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OBJECTIVES Ornithine alpha-ketoglutarate has proved to be an efficient nutritional support in trauma situations, especially after burn injury. To determine whether the action of ornithine alpha-ketoglutarate is due to its alpha-ketoglutarate moiety (as a glutamine precursor), we studied the effects of alpha-ketoglutarate administered to rats as ornithine alpha-ketoglutarate, or in combination with arginine salt (arginine alpha-ketoglutarate), as the two closely related amino acids have similar metabolic behavior. DESIGN Prospective, randomized trial. SETTING Animal laboratory. SUBJECTS Forty-six male Wistar rats, weighing approximately 90 g. INTERVENTIONS Rats were burned over 20% of their body surface area, starved for 24 hrs, with water ad libitum, and then enterally refed for 48 hrs using Osmolite (210 kcal/kg/day, 1.2 g of nitrogen/kg/day), supplemented with one of the following: a) an amount of glycine isonitrogenous to ornithine alpha-ketoglutarate (group 1); b) 5 g of monohydrated ornithine alpha-ketoglutarate/kg/day (group 2); c) an amount of arginine alpha-ketoglutarate isonitrogenous to ornithine alpha-ketoglutarate (group 3); or d) an amount of arginine alpha-ketoglutarate isomolar to ornithine alpha-ketoglutarate (group 4). MEASUREMENTS AND MAIN RESULTS We measured amino acid concentrations in plasma, muscle, and liver, and plasma urea concentration. At refeeding, ornithine alpha-ketoglutarate increased plasma glutamine concentration (p < .05 vs. the three other groups), and counteracted the increase in plasma phenylalanine concentration. In muscle, although the three alpha-ketoglutarate combinations induced similar increases in the glutamate pool, ornithine alpha-ketoglutarate induced the highest increase in glutamine (7.0 +/- 0.3 vs. 5.4 +/- 0.3 micromol/g in group 3, 6.3 +/- 0.3 in group 4, and 4.6 +/- 0.2 in group 1, p < .01 between group 2 and groups 3 or 1). Also, only ornithine alpha-ketoglutarate increased liver glutamine concentration. Finally, isomolar arginine alpha-ketoglutarate increased plasma urea concentration (+50% vs. the three other groups, p < .01). CONCLUSIONS Our results demonstrate, for the first time, the following: a) the action of ornithine alpha-ketoglutarate as a glutamine precursor cannot solely be ascribed to alpha-ketoglutarate since arginine alpha-ketoglutarate combinations did not exhibit this effect to the same extent; and b) the action of ornithine alpha-ketoglutarate is not due to its nitrogen content since isonitrogenous arginine alpha-ketoglutarate did not reproduce the effects of ornithine alpha-ketoglutarate.

International audience; BACKGROUND: Aging is associated with reduced structural and functional adaptation to chronic changes in blood flow (shear stress) in small arteries. As heme oxygenase-1 (HO-1) is induced by hemodynamic forces in vascular smooth muscle and endothelial cells, we hypothesized that it might improve flow-dependent remodeling in aging.METHOD: First-order mesenteric arteries from 3 and 16-month-old rats were exposed to high, low, or normal flow by alternate ligation in vivo. Rats were treated with the HO-1 inducer, cobalt protoporphyrin (CoPP, 5 mg/kg) or vehicle. 14 days later, local blood flow was measured in vivo, and arteries were studied in vitro.RESULTS: Despite an equivalent change in blood flow, diameter enlargement in the high-flow arteries was blunted in old compared to young rats and was associated with decreased endothelium-dependent relaxation to acetylcholine. In old rats, HO-1 induction with CoPP restored outward remodeling, via a paradoxical reactive oxygen species-dependent mechanism, and was associated with a Mn-superoxide dismutase (SOD) overexpression, as well as a significant reduction of mitochondrial aconitase activity, used as a biomarker for oxidative stress. The heme oxygenase activity inhibitor, Sn-protoporphyrin, and the SOD-mimetic, TEMPOL, prevented the effect of CoPP on remodeling and oxidative status in old rats. Furthermore, HO-1 induction improved endothelial function, in association with increased endothelial nitric oxide synthase protein expression and phosphorylation (Ser-1177). In low-flow arteries, inward remodeling was unaffected by aging or by CoPP. Thus, in old rats, CoPP-induced up-regulation of HO-1 restored high-flow-dependent remodeling (diameter enlargement) and improved endothelial function in mesenteric arteries.CONCLUSION: This opens new perspectives in the treatment of ischemic diseases in aging.

The role of angiotensin II type 2 receptors (AT2R) is not fully understood, especially in vascular diseases. Although its vasodilatory and antitrophic properties are well accepted, in hypertensive rats AT2R stimulation induces vasoconstriction. Abnormalities in the renin-angiotensin system have a key role in cardiovascular disorders associated with the evolution of type II diabetes. Thus, we hypothesized that AT2R function might be altered in diabetic rats resistance arteries. Mesenteric resistance arteries (250 μm diameter) were isolated from type II diabetic Zucker (ZDF) and control rats (LZ) rats receiving the antioxidant tempol (16 mg/kg/day) or water for 3 weeks. Dilation to angiotensin II (due AT2R stimulation) in the presence of candesartan (angiotensin II type 1 receptor blocker) was studied in ring segment of arteries using a wire-myograph mesenteric wall force. AT2R induced endothelium and NO-dependent dilation in LZ (inhibited by L-NAME). It was not affected by cyclooxygenase (indomethacin) or reactive oxygen species (ROS) inhibition (TEMPOL). In ZDF rats AT2R-induced dilation was lower than in LZ rats and independent of NO (not inhibited by L-NAME). It was restored to control level after ROS (tempol) and cycloxygenase inhibition (indomethacin). Cycloxygenase-2 (NS398) and Thromboxane A2 receptor (SQ29548) inhibition also restored AT2R-dilation in ZDF rats to control (LZ) level. Cycloxygenase-2 and ROS were overexpressed (immuno-histological detection using confocal microscopy) in ZDF rats arteries. In ZDF rats chronically treated with the antioxydant Tempol (SOD mimetic) AT2R-induced dilation was equivalent to that in LZ (control) rats and it involved NO and cycloxygenase-2-derivatives in equivalent proportion (dilation inhibited in part by L-NAME and by NS398). In tempol-treated rats SQ29548 had no effect. We conclude that in type II diabetic rats AT2R induced dilation is reduced due to ROS and thromboxane A2-dependent vasoconstriction due to COX-2 activation. Chronic treatment of diabetic rats with tempol restored AT2R-dependent dilation through the suppression of ROS and TxA2 production. These findings might be important to consider in the choice of vasoactive drugs in diabetic patients.

Chronic increases in blood flow increase arterial diameter and NO-dependent dilation in resistance arteries. Because endothelial dysfunction accompanies metabolic syndrome, we hypothesized that flow-mediated remodeling might be impaired in obese rat resistance arteries. Obese and lean Zucker rat mesenteric resistance arteries were exposed to chronic flow increases through arterial ligation in vivo: arteries exposed to high flow were compared with normal flow arteries. Diameter was measured in vitro in cannulated arteries using pressure arteriography. After 7 days, outward remodeling (diameter increased from 346±9 to 412±11 μm at 100 mm Hg) occurred in lean high-flow arteries. Endothelium-dependent tone was reduced in high-flow arteries from obese rats by contrast with lean animals. On the other hand, diameter enlargement occurred similarly in the 2 strains. The involvement of NO in endothelium-dependent dilation (evidenced by NO blockade) and endothelial NO synthase phosphorylation was smaller in obese than in lean rats. Superoxide anion and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression (p67phox and gp91phox) increased in obese rats and were higher in high-flow than in control arteries. Acute Tempol (a catalase mimetic), catalase plus superoxide dismutase, and l -arginine plus tetrahydrobiopterin restored endothelium-dependent dilation in obese rat normal and high-flow arteries to the level found in lean control arteries. Thus, flow-induced remodeling in obese resistance arteries was associated with a reduced endothelium-mediated dilation because of a decreased NO bioavailability and an excessive superoxide production. This dysfunction might have negative consequences in ischemic diseases in patients with obesity or metabolic syndrome.

We recently demonstrated that a pressure-induced vasodilation results from local nonnociceptive stimulation of the skin of the human hand. We aimed to test the hypothesis that this vasodilation was not a short-lived response to a single type of pressure strain, but could be a widely activated and prolonged protective cutaneous response. We studied the dynamics of pressure-induced vasodilation during various ramp changes in local externally applied pressure using laser Doppler flowmetry. Changes from an adjacent control probe were subtracted from pressure-induced local changes. Following an initial transient decrease, continuous 4.4, 5.6, and 11.1 Pa.s(-1) increases of pressure resulted in a secondary increase of blood flow whose amplitude was maximal for 11.1 Pa.s(-1) (22.9 +/- 12.6% above baseline) (mean +/- SEM). The increase in flow was not noted at 16.7 Pa.s(-1). If the 16.7 Pa.s(-1) ramp pressure increase was interrupted at min 2 or 4, a prolonged vasodilation response was found, but not if it was stopped at min 8. When the 16.7 Pa.s(-1) increasing pressure was returned to zero after 4 min of pressure increase (-8.1 +/- 8.9% before pressure removal), vasodilation occurred and reached a maximum of 26.0 +/- 9.6% at 7 min after removal of pressure (P0.05 from baseline). Pressure-induced vasodilation is a slow-responding and transient adaptive phenomenon, initiated by a wide range of pressure changes below the range of noxious stimulation. We propose that this response is a protective mechanism without which certain pressure-associated lesions may develop.

Local warming alone induces a cutaneous vasodilation considered as maximal. The argument that local warming generates a maximum flow is being tested by vasodilation with alternate approaches to see if a greater vasodilation is possible: blockade of the release of transmitters from the adrenergic nerve endings with bretylium tosylate or direct pharmacological action on vascular smooth muscle using sodium nitroprusside. Nine healthy subjects participated in two experiments in which SkBF was measured simultaneously by laser Doppler flowmetry on the dorsal aspects of both hands. In the first protocol the vasodilator effects of 20 min of local warming at 44 degreesC were measured on one hand and the effects of iontophoresis of sodium nitroprusside on the other. The second protocol was like the first except that iontophoresis of bretylium tosylate instead of sodium nitroprusside was performed. Local warming induced an increase of SkBF from 17.6 +/- 4.4 to 140.2 +/- 33.2 AU (P < 0.01) while it rose from 16.7 +/- 4.0 to 114.7 +/- 11.0 AU (P < 0.001) during sodium nitroprusside iontophoresis. During the second protocol local warming induced an increase of SkBF from 14.9 +/- 2.1 to 117.7 +/- 25.4 AU (P < 0.01) while it rose from 19.6 +/- 2.6 to 120.5 +/- 11.3 AU (P < 0.001) during bretylium iontophoresis. However, in both experiments, the increase of SkBF attained during iontophoresis did not differ significantly from the increase achieved by local warming. We conclude that the effects of iontophoresis of sodium nitroprusside or of bretylium produce a cutaneous vasodilation as high as a local warming on the dorsal aspect of the hand.