Short-term improvement in submaximal exercise capacity by optimized therapy with ACE inhibitors and beta blockers in heart failure patients is associated with restoration of peripheral endothelial function

BACKGROUND: Improved exercise capacity in chronic heart failure (CHF) has been attributed to restoration of endothelial function. ACE inhibitors as well as beta blockers have previously been shown to enhance endothelial function and exercise capacity. The aim of this study was to determine whether short-term improvement in submaximal exercise capacity induced by optimized therapy with ACE inhibitors in combination with beta blockers is associated with restoration of endothelial function in CHF patients. METHODS: Thirty-three patients with CHF were evaluated: six-minute walk test, NYHA class, brain natriuretic peptide (BNP), big Endothelin-1 (bigET-1) and flow-mediated vasodilation (FMD) of the brachial artery were assessed at baseline and after a 3-month period of optimized neurohormonal therapy. Two groups were formed retrospectively based on the changes in submaximal exercise capacity (responders and non-responders). RESULTS: Optimization of neurohormonal therapy was comparable between groups. Responders (n=17) revealed a significant increase in walking distance (304+/-109 to 441+/-75 m; p<0.01), which was paralleled by a decrease in NYHA class (2.7+/-0.6 to 2.0+/-0.4; p<0.01), BNP (484+/-454 to 243+/-197 pg/ml; p<0.01), and bigET-1 (2.0+/-0.9 vs. 1.5+/-0.6 fmol/ml; p=0.04). By contrast, the latter variables did not change in non-responders. Improvement in functional capacity in responders was associated with an increase in FMD (8.2+/-3.9% to 11.0+/-5.6%; p<0.05). Increments in FMD were directly correlated with increases in walking distance (r=0.34; p<0.05). CONCLUSION: Short-term improvement of submaximal exercise capacity in CHF patients following optimized therapy with ACE inhibitors and beta blockers is associated with restoration of endothelial function in conduit arteries.     

Effects of acylcarnitine transferase blockade on metabolism and function in the normally and underperfused canine myocardium

The acylcarnitine transferase blocking agent, sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate (Clomoxir, INN), effectively inhibits free fatty acid oxidation, thereby decreasing myocardial oxygen consumption in the normally perfused myocardium without influencing cardiodynamic parameters. As a consequence, however, arterial free fatty acid levels increase significantly. In an acute dog model, we investigated the hypothesis that the sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate-induced decrease in myocardial oxygen consumption may also improve the energetic situation in the underperfused myocardium. Regional myocardial function was assessed by means of subendocardially inserted ultrasonic crystals, and changes in metabolism were measured regionally by means of a catheter inserted into a local myocardial vein in the underperfused area. The flow in the circumflex coronary artery was reduced on average by 53.5% followed 30 min later by an infusion of sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate (dosage: 20 mg/kg over 20 min). Arterial free fatty acid levels continuously increased, whereas arterial glucose levels decreased. In accordance with the situation in the normally perfused myocardium, free fatty acid uptake and oxygen uptake were also reduced in the underperfused area. However, sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate induced a further, transient increase in end-diastolic segment length and a sustained decrease in systolic shortening in the underperfused area, indicating a further deterioration in regional myocardial function. Control experiments with infusion of 9 g/l sodium chloride showed no change in the degree of regional myocardial dysfunction throughout the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blockade of endothelium-derived relaxing factor synthesis with NG-nitro-L-arginine methyl ester leads to enhanced venous reactivity in vivo.

This study was performed to examine whether endothelium-derived relaxing factor (EDRF) influences venous tone and reactivity in vivo. The inferior vena cava and abdominal aorta were studied simultaneously under continuous haemodynamic monitoring in anaesthetised rabbits. In addition, a 20-MHz intravascular ultrasound catheter was placed in the vena cava for on-line two-dimensional imaging of vessel cross-sectional area and calculation of wall stress (T(ension) = P(mean) * r(adius)/2). This approach enabled simultaneous visualisation of both venous (CA(ven)) and aortic (CA(art)) cross-sectional area with continuous recording of vessel dimensions. Measurements were made before and after administration of NG-nitro-l-arginine methyl ester (L-NAME; 10 mg.kg i.v.), a specific inhibitor of EDRF biosynthesis. After L-NAME there was a significant increase in central venous pressure and a decrease in CA(ven). On the arterial side, L-NAME caused a significant increase in mean pressure and CA(art), resulting in a significantly augmented arterial wall stress. The venodilatation elicited by increasing doses of glyceryltrinitrate was markedly enhanced after L-NAME. Norepinephrine caused a parallel shift of the dose-response curve for CA(ven) in the presence of a lower baseline value. These results suggest that EDRF contributes substantially to the control of large capacitance veins in vivo and that L-NAME increases venous reactivity to both norepinephrine and glyceryltrinitrate.     

Distribution and metabolism of NG-nitro-L-arginine and NG-nitro-L-arginine methylester in canine blood in vitro

Summary The aim of the present study was to investigate the metabolism of the two NO-synthase inhibitors N^G-nitro-L-arginine (L-NA) and N^G-nitro-Lrarginine methylester (L-NAME) in canine blood in vitro. Blood and plasma samples were incubated with IrNAME or L-NA respectively and the drug levels were determined in blood, plasma and blood cells by means of high performance liquid chromatography.Incubation of blood or plasma with LrNAME revealed that L-NAME is metabolized to L-NA in blood and plasma. After plasma incubation with L-NA, the L-NA levels remain stable over the whole observation period; in agreement with the data in plasma the whole amount of LNA added to blood was detectable in blood after 4 h of incubation suggesting that L-NA undergoes no further metabolism. Drug concentrations determined in blood cells after 4 h of blood incubation with L-NAME or LNA revealed that L-NAME easily enters the blood cells, whereas only a small portion of LNA is found in the blood cells 4 h after blood incubation with L-NA.In conclusion, the present study demonstrates that L-NAME is metabolized to L-NA in canine blood and plasma in vitro. The fact that L-NAME but nearly no L-NA enters the cellular blood compartment led us to the assumption that although L-NA is an active metabolite of L-NAME, NO synthase may be differently inhibited by L-NA and L -NAME due to their different distribution characteristics.Some of the results have been presented at the Autumn Meeting of the German Society for Pharmacology and Toxicology in Graz 1992 (Krejcy et al. 1992) Correspondence to K. Krejcy at the above address     

Regression of atherosclerosis: role of nitric oxide and apoptosis

BACKGROUND: We have recently found that administration of L-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the L-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of L-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway. METHODS AND RESULTS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5% L-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies. L-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9+/-3.9 vs 3.9+/-1. 4 apoptotic cells/mm2, P<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10(-5) mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion. L-Arginine (10(-3) mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by D-arginine, and they were antagonized by the NO synthase inhibitor L-nitro-arginine (10(-4) mol/L). The effect of L-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP. CONCLUSIONS: These results indicate that supplemental L-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis.     

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