Since initial reports over 4 decades ago, cases of patients with angina-like chest pain whose coronary angiograms show no evidence of obstructive coronary artery disease and who have no structural ...heart disease continue to be a common occurrence for cardiologists. Many features of this patient population have remained constant with successive reports over time: a female predominance, onset of symptoms commonly between 40 and 50 years of age, pain that is severe and disabling, and inconsistent responses to conventional anti-ischemic therapy. Because patients may have had abnormal noninvasive testing that led to performance of coronary angiography, investigators have sought to show an association of this syndrome with myocardial ischemia. Abnormalities in coronary flow and metabolic responses to stress have been reported by several groups, findings consistent with a microvascular etiology for ischemia and symptoms, but others have questioned the presence of ischemia, even in patients selected for abnormal noninvasive testing. Despite considerable efforts by many groups over 4 decades, the syndrome remains controversial with regard to pathophysiology, diagnosis, and management.
Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and ...mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 micromol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Diet‐induced weight loss in women may be associated with decreases not only in plasma levels of low‐density lipoprotein cholesterol (LDL‐C), but also in high‐density lipoprotein cholesterol (HDL‐C). ...Whether a decrease in HDL‐C is associated with altered HDL function is unknown. One hundred overweight or obese women (age 46 ± 11 years, 60 black; 12 diabetic) were enrolled in the 6‐month program of reduced fat and total energy diet and low‐intensity exercise. Serum cholesterol efflux capacity was measured in 3H‐cholesterol‐labeled BHK cells expressing ABCA1, ABCG1, or SR‐B1 transporters and incubated with 1% apolipoprotein B (apoB)‐depleted serum. Antioxidant properties of HDL were estimated by paraoxonase‐1 (PON1) activity and oxygen radical absorbance capacity (ORAC). Endothelial nitric oxide synthase (eNOS) activation was measured by conversion of l‐arginine to l‐citrulline in endothelial cells incubated with HDL from 49 subjects. Participants achieved an average weight loss of 2.2 ± 3.9 kg (P < 0.001), associated with reductions in both LDL‐C (−6 ± 21 mg/dl, P = 0.004) and HDL‐C (−3 ± 9 mg/dl, P = 0.016). Cholesterol efflux capacity by the ABCA1 transporter decreased by 10% (P = 0.006); efflux capacities by the ABCG1 and SR‐B1 transporters were not significantly altered. ORAC decreased by 15% (P = 0.018); neither PON1 activity nor eNOS activation was significantly altered by reduction in HDL‐C. Findings were similar for diabetic and nondiabetic subjects. Diet‐induced weight loss in overweight or obese women is associated with a decrease in HDL‐C levels, but overall HDL function is relatively spared, suggesting that decrease in HDL‐C in this setting is not deleterious to cardiovascular risk.
The recent discovery that nitrite is an intrinsic vasodilator and signaling molecule at near-physiological concentrations has raised the possibility that nitrite contributes to hypoxic vasodilation ...and to the bioactivity of nitroglycerin and mediates the cardiovascular protective effects of nitrate in the Mediterranean diet. However, important questions of potency, kinetics, mechanism of action, and possible induction of tolerance remain unanswered.
In the present study, we performed biochemical, physiological, and pharmacological studies using nitrite infusion protocols in 20 normal human volunteers and in nonhuman primates to answer these questions, and we specifically tested 3 proposed mechanisms of bioactivation: reduction to nitric oxide by xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin. We found that (1) nitrite is a relatively potent and fast vasodilator at near-physiological concentrations; (2) nitrite functions as an endocrine reservoir of nitric oxide, producing remote vasodilation during first-pass perfusion of the opposite limb; (3) nitrite is reduced to nitric oxide by intravascular reactions with hemoglobin and with intravascular reductants (ie, ascorbate); (4) inhibition of xanthine oxidoreductase with oxypurinol does not inhibit nitrite-dependent vasodilation but potentiates it; and (5) nitrite does not induce tolerance as observed with the organic nitrates.
We propose that nitrite functions as a physiological regulator of vascular function and endocrine nitric oxide homeostasis and suggest that it is an active metabolite of the organic nitrates that can be used therapeutically to bypass enzymatic tolerance.
Accumulating evidence suggests that the ubiquitous anion nitrite (NO2-) is a physiological signaling molecule, with roles in intravascular endocrine nitric oxide transport, hypoxic vasodilation, ...signaling, and cytoprotection. Thus, nitrite could enhance the efficacy of reperfusion therapy for acute myocardial infarction. The specific aims of this study were (1) to assess the efficacy of nitrite in reducing necrosis and apoptosis in canine myocardial infarction and (2) to determine the relative role of nitrite versus chemical intermediates, such as S-nitrosothiols.
We evaluated infarct size, microvascular perfusion, and left ventricular function by histopathology, microspheres, and magnetic resonance imaging in 27 canines subjected to 120 minutes of coronary artery occlusion. This was a blinded, prospective study comparing a saline control group (n=9) with intravenous nitrite during the last 60 minutes of ischemia (n=9) and during the last 5 minutes of ischemia (n=9). In saline-treated control animals, 70+/-10% of the area at risk was infarcted compared with 23+/-5% in animals treated with a 60-minute nitrite infusion. Remarkably, a nitrite infusion in the last 5 minutes of ischemia also limited the extent of infarction (36+/-8% of area at risk). Nitrite improved microvascular perfusion, reduced apoptosis, and improved contractile function. S-Nitrosothiol and iron-nitrosyl-protein adducts did not accumulate in the 5-minute nitrite infusion, suggesting that nitrite is the bioactive intravascular nitric oxide species accounting for cardioprotection.
Nitrite has significant potential as adjunctive therapy to enhance the efficacy of reperfusion therapy for acute myocardial infarction.
This article describes the detailed phenotype of 15 children, 1 to 17 years of age, with Hutchinson–Gilford progeria syndrome, a rare, sporadic autosomal dominant premature aging syndrome causing ...death at approximately 13 years of age. Most cases are caused by an
LMNA
gene mutation that produces an abnormal lamin A, “progerin.” Since progerin accumulates in normal cells with age, understanding this syndrome may offer insight into normal aging.
This article describes the detailed phenotype of 15 children with Hutchinson–Gilford progeria syndrome, a rare, sporadic autosomal dominant premature aging syndrome causing death at approximately 13 years of age.
Some aspects of human aging appear to be dramatically accelerated in the Hutchinson–Gilford progeria syndrome, an extremely rare sporadic disorder (Figure 1).
1
–
3
Within approximately 13 years after birth, affected children die from cardiovascular disease. The cause is abnormal lamin A (denoted “progerin,” to distinguish it from normal lamin A), which is produced by an activated cryptic splice donor site created by a change from glycine GGC to glycine GGT in codon 608 of exon 11 of the lamin A (
LMNA
) gene.
4
,
5
Progerin disrupts the structural integrity of the inner nuclear membrane in a dominant negative fashion. . . .
Although the deleterious vasoconstrictive effects of cell-free, hemoglobin-based blood substitutes have been appreciated, the systemic effects of chronic hemolysis on nitric oxide bioavailability ...have not been considered or quantified. Central to this investigation is the understanding that nitric oxide reacts at least 1,000 times more rapidly with free hemoglobin solutions than with erythrocytes. We hypothesized that decompartmentalization of hemoglobin into plasma would divert nitric oxide from homeostatic vascular function. We demonstrate here that plasma from patients with sickle-cell disease contains cell-free ferrous hemoglobin, which stoichiometrically consumes micromolar quantities of nitric oxide and abrogates forearm blood flow responses to nitric oxide donor infusions. Therapies that inactivate plasma hemoglobin by oxidation or nitric oxide ligation restore nitric oxide bioavailability. Decompartmentalization of hemoglobin and subsequent dioxygenation of nitric oxide may explain the vascular complications shared by acute and chronic hemolytic disorders.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
...if no ischemia is evident by stress cardiac MRI, in addition to reassurance I may try a combination of a beta blocker and imipramine to reduce pain symptoms and encourage regular aerobic exercise ...to promote wellness. ...a report of "normal coronary arteries" following angiography does not mean that the epicardial arteries are free of atherosclerosis, which, although not flow limiting and causative of ischemia, may increase risk for future cardiovascular events.
The emerging biology of the nitrite anion Hogg, Neil; Cannon, Richard O; Kelm, Malte ...
Nature chemical biology,
11/2005, Letnik:
1, Številka:
6
Journal Article, Conference Proceeding
Recenzirano
Nitrite has now been proposed to play an important physiological role in signaling, blood flow regulation and hypoxic nitric oxide homeostasis. A recent two-day symposium at the US National ...Institutes of Health highlighted recent advances in the understanding of nitrite biochemistry, physiology and therapeutics.
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