Background-Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor L-arginine is related to decreased endothelial function. Methods and Results-Radiotracer kinetics ([3 H]L-arginine) were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects (nϭ12) and in 2 groups of healthy volunteers with (nϭ15) and without (nϭ15) a family history of hypertension. In conjunction, forearm blood flow responses to acetylcholine and sodium nitroprusside were measured before and after a supplemental intra-arterial infusion of L-arginine. In vivo and in vitro measures of L-arginine transport were substantially reduced in the essential hypertension and positive family history groups compared with the negative family history group; however, no difference was detected in peripheral blood mononuclear cell mRNA or protein expression levels for the cationic amino acid transporter CAT-1. Plasma concentrations of L-arginine and N G ,N GЈ -dimethylarginine (ADMA) did not differ between groups. L-Arginine supplementation improved the response to acetylcholine only in subjects with essential hypertension and positive family history. Conclusions-Similar
Abstract-Altered nitric oxide (NO) bioavailability has been ascribed an important role in the pathophysiology of congestive heart failure (CHF). In the peripheral vasculature, we recently demonstrated a depression of L-arginine transport in association with pharmacological evidence of reduced endothelial function. In contrast, increased myocardial NO generation has been proposed to account for a component of the reduced myocardial contractility in CHF, although this remains controversial. We determined the whole body clearance rate and cardiac fractional extraction of L-arginine during a steady-state intravenous infusion of [ 3 H]L-arginine (300 nCi/min) in 9 healthy control subjects and 7 patients with moderate to severe CHF. In patients with CHF, there was a 30% reduction in the transcardiac extraction of [ 3 H]L-arginine compared with controls (PϽ0.05), which was accompanied by a trend toward reduced [3 H]L-citrulline release (Pϭ0.06). In conjunction, the systemic clearance rate of [ 3 H]L-arginine was significantly lower in patients with CHF (778Ϯ148 versus 1278Ϯ144 mL/min, PϽ0.05). In association with these biochemical indices, we observed a 38% reduction (PϽ0.05) in the mRNA expression of the cationic amino acid transporter CAT-1 in ventricular myocardial samples from patients with CHF compared with healthy unused donor myocardium, whereas myocardial NOS enzymatic activity and NOS protein were unchanged. These data indicate the presence of a significant reduction in the myocardial uptake of L-arginine in patients with CHF. Furthermore, this abnormality seems to be part of a systemic downregulation of L-arginine transport. Key Words: heart failure Ⅲ nitric oxide Ⅲ amino acids Ⅲ radioisotopes C ongestive heart failure (CHF) is a common cardiovascular disorder characterized by considerable morbidity and mortality. The pathophysiology of CHF is increasingly being appreciated as highly complex, representing the result of interactions between multiple processes, including maladaptive ventricular remodeling, activation of neurohormonal and cytokine systems, and alterations in vascular and skeletal muscle function.The well-documented process of progressively worsening cardiac performance in CHF 1,2 has been ascribed to multiple processes. These include primary alterations in myocardial structure, including geometric considerations, the number of cardiomyocytes (resulting from necrosis and apoptosis), and the presence of myocardial fibrosis. 3 In conjunction, fundamental changes in cardiomyocyte cellular and molecular biology that alter contractile function are also well recognized. These include changes in calcium-handling proteins, contractile protein expression, and the -adrenoceptor signaling pathway, as recently reviewed. 2 Within this context, considerable emphasis has been placed on the potential negative inotropic effects of several autocrine/paracrine and circulating factors, such as nitric oxide (NO) 4,5 and tumor necrosis factor ␣. 6Although several investigators have documented increased expression of ...
Systemic arterial compliance (SAC) makes an important contribution to cardiac afterload, and thus is a significant determinant of left ventricular work. Previous studies have suggested that arterial compliance may be reduced in patients with congestive heart failure (CHF), and that SAC is increased after a 4-week exercise training programme in healthy, sedentary individuals. The present study aimed to investigate the effects of an 8-week exercise training programme on arterial mechanical properties, left ventricular performance and quality of life in CHF patients. A total of 21 patients with NYHA class II or III CHF (mean+/-S.D. age 55+/-13 years) were randomly allocated to either an 8-week exercise training group or a "usual lifestyle" control group. SAC, as determined non-invasively using applanation tonometry and Doppler aortic velocimetry, increased from 0.57+/-0.11 to 0.77+/-0.14 arbitrary compliance units (mean+/-S.E.M.; P=0.01) in the exercise group, while no change occurred in the control group. Left ventricular structure and function was assessed by echocardiography, and these parameters were unchanged over the 8-week study period. Exercise training significantly increased exercise capacity, measured by a 6-min walking test (474+/-27 to 547+/-34 m; P=0.008). Quality of life, as assessed using the Minnesota Living with Heart Failure Evaluation, demonstrated a decrease in heart failure symptoms from 46+/-7 to 24+/-5 units (P=0.01) following the exercise training programme. These data show that exercise training improves SAC in patients with CHF. The accompanying improvement in exercise capacity may be due, in part, to an improvement in arterial function.
We have reported previously a decrease in the clearance of the NO (nitric oxide) precursor L-arginine in the forearm circulation of CHF (congestive heart failure) patients, suggesting a potential rate-limiting mechanism contributing to the common finding of endothelial dysfunction in CHF. Given data that show exercise training augments endothelial function in CHF, the aim of the present study was to investigate whether these improvements were due to an increase in L-arginine transport. Measures of L-arginine transport, endothelial function and exercise capacity were repeated before and after 8 weeks of "usual living" or exercise training in 21 CHF patients [NYHA (New York Heart Association) class II/III]. Exercise capacity (6-min walk test) increased following exercise training (496+/-21 to 561+/-17 m; P=0.005), whereas the control group demonstrated no change [488+/-18 to 484+/-21 m; P=ns (not significant)]. Basal FBF (forearm blood flow) remained stable following exercise training (2.68+/-0.55 to 2.46+/-0.32 ml.min(-1).100 ml(-1) of tissue) and "usual living" (2.16+/-0.37 to 2.91+/-0.55 min(-1).100 ml(-1) of tissue). FBF responses to ACh (acetylcholine) increased following exercise by 49.6+/-17.7% (area under curve; P=0.01) demonstrating augmented endothelial function. FBF responses to SNP (sodium nitroprusside) were also improved following exercise training (30.8+/-8.2%; P=0.02). There was no change in vascular function in the "usual living" group. The clearance of L-arginine was significantly increased following involvement in the exercise programme (69.4+/-7.8 to 101.0+/-9.5 ml/min; P=0.04), whereas there was no change in the "usual living" group (78.4+/-17.5 to 81.0+/-14.9 ml/min; P=ns). In conclusion, the augmentation in endothelial function observed following exercise may be due, in part, to an increase in the transport of L-arginine in CHF patients.
Systemic arterial compliance (SAC) makes an important contribution to cardiac afterload, and thus is a significant determinant of left ventricular work. Previous studies have suggested that arterial compliance may be reduced in patients with congestive heart failure (CHF), and that SAC is increased after a 4-week exercise training programme in healthy, sedentary individuals. The present study aimed to investigate the effects of an 8-week exercise training programme on arterial mechanical properties, left ventricular performance and quality of life in CHF patients. A total of 21 patients with NYHA class II or III CHF (mean+/-S.D. age 55+/-13 years) were randomly allocated to either an 8-week exercise training group or a "usual lifestyle" control group. SAC, as determined non-invasively using applanation tonometry and Doppler aortic velocimetry, increased from 0.57+/-0.11 to 0.77+/-0.14 arbitrary compliance units (mean+/-S.E.M.; P=0.01) in the exercise group, while no change occurred in the control group. Left ventricular structure and function was assessed by echocardiography, and these parameters were unchanged over the 8-week study period. Exercise training significantly increased exercise capacity, measured by a 6-min walking test (474+/-27 to 547+/-34 m; P=0.008). Quality of life, as assessed using the Minnesota Living with Heart Failure Evaluation, demonstrated a decrease in heart failure symptoms from 46+/-7 to 24+/-5 units (P=0.01) following the exercise training programme. These data show that exercise training improves SAC in patients with CHF. The accompanying improvement in exercise capacity may be due, in part, to an improvement in arterial function.
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