RESUMO
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 mumol/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 micromol/min (P<0.001) and was similar during hypoxia. In normoxia, arterial blood flow, assessed by the forearm blood flow ratio, increased from 1.04+/-0.09 (baseline) to 1.62+/-0.18 (nitrite; P<0.05) versus 1.07+/-0.09 (baseline) to 2.37+/-0.15 (nitrite; P<0.005) during hypoxia. This result was recapitulated in vitro in vascular rings. 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.
Assuntos
Hipóxia/fisiopatologia , Nitrito de Sódio/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/fisiologia , Eletrocardiografia , Antebraço/irrigação sanguínea , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipóxia/prevenção & controle , Infusões Intravenosas , Masculino , Pletismografia , Coelhos , Valores de Referência , Nitrito de Sódio/administração & dosagem , Decúbito Dorsal , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia , Veias/anatomia & histologia , Veias/fisiologia , Veia Cava Inferior/efeitos dos fármacos , Veia Cava Inferior/fisiologiaRESUMO
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.
Assuntos
Mioglobina/genética , Mioglobina/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Vasodilatação/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Monóxido de Carbono/metabolismo , Monóxido de Carbono/farmacologia , Interações Medicamentosas , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Doadores de Óxido Nítrico/farmacologia , Nitrito Redutases/metabolismo , Nitroprussiato/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
Reduced endothelial surface charge markedly increases the rate of LDL uptake into blood vessels. Previous work in the streptozotocin diabetic rat reported reduced endothelial surface charge. We compared endothelial surface charge density in internal mammary artery rings from patients with type 2 diabetes (n = 12) and from non diabetic patients undergoing coronary artery bypass grafting, and observed a substantial (52%) reduction in the former. This was associated with higher plasma sialic acid levels suggesting loss of sialic acid residues from the glycocalyx as a possible mechanism.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Endotélio Vascular/química , Artéria Torácica Interna/química , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Endotélio Vascular/ultraestrutura , Ferritinas , Glicocálix/metabolismo , Humanos , Artéria Torácica Interna/ultraestrutura , Microscopia Eletrônica , Ácido N-Acetilneuramínico/sangue , Coloração e Rotulagem/métodos , Propriedades de SuperfícieAssuntos
Arteriosclerose/metabolismo , Proteínas Sanguíneas/metabolismo , Endotélio Vascular/metabolismo , Animais , Artérias/citologia , Artérias/metabolismo , Arteriosclerose/etiologia , Arteriosclerose/patologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Fármacos Cardiovasculares/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Transporte ProteicoRESUMO
The effects of long-term low-dose treatment with reserpine on plasma lipoproteins and arterial cholesterol were determined in cholesterol-fed rabbits. Hepatic low-density lipoprotein (LDL) receptors; uptake of LDL by liver, heart, and kidneys; plasma fibrinogen; blood pressure; and heart rate were also determined. Reserpine at 43 microg/kg. d was continuously infused subcutaneously via implanted minipumps for 6 weeks into conscious unrestrained male New Zealand White rabbits (n = 5) fed a 0.2% cholesterol-enriched diet. Compared with controls, reserpine (n = 4) significantly reduced the elevated levels of plasma total cholesterol and esterified and unesterified cholesterol throughout the study, and at 6 weeks of treatment these reductions were 42, 41, and 49%, respectively. The increased cholesterol in the aortic walls (n = 5) produced by the atherogenic diet was reduced by 73% (p < 0.004) and 125I-tyramine cellobiose-labeled LDL by 67 to 86% (0.05 < p <0.004), respectively. The aortic intimal-medial thickness ratio was reduced by 70%. The decrease in elevated plasma total cholesterol was mainly due to cholesterol reductions in both LDL (41%) and non-high density lipoprotein (HDL) of density < 1.019 g/ml (51%). HDL cholesterol and triglyceride levels were unchanged. Reserpine had no significant effects on the clearance of 125I-tyramine cellobiose-LDL from plasma and there was a trend towards an increase in hepatic LDL receptor expression. Heart rate was decreased by 28%. There were no significant effects on blood pressure, liver and heart lipids, hematocrit, or plasma fibrinogen. The results suggest that treatment of cholesterol-fed rabbits with reserpine at a low dose over a long period prevents increases in plasma atherogenic lipoproteins. Reserpine decreases the cholesterol in aortic walls and the intima-media thickness ratio. This anti-atherosclerotic effect of reserpine may have therapeutic implication.