nine additional subjects, Glib was followed by combined infusion of NG-nitro-L-arginine methyl ester (L-NAME) plus ketorolac (to inhibit NO and PGs, respectively). As above, Glib had no effect on FBF but addition of L-NAME + ketorolac (i.e., triple blockade) reduced FBF by approximately 15% below steady-state exercise levels in seven of nine subjects. Interestingly, triple blockade in two subjects caused FBF to transiently and dramatically decrease. This was followed by an acute recovery of flow above steady-state exercise values. We conclude 1) opening of KATP channels is not obligatory for forearm exercise hyperemia, and 2) triple blockade of NO, PGs, and KATP channels does not reduce hyperemia more than the inhibition of NO and PGs in most subjects. However, some subjects are sensitive to triple blockade, but they are able to restore FBF acutely during exercise. Future studies are required to determine the nature of these compensatory mechanisms in the affected individuals.     

Vasoconstrictor effects in vivo and plasma disappearance rate of neuropeptide Y in man

Vascular effects of neuropeptide Y (NPY) and noradrenaline (NA) were studied in six human volunteers. Systemic infusion of human NPY for 40 min (5 pmol X kg-1 X min-1) increased arterial plasma NPY-like immunoreactivity (NPY-LI) from 12 +/- 2 to 356 +/- 30 pM. This concentration caused no systemic cardiovascular effects. The disappearance curve for NPY-LI was biphasic; the slopes of the two phases corresponding to half lives of 4.1 +/- 0.4 and 20 +/- 2 min respectively. Close i.a. infusion of human NPY in the forearm caused a slowly developing and dose dependent decrease in forearm blood flow (FBF) and increase in venous tone with maximal values of 44 +/- 6 and 235 +/- 81% of control respectively at 5 nmol X min-1. The corresponding values for NA (5 nmol X min-1) were 21 +/- 9 and 489 +/- 78% of control. A threshold concentration for a decrease in FBF was obtained at a plasma NPY-LI of 3.7 +/- 0.6 nM. The decrease in FBF caused by NPY was maintained for a much longer period compared to that of NA.     

Blood flow and muscle oxygen uptake at the onset and end of moderate and heavy dynamic forearm exercise

We hypothesized that forearm blood flow (FBF) during moderate intensity dynamic exercise would meet the demands of the exercise and that postexercise FBF would quickly recover. In contrast, during heavy exercise, FBF would be inadequate causing a marked postexercise hyperemia and sustained increase in muscle oxygen uptake (VO(2musc)). Six subjects did forearm exercise (1-s contraction/relaxation, 1-s pause) for 5 min at 25 and 75% of peak workload. FBF was determined by Doppler ultrasound, and O(2) extraction was estimated from venous blood samples. In moderate exercise, FBF and VO(2musc) increased within 2 min to steady state. Rapid recovery to baseline suggested adequate O(2) supply during moderate exercise. In contrast, FBF was not adequate during heavy dynamic exercise. Immediately postexercise, there was an approximately 50% increase in FBF. Furthermore, we observed for the first time in the recovery period an increase in VO(2musc) above end-exercise values. During moderate exercise, O(2) supply met requirements, but with heavy forearm exercise, inadequate O(2) supply during exercise caused accumulation of a large O(2) deficit that was repaid during recovery.     

Effects of polycythemia on systemic endothelial function in chronic hypoxic lung disease

Chronic obstructive pulmonary disease (COPD) is a major risk factor for cardiovascular disease. Polycythemia, a common complication of hypoxic COPD, may affect systemic vascular function by altering blood viscosity, vessel wall shear stress (WSS), and endothelium-derived nitric oxide (NO) release. Here, we evaluated the effects of hypoxia-related polycythemia on systemic endothelial function in patients with COPD. We investigated blood viscosity, WSS, and endothelial function in 15 polycythemic and 13 normocythemic patients with COPD of equal severity, by recording brachial artery diameter variations in response to hyperemia and by using venous occlusion plethysmography (VOP) to measure forearm blood flow (FBF) responses to a brachial artery infusion of acetylcholine (ACh), bradykinin (BK), sodium nitroprusside (SNP), substance P (SP), isoptin, and N-monomethyl-L-arginine (L-NMMA). At baseline, polycythemic patients had higher blood viscosity and larger brachial artery diameter than normocythemic patients but similar calculated WSS. Flow-mediated brachial artery vasodilation was increased in the polycythemic patients, in proportion to the hemoglobin levels. ACh-induced vasodilation was markedly impaired in the polycythemic patients and negatively correlated with hemoglobin levels. FBF responses to endothelium- (BK, SP) and non-endothelium-dependent (SNP, isoptin) vasodilators were not significantly different between the two groups. L-NMMA infusion induced a similar vasoconstrictor response in both groups, in accordance with their similar baseline WSS. In conclusion, systemic arteries in polycythemic patients adjust appropriately to chronic or acute WSS elevations by appropriate basal and stimulated NO release. Overall, our results suggest that moderate polycythemia has no adverse effect on vascular function in COPD.     

C-peptide increases forearm blood flow in patients with type 1 diabetes via a nitric oxide-dependent mechanism

Proinsulin C-peptide has been shown to increase muscle blood flow in type 1 diabetic patients. The underlying mechanism is not fully understood. The aim of this study was to evaluate if the vasodilator effect of C-peptide is mediated by nitric oxide (NO). Eleven type 1 diabetic patients were studied two times and randomized to administration of intravenous and intra-arterial infusion of C-peptide or saline. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during infusion of C-peptide or saline before, during, and after NO synthase (NOS) blockade. Endothelium-dependent and -independent vasodilatation was evaluated by administration of acetylcholine and sodium nitroprusside, respectively. FBF increased by 35% during intravenous C-peptide (P < 0.01) but not during saline infusion (-2%, not significant). NOS blockade resulted in a more pronounced reduction in FBF during intravenous C-peptide than during saline infusion (-41 vs. -26%, P < 0.05). Intra-arterial C-peptide failed to increase FBF during NOS blockade. However, when C-peptide was given after the recovery from NOS blockade, FBF rose by 30% (P < 0.001). The vasodilator effects of acetylcholine and nitroprusside were not influenced by C-peptide. It is concluded that the stimulatory effect of C-peptide on FBF in type 1 diabetic patients is mediated via the NO system and that C-peptide increases basal endothelial NO levels.     

Vitamin C prevents hyperoxia-mediated vasoconstriction and impairment of endothelium-dependent vasodilation

High arterial blood oxygen tension increases vascular resistance, possibly related to an interaction between reactive oxygen species and endothelium-derived vasoactive factors. Vitamin C is a potent antioxidant capable of reversing endothelial dysfunction due to increased oxidant stress. We tested the hypotheses that hyperoxic vasoconstriction would be prevented by vitamin C, and that acetylcholine-mediated vasodilation would be blunted by hyperoxia and restored by vitamin C. Venous occlusion strain gauge plethysmography was used to measure forearm blood flow (FBF) in 11 healthy subjects and 15 congestive heart failure (CHF) patients, a population characterized by endothelial dysfunction and oxidative stress. The effect of hyperoxia on FBF and derived forearm vascular resistance (FVR) at rest and in response to intra-arterial acetylcholine was recorded. In both healthy subjects and CHF patients, hyperoxia-mediated increases in basal FVR were prevented by the coinfusion of vitamin C. In healthy subjects, hyperoxia impaired the acetylcholine-mediated increase in FBF, an effect also prevented by vitamin C. In contrast, hyperoxia had no effect on verapamil-mediated increases in FBF. In CHF patients, hyperoxia did not affect FBF responses to acetylcholine or verapamil. The addition of vitamin C during hyperoxia augmented FBF responses to acetylcholine. These results suggest that hyperoxic vasoconstriction is mediated by oxidative stress. Moreover, hyperoxia impairs acetylcholine-mediated vasodilation in the setting of intact endothelial function. These effects of hyperoxia are prevented by vitamin C, providing evidence that hyperoxia-derived free radicals impair the activity of endothelium-derived vasoactive factors.     

Muscle chemoreflex elevates muscle blood flow and O2 uptake at exercise onset in nonischemic human forearm.

We tested the hypothesis that increases in forearm blood flow (FBF) during the adaptive phase at the onset of moderate exercise would allow a more rapid increase in muscle O2 uptake (VO2 mus). Fifteen subjects completed forearm exercise in control (Con) and leg occlusion (Occ) conditions. In Occ, exercise of ischemic calf muscles was performed before the onset of forearm exercise to activate the muscle chemoreflex evoking a 25-mmHg increase in mean arterial pressure that was sustained during forearm exercise. Eight subjects who increased FBF during Occ compared with Con in the adaptation phase by >30 ml/min were considered "responders." For the responders, a higher VO2 mus accompanied the higher FBF only during the adaptive phase of the Occ tests, whereas there was no difference in the baseline or steady-state FBF or VO2 mus between Occ and Con. Supplying more blood flow at the onset of exercise allowed a more rapid increase in VO2 mus supporting our hypothesis that, at least for this type of exercise, O2 supply might be limiting.     

Effect of high local temperature on reflex cutaneous vasodilation

We examined the effect of high local forearm skin temperature (Tloc) on reflex cutaneous vasodilator responses to elevated whole-body skin (Tsk) and internal temperatures. One forearm was locally warmed to 42 degrees C while the other was left at ambient conditions to determine if a high Tloc could attenuate or abolish reflex vasodilation. Forearm blood flow (FBF) was monitored in both arms, increases being indicative of increases in skin blood flow (SkBF). In one protocol, Tsk was raised to 39-40 degrees C 30 min after Tloc in one arm had been raised to 42 degrees C. In a second protocol, Tsk and Tloc were elevated simultaneously. In protocol 1, the locally warmed arm showed little or no change in blood flow in response to increasing Tsk and esophageal temperature (average rise = 0.76 +/- 1.18 ml X 100 ml-1 X min-1), whereas FBF in the normothermic arm rose by an average of 8.84 +/- 3.85 ml X 100 ml-1 X min-1. In protocol 2, FBF in the normothermic arm converged with that in the warmed arm in three of four cases but did not surpass it. We conclude that local warming to 42 degrees C for 35-55 min prevents reflex forearm cutaneous vasodilator responses to whole-body heat stress. The data strongly suggest that this attenuation is via reduction or abolition of basal tone in the cutaneous arteriolar smooth muscle and that at a Tloc of 42 degrees C a maximum forearm SkBF has been achieved. Implicit in this conclusion is that local warming has been applied for a duration sufficient to achieve a plateau in FBF.     

Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction

Acute inflammation causes endothelial dysfunction, which is partly mediated by oxidant stress and inactivation of nitric oxide. The contribution of depletion of tetrahydrobiopterin (BH(4)), the cofactor required for nitric oxide generation, is unclear. In this randomized, double-blind, three-way crossover study, forearm blood flow (FBF) responses to ACh and glyceryltrinitrate (GTN) were measured before and 3.5 h after infusion of Escherichia coli endotoxin (LPS, 20 IU/kg iv) in eight healthy men. The effect of intra-arterial BH(4) (500 microg/min), placebo, or vitamin C (24 mg/min) was studied on separate days 3.5 h after LPS infusion. In addition, human umbilical vein endothelial cells were incubated for 24 h with vitamin C and LPS. ACh and GTN caused dose-dependent forearm vasodilation. The FBF response to ACh, which was decreased by 23 +/- 17% (P < 0.05) by LPS infusion, was restored to baseline reactivity by BH(4) and vitamin C. FBF responses to GTN were not affected by BH(4) or vitamin C. LPS increased leukocyte count, high-sensitivity C-reactive protein, IL-6, IL-1beta, IFN-gamma, monocyte chemoattractant protein-1, pulse rate, and body temperature and decreased platelet count and vitamin C concentration. Vitamin C increased forearm plasma concentration of BH(4) by 32% (P < 0.02). Incubation with LPS and vitamin C, but not LPS alone, increased intracellular BH(4) concentration in human umbilical vein endothelial cells. Impaired endothelial function during acute inflammation can be restored by BH(4) or vitamin C. Vitamin C may exert some of its salutary effects by increasing BH(4) concentration.     

Do vasoregulatory mechanisms in exercising human muscle compensate for changes in arterial perfusion pressure?

We tested the hypothesis that vasoregulatory mechanisms completely counteract the effects of sudden changes in arterial perfusion pressure on exercising muscle blood flow. Twelve healthy young subjects (7 female, 5 male) lay supine and performed rhythmic isometric handgrip contractions (2 s contraction/ 2 s relaxation 30% maximal voluntary contraction). Forearm blood flow (FBF; echo and Doppler ultrasound), mean arterial blood pressure (arterial tonometry), and heart rate (ECG) were measured. Moving the arm between above the heart (AH) and below the heart (BH) level during contraction in steady-state exercise achieved sudden approximately 30 mmHg changes in forearm arterial perfusion pressure (FAPP). We analyzed cardiac cycles during relaxation (FBF(relax)). In an AH-to-BH transition, FBF(relax) increased immediately, in excess of the increase in FAPP (approximately 69% vs. approximately 41%). This was accounted for by pressure-related distension of forearm resistance vasculature [forearm vascular conductance (FVC(relax)) increased by approximately 19%]. FVC(relax) was restored by the second relaxation. Continued slow decreases in FVC(relax) stabilized by 2 min without restoring FBF(relax). In a BH-to-AH transition, FBF(relax) decreased immediately, in excess of the decrease in FAPP (approximately 37% vs. approximately 29%). FVC(relax) decreased by approximately 14%, suggesting pressure-related passive recoil of resistance vessels. The pattern of FVC(relax) was similar to that in the AH-to-BH transition, and FBF(relax) was not restored. These data support rapid myogenic regulation of vascular conductance in exercising human muscle but incomplete flow restoration via slower-acting mechanisms. Local arterial perfusion pressure is an important determinant of steady-state blood flow in the exercising human forearm.     

Relationship between changes in brachial artery flow-mediated dilation and basal release of nitric oxide in subjects with Type 2 diabetes

Assessment of flow-mediated dilation (FMD) after forearm ischemia is widely used as a noninvasive bioassay of stimulated nitric oxide (NO)-mediated conduit artery vasodilator function in vivo. Whether this stimulated endothelial NO function reflects basal endothelial NO function is unknown. To test this hypothesis, retrospective analysis of randomized crossover studies was undertaken in 17 subjects with Type 2 diabetes; 9 subjects undertook an exercise training or control period, whereas the remaining 8 subjects were administered an angiotensin II receptor blocker or placebo. FMD was assessed by using wall tracking of high-resolution brachial artery ultrasound images in response to reactive hyperemia. Resistance vessel basal endothelium-dependent NO function was assessed by using intrabrachial administration of NG-monomethyl-L-arginine (L-NMMA) and plethysmographic assessment of forearm blood flow (FBF). FMD was higher after intervention compared with control/placebo (6.15+/-0.53 vs. 3.81+/-0.72%, P<0.001). There were no significant changes in the FBF responses to L-NMMA. Regression analysis between FMD and L-NMMA responses at entry to the study revealed an insignificant correlation (r=-0.10, P=0.7), and improvements in FMD with the interventions were not associated with changes in the L-NMMA responses (r=-0.04, P=0.9). We conclude that conduit artery-stimulated endothelial NO function (FMD) does not reflect basal resistance vessel endothelial NO function in subjects with Type 2 diabetes.     

Active and inactive renin in human forearm of hypertensive patients.

Although many in vitro and animal studies indicate the existence of a local renin--angiotensin system, data regarding its physiological role are quite controversial, and moreover, evidence suggesting inactive and active renin release from vascular tissue in vivo is lacking both in animal and humans. The aim of our study was to evaluate whether beta-adrenoceptor stimulation, a well-known stimulus to renin production, through isoproterenol might cause local renin production from vessels of the forearm of hypertensive patients. Drugs were infused into the brachial artery at systemically ineffective rates, while forearm blood flow (FBF, venous plethysmography), mean intra-arterial pressure, and heart rate were monitored throughout. Active and inactive vessel renin production was measured by calculating venous-arterial (V-A) differences by simultaneous sampling from brachial artery and an ipsilateral deep vein. Active renin (PRA) and total renin (Sepharose bound trypsin activation) were measured by radioimmunoassay while inactive renin was calculated as the difference between total and active renin. V-A differences were corrected for FBF to calculate renin extraction or production. In a group of 10 patients, isoproterenol, which was infused at increasing cumulative rates (0.03, 0.1, 0.3 micrograms.100 mL-1 forearm tissue.min-1 for 5 min each), caused a dose-dependent increment in FBF that was blunted by intra-arterial propranolol (n = 5) pretreatment (10 micrograms.100 mL-1 forearm tissue.min-1 for 10 min). beta-Adrenoceptor stimulation caused a dose-dependent outflow of both active and inactive renin, an effect antagonized by propranolol. In conclusion, our data represent the first evidence in humans of tissue active and inactive renin production in the forearm vascular bed.