Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation

OBJECTIVE: Hypercholesterolemia has been shown to impair endothelium-mediated, nitric oxide (NO)-dependent responses to acetylcholine (ACh), serotonin, substance P and flow-mediated dilation. We have recently shown that NO contributes to metabolic vasodilation in the human forearm. We sought to determine whether metabolic vasodilation is impaired in healthy subjects with hypercholesterolemia. METHODS: We compared the forearm blood flow (FBF) responses to isotonic exercise, ACh and the endothelium-independent vasodilator sodium nitroprusside in young, otherwise healthy volunteers with hypercholesterolemia and controls before and after the NO inhibitor NG-monomethyl-L-arginine (L-NMMA). FBF was measured using venous occlusion plethysmography. Hypercholesterolemic (n = 20) and control (n = 20) subjects were age- and gender-matched. RESULTS: Total cholesterol (6.9 +/- 0.3 vs. 4.6 +/- 0.1 mmol/l, P < 0.0001), low density lipoprotein (4.9 +/- 0.4 vs. 2.7 +/- 0.1 mmol/l, P < 0.001) and triglyceride (1.3 +/- 0.2 vs. 0.8 +/- 0.1 mmol/l, P = 0.005) levels were higher in the hypercholesterolemic group. Basal FBF and resistance were similar in the two groups. Hypercholesterolemia impaired the peak FBF response to ACh (11.1 +/- 1.9 vs. 17.6 +/- 2.2 ml/100 ml/min, P = 0.03), and reduced the peak response to sodium nitroprusside (6.0 +/- 0.4 vs. 8.1 +/- 0.6 ml/100 ml/min, P < 0.01). However, hypercholesterolemia did not affect peak hyperemic FBF (13.1 +/- 1.0 vs. 13.2 +/- 1.0 ml/100 ml/min, P = 1.0) or the FBF volume repayment during the 1 or 5 min after exercise. Resting FBF was reduced by L-NMMA to a similar degree (by 33% vs. 40%, P = 0.17) in both groups. Although L-NMMA reduced peak hyperemic FBF (by 16% vs. 17%, P = 0.93) and the volume repaid after exercise in both groups, there were no differences between the two groups. CONCLUSIONS: Exercise-induced metabolic vasodilation is in part dependent on NO release. Hypercholesterolemia impairs NO-mediated vasodilation, but is not associated with a reduction in exercise-induced hyperemia. This may indicate that multiple compensatory mechanisms are operative in skeletal muscle metabolic vasodilation.     

Regulation of coronary resistance vessel tone in response to exercise

Exercise is a primary stimulus for increased myocardial oxygen demand. The ~6-fold increase in oxygen demand of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already ~70% at rest) increase only modestly in most species. As a result, coronary blood flow is tightly coupled to myocardial oxygen consumption over a wide range of physical activity. This tight coupling has been proposed to depend on periarteriolar oxygen tension, signals released from cardiomyocytes and the endothelium as well as neurohumoral influences, but the contribution of each of these regulatory pathways, and their interactions, to exercise hyperemia in the heart remain incompletely understood. In humans, nitric oxide, adenosine and K(ATP) channels each appear to contribute to resting coronary resistance vessel tone, but evidence for a critical contribution to exercise hyperemia is lacking. In dogs K(ATP)-channel activation together with adenosine and nitric oxide contribute to exercise hyperemia in a non-linear redundant fashion. In contrast, in swine nitric oxide, adenosine and K(ATP) channels contribute to resting coronary resistance vessel tone control in a linear additive manner, but do not appear to be mandatory for exercise hyperemia. Rather, exercise hyperemia in swine appears to involve β-adrenergic activation in conjunction with exercise-induced blunting of an endothelin-mediated vasoconstrictor influence. In view of these remarkable species differences in coronary vasomotor control during exercise, future studies are required to determine the system of vasodilator components that mediate exercise hyperemia in humans. This article is part of a Special Issue entitled "Coronary Blood Flow".     

Impaired exercise-induced vasodilatation in chronic atrial fibrillation--role of endothelium-derived nitric oxide.

Exercise capacity is often reduced in patients with atrial fibrillation (AF), but very few studies have focused on changes in endothelial function as a potential mechanism for the exercise limitation. The present study used using venous occlusion plethysmography to investigate whether nitric oxide (NO)-mediated vasodilatation is attenuated during exercise in patients with AF by measuring forearm blood flow (FBF) in 10 patients at rest and immediately after 2 levels of rhythmic handgrip exercise, before and after inhibition of NO synthesis with N(G)-monomethyl-L-arginine (L-NMMA, 100 micromol). The measurements were repeated 1 day after restoration of sinus rhythm by cardioversion. FBF responses to graded doses of acetylcholine (ACh) were also observed before and after cardioversion. Heart rate decreased after cardioversion, but blood pressure did not change. FBF at rest was not affected by cardioversion, but at the highest level of exercise it increased from 28.4+/-2.3 ml x min(-1) x dl(-1) before to 39.4+/-3.2 ml x min(-1) x dl(-1) after cardioversion (p<0.05). L-NMMA significantly decreased FBF at rest (p<0.01) and depressed the increase in FBF response to exercise after (p<0.01), but not before cardioversion. The FBF response to ACh was also accelerated significantly after cardioversion. The present results provide new evidence that NO bioavailability is depressed at rest and during exercise in patients with AF.     

Effect of intensive therapy for heart failure on the vasodilator response to exercise

OBJECTIVES: The purpose of the study was to evaluate the lower extremity vascular responsiveness to metabolic stimuli in patients with heart failure and to determine whether these responses improve acutely after intensive medical therapy. BACKGROUND: Metabolic regulation of vascular tone is an important determinant of blood flow, and may be abnormal in heart failure. METHODS: The leg blood flow responses were measured in 11 patients with nonedematous class III-IV heart failure before and after inpatient medical therapy and in 10 normal subjects. Venous occlusion plethysmography was used to measure peak blood flow and total hyperemia in the calf after arterial occlusion and also after isotonic ankle exercise. Measurements were repeated following short-term inpatient treatment with vasodilators and diuretics administered to decrease right atrial pressure (18+/-2 to 7+/-1 mm Hg), pulmonary wedge pressure (32+/-3 to 15+/-2 mm Hg), and systemic vascular resistance (1581+/-200 to 938+/-63 dynes.s.cm(-5), all p < 0.02). RESULTS: Leg blood flow at rest, after exercise, and during reactive hyperemia was less in heart failure patients than in control subjects. Resting leg blood flow did not increase significantly after medical therapy, but peak flow after the high level of exercise increased by 59% (p = 0.009). Total hyperemic volume in the recovery period increased by 73% (p = 0.03). Similarly, the peak leg blood flow response to ischemia increased by 88% (p = 0.04), whereas hyperemic volume rose by 98% (p = 0.1). CONCLUSIONS: The calf blood flow responses to metabolic stimuli are blunted in patients with severe heart failure, and improve rapidly with intensive medical therapy.     

Long-term treatment with eicosapentaenoic acid improves exercise-induced vasodilation in patients with coronary artery disease.

We have previously shown that long-term treatment with eicosapentaenoic acid (EPA) improves endothelium-dependent vasodilation of the atherosclerotic arteries in both animals and humans. The aim of the present study was to examine whether EPA treatment also improves metabolic vasodilation evoked by exercise in patients with coronary artery disease (CAD). Forearm blood flow (FBF) was measured by strain gauge plethysmography in 10 patients with stable CAD, before and 3 months after oral treatment with EPA (1,800 mg/kg). FBF was measured at rest and during intra-arterial infusion of acetylcholine or sodium nitroprusside, before and after intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, an inhibitor of nitric oxide (NO) synthesis). A rhythmic handgrip exercise was also performed for 3 min before and after L-NMMA, and FBF was measured for 3 min just after the handgrip exercise. These protocols were repeated after the long-term treatment with EPA for 3 months. The long-term treatment with EPA significantly improved the FBF responses to acetylcholine (p < 0.01), which was significantly reduced by acute administration of L-NMMA (p < 0.01). By contrast, the EPA treatment did not affect the endothelium-independent responses to sodium nitroprusside. Metabolic increases in FBF caused by the handgrip exercise were not significantly decreased by L-NMMA before the EPA treatment. The EPA treatment significantly augmented the exercise-induced increases in FBF (p < 0.05) and L-NMMA acutely abolished this augmentation (p < 0.01). These results indicate that long-term treatment with EPA improves both endothelium-dependent and exercise-induced forearm vasodilations in patients with CAD and that NO is substantially involved in the EPA-induced improvement of the FBF responses in patients with CAD.     

Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels

The purpose of the study was to examine endothelium-dependent and -independent vasodilation of conduit and resistance vessels in sickle cell anemia (HbSS). We measured the effects of intra-arterial infusion of methacholine, sodium nitroprusside, and NG-monomethyl-L-arginine (L-NMMA) on forearm blood flow using venous occlusion plethysmography in eight patients with HbSS and 11 HbAA controls. We assessed vasodilation of the conduit brachial artery using ultrasound in 17 patients with HbSS and 41 nonanemic controls. Forearm blood flow response to methacholine was similar in HbSS and HbAA, while the response to sodium nitroprusside was greater in those with HbSS. Nitric oxide synthase inhibition with L-NMMA attenuated methacholine-induced forearm blood flow to a lesser extent in HbSS compared to HbAA, suggesting diminished nitric oxide (NO) contribution to endothelium-dependent vasodilation. Flow-mediated and nitroglycerin-induced dilation were impaired in HbSS compared to controls and were not affected by the antioxidant vitamin C or the precursor substrate for NO synthesis L-arginine. NO bioactivity is reduced but differs in peripheral conduit and resistance vessels in HbSS. Resistance vessels have preserved response to exogenous NO donors but have diminished contribution of NO to endothelium-dependent vasodilation. Conduit vessels demonstrate impaired vasodilation to endogenous and exogenous NO.     

Effects of inhibition of nitric oxide formation on the regulation of coronary blood flow in anesthetized dogs

In 11 open-chest dogs with a flowmeter on the left circumflex artery, L-NMMA, a selective inhibitor of nitric oxide-formation, was subselectively infused into the left circumflex artery at a rate of 2.5mg/ml (ml/min) to avoid systemic hemodynamic effects. The coronary blood flow at normal arterial blood pressure was similar prior to and during L-NMMA infusion. However, when the arterial blood pressure was raised by inflating a balloon in the descending aorta, the nitric oxide suppression induced a dramatic increase in coronary vascular resistance by almost 40% compared to control conditions without L-NMMA infusion at identically elevated arterial blood pressure. L-NMMA induced a significant downward shift and flattening of the pressure-flow relation over a pressure range from 60–150 mmHg. Peak hyperemic coronary flow after 20-s transient coronary occlusion was similar prior to and during L-NMMA infusion, but the duration of the hyperemic flow response was significantly shortened during L-NMMA infusion indicating exaggerated constriction after hyperemic stimulus. The EDRF/nitric oxide-system plays an important role for the regulation of coronary blood flow by counteracting autoregulatory constrictor responses to increased driving pressure and shear stress in the intact canine circulation.Supported in part by grant 1 RO1 HL-40865 from the National Heart, Lung, and Blood Institute. U.S. is the recipient of research grant So 241/1-1 from the Deutsche Forschungsgemeinschaft     

Comparison between reactive and exercise hyperemia in normal subjects and patients with peripheral arterial disease.

Reactive and exercise hyperemia were compared in healthy men and in patients with PAD. In both patients and normals the calf blood flow of reactive hyperemia was recorded after a 5-minute ischemia. Exercise hyperemia was measured in normals after variable work loads (30 and 50 kg) and immediately after the occurrence of pain in patients with PAD. In healthy limbs the first and peak flows of exercise and reactive hyperemia are similar. The recovery time for basal flow is prolonged after exercise. However, reactive and exercise hyperemia differ significantly when arterial obstruction due to arteriosclerosis obliterans is present. First flow and peak flow are higher and recovery time more prolonged after exercise. It is also likely that the control mechanisms of the two hyperemic reactions are different. Muscular exercise, when protracted until pain occurs, can produce a metabolic and circulatory adjustment other than that of ischemia. There is experimental evidence to support this hypothesis.     

Effects of Prostaglandin E1 Infusion on Limb Hemodynamics and Vasodilatory Response in Patients with Arteriosclerosis Obliterans

It is well known that prostaglandin E1 (PGE1>) increases peripheral blood flow. The aim of this study was to investigate the effects of PGE1 infusion on the hemodynamics and vasodilatory response of the leg affected by intermittent claudication in patients with arteriosclerosis obliterans (ASO). Fourteen legs of 8 male patients with ASO were infused intravenously with PGE1 (120 µg/day) for 7 consecutive days. Before the infusion and 5 days after cessation of the infusion, resting skin and skeletal muscle blood flow in the calf and occlusion-induced reactive hyperemic flow were measured using plethysmography and a laser Doppler flowmeter. Clinical symptoms in the legs were assessed by treadmill exercise testing. Resting calf blood flow was found to have increased significantly (skin, from 2.6 ± 0.1 ml/min/100 g tissue to 2.9 ± 0.1 ml/min/100 g tissue, p > 0.02; skeletal muscle, from 3.1 ± 0.2 ml/min/dl tissue to 4.0 ± 0.5 ml/min/dl tissue, p > 0.02). There was also a significant reduction in the peripheral vascular resistance (–17.8 ± 7.2%, p > 0.05) 5 days after the cessation of infusion. The time to the half-maximum post peak of hyperemia was significantly elongated (from 34.6 ± 5.7 sec to 58.6 ± 9.2 sec, p > 0.01). Borg's score of the legs on exercise testing was markedly reduced, and symptom-free walking distance was increased by an average of 70.9 ± 15.6%. In conclusion, PGE1 infusion has vascular effects on not only resting calf blood flow but also hyperemic flow responses. These retentive effects may be due to alteration in vascular functions and/or rheological state as a result of PGE1-induced regular enhancement of blood flow, rather than the direct vasodilatory effect of the agent.     

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

AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.     

Gender and nitric oxide-mediated vasodilation in humans.

BACKGROUND: We compared forearm vasodilator responses between females and males after administration of compounds that stimulate nitric oxide (NO) release, act as NO donors, or are NO-independent. METHODS AND RESULTS: We studied nine premenopausal females and nine age-matched males. Forearm blood flow (FBF) was measured with plethysmography. Graded doses of the endothelial-dependent vasodilators acetylcholine and bradykinin and the endothelial-independent vasodilator sodium nitroprusside were given via a brachial artery catheter to the non-dominant arm. Reactive hyperemia was measured as an index of NO-independent vasodilation. In females estradiol levels were greater, and serum triglycerides were lower, but cholesterol was similar to that of males. FBF responses to all doses of the three drugs were approximately 30% less in females. Females had smaller forearms and lower peak FBF during reactive hyperemia. Blood flow responses to the drugs as a fraction of the peak reactive hyperemia values were similar in females and males. In the females, but not in the males, FBF responses to all three drugs and reactive hyperemia correlated with estradiol levels. CONCLUSIONS: The smaller FBF responses in females were likely due to smaller forearm volume and muscle mass. Estradiol levels are associated with both NO-mediated and non-NO-mediated dilator responses in females.     

Effect of calcium antagonist or beta blockade treatment on nitric oxide-dependent vasodilation and oxidative stress in essential hypertensive patients

OBJECTIVES: Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxygen free radical-induced nitric oxide (NO) breakdown. Since calcium antagonists can improve endothelial function in hypertensive patients, we tested whether this beneficial effect could be related to restoration of NO availability by antioxidant activity. METHODS: In 10 healthy subjects and 20 essential hypertensive patients, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (from 0.15-15 microg/100 ml per min), bradykinin (0.005-0.05 microg/100 ml per min), two endothelium-dependent vasodilators, and sodium nitroprusside (1-4 microg/100 ml forearm tissue per min), an endothelium independent vasodilator, in the absence and presence of NG-monomethyl-L-arginine (L-NMMA) (100 microg/100 ml forearm tissue per min), an NO synthase inhibitor. RESULTS: In controls, vasodilation to acetylcholine and bradykinin was inhibited by L-NMMA. In hypertensive patients, vasodilation to acetylcholine and bradykinin, but not to sodium nitroprusside, was blunted and resistant to L-NMMA. Hypertensive patients were randomized to a 12-week treatment with lacidipine (4-6 mg/daily) or atenolol (50-100 mg/daily) (n = 10 each group). Lacidipine but not atenolol increased the vasodilation to acetylcholine and bradykinin and restored the inhibiting effect of L-NMMA on endothelium-dependent vasodilation, without affecting the response to sodium nitroprusside. Moreover, lacidipine reduced circulating markers of oxidative stress including plasma and low-density lipoprotein (LDL) hydroperoxides, the susceptibility of LDL to Cu2+-induced oxidation and the reactive oxygen species generated from human umbilical vein endothelial cells after incubation with LDL derived from plasma of the patients. CONCLUSIONS: Lacidipine increases endothelium-dependent vasodilation by restoring NO availability, and this effect possibly is related to antioxidant activity.     

L－精氨酸逆转一氧化氮抑制后的犬冠脉血流动力学改变和内皮素－1含量升高

观察了犬冠脉内灌注Ｎ－单甲基左旋精氨酸（Ｌ－ＮＭＭＡ）后再灌注Ｌ－精氨酸（Ｌ－Ａｒｇ）和单独灌注Ｌ－ＮＭＭＡ前后冠脉血流动力学、冠脉血流储备以及冠脉对不同浓度的乙酰胆碱（Ａｃｈ）反应的变化，同时用放免法测定冠脉前降支（ＬＡＤ）伴行静脉血中内皮素－１（ＥＴ－１）含量。结果发现，Ｌ－Ａｒｇ完全逆转了灌注Ｌ－ＮＭＭＡ引起的血流动力学改变，使心率回升，下降的基础冠脉流量（ＣＢＦ），从２０±８ｍｌ／ｍｉｎ回升至２８±７ｍｌ／ｍｉｎ，Ｐ＜０．０５），降低的冠脉储备恢复，从５１±１０ｍｌ／ｍｉｎ升至９４±１５ｍｌ／ｍｉｎ，Ｐ〈０．０１），ＥＴ－１的含量不再升高，从１５．５±３．０ｎｇ／Ｌ下降至５．０±２．０ｎｇ／Ｌ，Ｐ〈０．０１），Ａｃｈ介导的ＣＢＦ增加不再受到抑制（Ｐ〈０．０１）。结果提示提供外源性Ｌ－Ａｒｇ可增加一氧化氮（ＮＯ）的产生，使由于ＮＯ抑制而产生的血流动力学改变和ＥＴ－１升高发生逆转。     

Effect of enalaprilat on nitric oxide activity in coronary artery disease.

Atherosclerosis is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) activity. Enhancement of NO activity may have an antiatherogenic action. This study was performed to determine whether angiotensin-converting enzyme (ACE) inhibition improves peripheral vascular NO activity in patients with atherosclerosis. In the femoral circulation of 43 patients with atherosclerosis and 10 controls, we studied endothelium-dependent vasodilation with bradykinin and acetylcholine, and endothelium-independent vasodilation with sodium nitroprusside before and after enalaprilat. In 22 patients, we repeated these infusions in the presence of L-N(G) monomethyl arginine (L-NMMA). Doppler-femoral artery flow velocity was measured. Before ACE inhibition, acetylcholine responses were depressed in patients with atherosclerosis compared with controls (p = 0.03). Enalaprilat did not alter femoral vascular tone at rest or vasodilation with sodium nitroprusside, but potentiated bradykinin-mediated vasodilation in patients (p<0.001) and controls (p = 0.02). Acetylcholine-mediated vasodilation was augmented only in patients (p<0.001), but not in control subjects. L-NMMA inhibited the potentiation by enalaprilat of acetylcholine and bradykinin responses. This study demonstrates that ACE inhibition selectively improves endothelial dysfunction in human atherosclerosis by enhancing NO activity. The antithrombotic and antiproliferative effects of NO may reduce adverse manifestations related to atherosclerosis during long-term therapy.     

Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress-mediated vasodilation

Interactions between the endothelium and erythrocytes may contribute to the vascular complications of sickle cell disease (SCD). Endothelium-derived nitric oxide (NO) plays a major role in the regulation of vasomotor tone in response to wall shear stress (WSS) variations and pharmacologic stimuli. However, little is known about endothelial NO production in patients with steady-state SCD. We investigated endothelial NO production in response to flow or vasoactive agonists in 16 homozygous patients with steady-state SCD and 15 controls. Flow-mediated dilation (FMD), arterial diameter changes in response to 100% oxygen inhalation, blood viscosity, and calculated WSS were determined in all patients and controls. At baseline, WSS was higher in SCD patients than in controls, whereas arterial diameter was similar. In patients with SCD, FMD was impaired (1.73% +/- 0.44% vs 3.97% +/- 0.24% in the controls, P <.001) and vasoconstriction in response to 100% oxygen was abolished. Using venous occlusion plethysmography, forearm blood flow (FBF) was evaluated in response to acetylcholine, nitro-monomethyl-L-arginine (L-NMMA), and sodium nitroprusside (SNP) in subgroups of 9 controls and 7 patients with SCD. Acetylcholine induced a significantly greater FBF increase in the patients (9.7 +/- 2.9 mL/min/100 mL of forearm volume vs 2.5 +/- 1.5 mL/min/100 mL in the controls, P <.001), whereas responses to L-NMMA and SNP were similar. These results suggest that endothelial dysfunction may prevent the arterial diameter of patients with SCD from adapting to chronic or acute shear stress elevations. This may contribute to the pathophysiology of vaso-occlusive crisis in patients with SCD.     

Contribution of endogenous nitric oxide to basal vasomotor tone of peripheral vessels and plasma B-type natriuretic peptide levels in patients with congestive heart failure

OBJECTIVES: We examined whether a relationship exists between the vasoconstrictive response to endogenous nitric oxide (NO) synthesis inhibition and the severity of heart failure in patients with congestive heart failure (CHF). BACKGROUND: Controversy exists as to whether the vasoconstrictive response to NO synthesis inhibition in patients with CHF is comparable to that in normal subjects or is enhanced. METHODS: Forearm blood flow (FBF) and calculated forearm vascular conductance (FVC) were obtained using plethysmography before and after administration of the NO synthesis inhibitor L-NMMA (NG-monomethyl-L-arginine) in 40 patients with CHF due to dilated cardiomyopathy and in 16 normal control subjects. Basal plasma B-type natriuretic peptide (BNP) and nitric oxide concentrations were measured in all subjects. RESULTS: Plasma BNP and nitrite/nitrate (NOx) levels in the patients group were significantly greater and baseline FBF was significantly less. Administration of L-NMMA significantly decreased FBF and FVC in both groups. The percent changes in FBF (%FBF) and FVC (%FVC) from the baseline after L-NMMA correlated significantly with plasma BNP level (%FBF: r = 0.72; %FVC: r = 0.76; both p < 0.001). Percent changes in both FBF and FVC were greater in patients with BNP > or = 100 pg/ml than in normal subjects; however, in patients with BNP < 100 pg/ml they were comparable to those in normal subjects. CONCLUSIONS: Vasoconstrictive response to L-NMMA in patients with CHF was preserved or enhanced in proportion to the basal plasma BNP level, indicating a close relationship between the contribution of endogenous NO to basal vasomotor tone and the severity of heart failure.     

Endothelial function in chronic congestive heart failure.

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. The hypothesis that an impairment of this mechanism is involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF) was tested. Acetylcholine and N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine, were infused in the brachial artery of healthy volunteer subjects (controls) and patients with severe CHF. The radial artery diameter was determined by a high-precision A-mode ultrasound device, using a 10 MHz probe. Forearm blood flow was calculated from vessel diameter and blood flow velocity measured simultaneously by Doppler. The blood flow response to acetylcholine was blunted in patients with CHF compared with that in control subjects. In contrast, the decrease in blood flow induced by L-NMMA was exaggerated in CHF, and the blood flow response to nitroglycerin was preserved. The changes in radial artery diameter induced by acetylcholine and L-NMMA were not significant in control subjects and CHF patients, but dilation of the radial artery by nitroglycerin was significantly reduced in CHF. The results demonstrate an impaired endothelium-dependent dilation of forearm resistance vessels in CHF, suggesting a reduced release of nitric oxide on stimulation. In contrast, the basal release of nitric oxide from endothelium of forearm resistance vessels is preserved or may even be enhanced, and may play an important compensatory role in chronic CHF by antagonizing neurohumoral vasoconstrictor forces in CHF.     

Inhibition of endogenous nitric oxide reduces basal mesenteric vascular tone but does not alter intraduodenal hydrochloric acid-induced intestinal hyperemia in rats

There are conflicting reports on the role of endogenous nitric oxide (NO) in the regulation of basal intestinal blood flow. The effect of inhibition of NO on intraduodenal hydrochloric acid (HCl) induced intestinal hyperemia remains to be confirmed. We investigated the effect of inhibition of endogenous NO on basal intestinal blood flow, HCl-induced intestinal hyperemia, and duodenal villous injury. Superior mesenteric artery blood flow in rats was measured by pulsed Doppler flowmetry and duodenal villous injury evaluated by histology. Intravenous N^G-nitro-l-arginine methyl ester (l-NAME), orl-arginine ord-arginine followed byl-NAME, was given to show inhibition, reversal of inhibition of endogenous NO synthase, and stereospecificity, respectively. An intraduodenal 2 ml/kg bolus or perfusion for 30 min of 0.1 N HCl was given 15 min afterl-NAME or vehicle. Mean arterial blood pressure was increased byl-NAME, which also significantly reduced intestinal blood flow under basal condition and after intraduodenal HCl. Basal mesenteric blood flow was not altered byl- ord-arginine. Thel-NAME-induced increase in blood pressure and decrease in basal blood flow was attenuated byl- but notd-arginine. The villous damage and the magnitude of the peak hyperemia was unchanged byl-NAME,l- ord-arginine. Inhibition of endogenous NO byl-NAME is suggested by the significant rise in blood pressure. The rise in blood pressure and reduction in blood flow are attenuated byl- but notd-arginine, indicating stereospecificity. Inhibition of endogenous NO reduces basal mesenteric vascular tone but does not alter intraduodenal HCl-induced intestinal hyperemia. The increase in blood flow after intraduodenal HCl predicts the absence of exacerbation of HCl-induced duodenal villous damage.     

Contribution of prostaglandins to muscle blood flow in anesthetized dogs at rest, during exercise, and following inflow occlusion.

The role of locally formed cyclo-oxygenase products (endoperoxide intermediates, prostaglandins, or prostacyclins) in resistance to blood flow was studied in the hindlimbs of anesthetized dogs during rest, during exercise, and following release of inflow occlusion. Meclofenamic acid, indomethacin, or sodium meclofenamate reduced mean resting blood flows of 86, 113, and 118 ml/min to 54, 82, and 67 ml/min, respectively. Inhibitors of prostaglandin synthesis reduced the vasodilator response to arachidonic acid by 81%. In addition, prostaglandin synthesis inhibitors attenuated the hyperemic responses following inflow occlusions in the resting hindlimb. The attenuation was most marked following a 1-second occlusion (74%) and progressively less following a 10-second (44%) and a 300-second (24%) occlusion. However, the portion of the total postocclusive hyperemic response attributable to prostaglandins was constant and independent of occlusion duration. Inhibition of prostaglandin synthesis did not affect the hyperemia of exercise, but reduced significantly the postocclusion hyperemia that followed the release of a 1-second (63%) and a 2-second (43%) period of inflow occlusion in the exercising hindlimb; attenuation was minor following a 10-second occlusion (10%). In three of four exercising hindlimbs, the portion of the postocclusion hyperemia attributable to prostaglandins was inversely related to the duration of the occlusion. These data indicate that locally synthesized cyclo-oxygenase products, possibly prostaglandins, are important in the maintenance of blood flow in resting but not exercising muscle, contribute significantly to postocclusive hyperemia in resting and exercising hindlimbs, and mediate the hyperemia that follows occlusions of 5 seconds or less in resting and 2 seconds or less in exercising hindlimbs.     

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.