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Background and Purpose Nitrite (NO2−) has recently been shown to represent a potential source of NO, in particular under hypoxic conditions. The aim of the current study was to compare the haemodynamic effects of NO2− in healthy volunteers and patients with stable congestive heart failure (CHF). Experimental Approach The acute haemodynamic effects of brachial artery infusion of NO2− (0.31 to 7.8 μmol·min−1) was assessed in normal subjects (n = 20) and CHF patients (n = 21). Key Results NO2− infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF patients at NO2− infusion rates which induced no changes in normal subjects (anova: F = 5.5; P = 0.02). Unstressed venous volume (UVV) increased even with the lowest NO2− infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (anova: F = 6.2; P = 0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO2− infusion. Venous plasma NO2− concentrations were lower in CHF patients at baseline, and rose substantially less with NO2− infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF patients than normal subjects at baseline. This difference was attenuated during NO2− infusion. Prolonged NO2− exposure in vivo did not induce oxidative stress, nor did it induce tolerance in vitro. Conclusions and Implications The findings of arterial hyper-responsiveness to infused NO2− in CHF patients, with evidence of accelerated transvascular NO2− clearance (presumably with concomitant NO release) suggests that NO2− effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO2− as a therapeutic modality in CHF.

Background— It has been proposed that under hypoxic conditions, nitrite may release nitric oxide, which causes potent vasodilation. We hypothesized that nitrite would have a greater dilator effect in capacitance than in resistance vessels because of lower oxygen tension and that resistance-vessel dilation should become more pronounced during hypoxemia. The effect of intra-arterial infusion of nitrite on forearm blood flow and forearm venous volumes was assessed during normoxia and hypoxia. Methods and Results— Forty healthy volunteers were studied. After baseline infusion of 0.9% saline, sodium nitrite was infused at incremental doses from 40 nmol/min to 7.84 μmol/min. At each stage, forearm blood flow was measured by strain-gauge plethysmography. Forearm venous volume was assessed by radionuclide plethysmography. Changes in forearm blood flow and forearm venous volume in the infused arm were corrected for those in the control arm. The peak percentage of venodilation during normoxia was 35.8±3.4% (mean±SEM) at 7.84 μmol/min ( P P P Conclusions— Nitrite is a potent venodilator in normoxia and hypoxia. Arteries are modestly affected in normoxia but potently dilated in hypoxia, which suggests the important phenomenon of hypoxic augmentation of nitrite-mediated vasodilation in vivo. The use of nitrite as a selective arterial vasodilator in ischemic territories and as a potent venodilator in heart failure has therapeutic implications.

AIMS: This work investigates the role of myoglobin in mediating the vascular relaxation induced by nitrite. Nitrite, previously considered an inert by-product of nitric oxide metabolism, is now believed to play an important role in several areas of pharmacology and physiology. Myoglobin can act as a nitrite reductase in the heart, where it is plentiful, but it is present at a far lower level in vascular smooth muscle-indeed, its existence in the vessel wall is controversial. Haem proteins have been postulated to be important in nitrite-induced vasodilation, but the specific role of myoglobin is unknown. The current study was designed to confirm the presence of myoglobin in murine aortic tissue and to test the hypothesis that vascular wall myoglobin is important for nitrite-induced vasodilation. METHODS AND RESULTS: Aortic rings from wild-type and myoglobin knockout mice were challenged with nitrite, before and after exposure to the haem-protein inhibitor carbon monoxide (CO). CO inhibited vasodilation in wild-type rings but not in myoglobin-deficient rings. Restitution of myoglobin using a genetically modified adenovirus both increased vasodilation to nitrite and reinstated the wild-type pattern of response to CO. CONCLUSION: Myoglobin is present in the murine vasculature and contributes significantly to nitrite-induced vasodilation.

In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3±2.1%, P

Background Nitric oxide (NO) is an important endogenous paracrine vasodilator. The nitrite anion represents an alternate humoural source of NO under hypoxic and/or acidotic conditions. During hypoxia and ischaemia, the usual production of NO by NO synthase enzymes, is markedly reduced. Recently it has emerged that nitrite serves as a biological reservoir for NO under hypoxic conditions. Animal studies have shown that exogenous treatment with nitrite has important hypoxia-specific vasodilator and cytoprotective effects. Our group demonstrated that when administered intra-arterially under normoxic conditions, nitrite substantially vasodilated the venous capacitance bed, but only modestly dilated resistance human forearm vessels. In contrast during hypoxia, potent vasodilation was also observed in resistance vessels. Therefore, in this study we assessed the effects of nitrite on cardiac and peripheral haemodynamics in humans. We hypothesised that an intravenous infusion of sodium nitrite would cause a significant reduction in blood pressure during hypoxia compared to normoxia. Methods Thirty-three healthy subjects (mean age 32±10 years) were recruited. An intravenous infusion of sodium nitrite was administered at incremental doses (3, 8, 30 and 60 μmol/min) during normoxic or hypoxic conditions in random order. Hypoxia was administered by asking subjects to inspire 12% oxygen via a facemask until oxygen saturations of 83–88% were achieved. Haemodynamic measurements were determined non-invasively through the use of impedance cardiography (Taskforce ® ). Aplanation tonometry (SphygmoCor) was used to delineate central (aortic) blood pressure (CBP). Results To allow for the time-dependent effect of hypoxia all measurements in this group were placebo-corrected. During hypoxia, systolic blood pressure (SBP) fell by a mean of 11 mmHg (123±19 mmHg to 112±15 mmHg, p≤0.05) from baseline during peak nitrite dose. There was a non-significant reduction in SBP during normoxia of 6 mmHg (120±13 mmHg to 114±22 mmHg, p=NS). No significant changes were observed in stroke volume or cardiac output in either group. In the hypoxia group, total peripheral resistance mirrored changes in SBP. CBP fell in both groups (9 vs13 mmHg, normoxia vs hypoxia, p=NS) from baseline. No significant changes were observed in parameters between the normoxia and hypoxia group. Conclusion An acute intravenous infusion of nitrite was safe and well tolerated in healthy volunteers. A significant decrease in blood pressure was observed during hypoxia, but not during normoxia, thus supporting the role of nitrite as a hypoxia-specific vasodilator.