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PubMed1978

Effect of carnitine on branched-chain amino acid oxidation by liver and skeletal muscle.

The effect of L-carnitine (0.5-2.0 mM) on the rates of alpha-decarboxylation of 1-14C-labeled branched-chain amino acids by gastrocnemius muscle and liver homogenates of fed rats was investigated. Carnitine increased the rate of alpha-decarboxylation of leucine (125%) and valine (28%) by muscle, but it was without effect on the oxidation of these amino acids by liver. Carnitine increased the rate of alpha-decarboxylation of alpha-ketoisocaproate by both tissues. This effect was more pronounced in muscle (130% increase) than in liver (41% increase). The activity of carnitine acyltransferase, with isovaleryl-CoA as a substrate, was 18 times higher in muscle mitochondria than in liver mitochondria. Both starvation and diabetes increased the rate of alpha-decarboxylation of leucine by muscle without having a remarkable effect on the concentration of carnitine or the activity of carnitine acyltransferase. We conclude that: a) carnitine stimulates decarboxylation of branched-chain amino acids by increasing the conversion of their ketoanalogues into carnitine esters, b) a greater carnitine acyltransferase activity in muscle than in liver may be responsible for the greater carnitine effect in muscle, c) carnitine does not appear responsible for the enhancement of leucine oxidation by muscle of starved and diabetic rats.

Amino Acids↗
PubMed1979

alpha-Ketoisocaproate stimulates branched-chain amino acid transaminase in kidney and muscle.

We have reported that branched-chain amino acid transaminase (BATase) activity of isolated rat kidney is stimulated by perfusion with alpha-ketoisocaproate (KL). This study examines the mechanism of this effect in kidney and documents that stimulation occurs in intact skeletal muscle. Increased activity was not attributable to synthesis of enzyme because it occurred in the presence of cycloheximide. The in vivo degradation rate of BATase estimated from sequential measurements of activity following intravenous cycloheximide was longer than 90 min, whereas during in vitro perfusion stimulation could be detected within 5 min. Incubation of supernatant from kidney homogenate with KL stimulated BATase; incubation with alpha-keto-beta-methylvalerate (KI), alpha-ketoisovalerate (KV), leucine (leu), or isovaleryl CoA did not. Perfusion of rat hindquarter with KL increased muscle BATase activity; perfusion with acetoacetate, KI, KV, or leu did not. Again, cycloheximide studies indicated a direct effect of KL on muscle BATase. These findings suggest that alpha-ketoisocaproate can increase BATase activity and thus may be involved in regulation of its activity.

Amino Acids, Branched-Chain↗
PubMed1981

Effects of hypophysectomy and thyroidectomy on leucine metabolism in adipose tissue.

Hypophysectomy doubled the rate of oxidation of L-[1-14C]leucine to 14CO2 by segments of rat epididymal adipose tissue. Thyroidectomy, but not adrenalectomy, produced identical results. Acceleration of leucine oxidation occurred even in the presence of glucose and saturating concentrations of insulin and leucine, suggesting that thyroidectomy increased the capacity to degrade leucine. Treatment of thyroidectomized rats with triiodothyronine (T3) decreased leucine oxidation, but at least 4 days were required. Treatment of hypophysectomized rats with T3 for 6 days was ineffective unless growth hormone was also given. A similar acceleration was also seen in the rate of oxidation of alpha-keto[1-14C]isocaproate, the deaminated analogue of leucine, but neither hypophysectomy nor thyroidectomy accelerated the rate of oxidation of isovalerate, the next metabolite in the degradative sequence. These observations suggested that hypothyroidism, whether primary or secondary, might increase the activity of the mitochondrial reaction responsible for the decarboxylation of alpha-ketoisocaproate. Because thyroidectomy failed to modify the rate of oxidation of [1-14C]pyruvate that occurs by an analogue reaction and requires the same cofactors, an effect of thyroidectomy on cofactor availability was ruled out. Direct assay in a cell-free homogenate revealed a nearly twofold increase in the activity of the alpha-ketoisocaproate dehydrogenase enzyme complex. The findings support the conclusion that hypothyroidism increases the amount or activity of the mitochondrial enzyme complex responsible for decarboxylation of branched-chain alpha-keto acids.

Adipose Tissue↗
PubMed1981

Effects of fasting on flux and interconversion of leucine and alpha-ketoisocaproate in vivo.

To determine directly the interconversion of circulating leucine and alpha-ketoisocaproate (KIC) in vivo, as well as the effects of fasting on leucine and KIC metabolism, 14- and 96-h fasted dogs were studied during simultaneous infusion of L-[4,5-3H]leucine and [U-14C]KIC. The specific radioactivities of 3H- and 14C-labeled leucine and KIC were determined and transfer rates calculated using a two-pool reversible model. In both groups, approximately 32% of the total leucine carbon entering was converted to KIC, whereas 60% of circulating KIC is converted to leucine. Plasma [3H]KIC specific radioactivity was only half of the circulating [3H]leucine specific activity, suggesting entry of KIC from an unlabeled pool. Fasting decreased the leucine-KIC interconversion, entry of unlabeled KIC, and irreversible loss of KIC. These data demonstrate that interconversion of circulating leucine and KIC is extensive and that fasting decreases the conversion of leucine to KIC in the labeled and unlabeled KIC pools, suggesting that transamination is a major regulator of leucine metabolism in fasting dogs.

Animals↗
PubMed1982

Regulation of alpha-ketoisocaproate binding to albumin in vivo by free fatty acids.

The importance of alpha-keto acid binding to plasma proteins was investigated both in vitro and in vivo using alpha-ketoisocaproate (KIC), the alpha-keto acid of leucine. Gel chromatography indicated that 65% of the radioactivity comigrated with serum albumin. An ultrafiltration assay was developed to estimate the percentage of free and bound KIC. These percentages, along with total plasma KIC concentrations, were used to calculate the circulating concentrations of free and bound KIC. KIC or free fatty acids (FFA) displaced [14C]KIC bound to bovine albumin or whole plasma. KIC was totally displaced from plasma proteins by 10 mM oleate, stearate, and myristate; whereas the alpha-keto acids of isoleucine and value were 50 and 85%, respectively, as effective as KIC. To determine whether increased plasma FFA concentrations alter the binding of KIC to plasma proteins in vivo, five postabsorptive humans were infused with triglyceride and heparin during the simultaneous administration of somatostatin, glucagon, and insulin. During the FFA elevation, plasma leucine decreased by 9% (P less than 0.02). Total plasma KIC remained constant, whereas free KIC increased (P less than 0.02) and bound KIC decreased (P less than 0.001). These results indicate that KIC is bound to plasma albumin in vivo and suggests that FFA, by altering circulating free KIC concentrations, may influence protein metabolism in man.

Animals↗
PubMed1983

Characterization of alpha-keto acid transport across blood-brain barrier in rats.

The transport of keto acids, monocarboxylic acids, and ketone bodies was studied in barbiturate-anesthetized, adult male Sprague-Dawley rats. [1-14C]propionate and D-3-[3-14C]hydroxybutyrate were found to cross the blood-brain barrier with brain uptake indexes of 43.53 and 7.10%, respectively. Transport of both of these substrates was saturable, with the values of transport Km being 2.03 and 6.54 mM, respectively. A Ki of 0.68 mM was derived from competition data measuring the uptake of [1-14C]alpha-ketoisocaproate in the presence of unlabeled alpha-ketobutyrate. This finding and results from classical inhibition studies support competition for transport of keto acids for a common carrier. The brain uptake of [1-14C]propionate was significantly reduced by keto acids and ketone bodies and the transport of D-3-[3-14C]hydroxybutyrate was significantly inhibited by unlabeled monocarboxylic acids, keto acids, and acetoacetate. Evidence for competitive transport of alpha-keto acids, monocarboxylic acids, and ketone bodies is presented in the form of classical double-reciprocal inhibition plots and of labeled monocarboxylic acids and ketone bodies by an increasing concentration of unlabeled alpha-ketoisocaproate, the latter method yielding Ki values of 0.29 and 0.63 mM, respectively. The brain uptake of labeled propionate was inhibited by unlabeled D-3-hydroxybutyrate. A Ki of 6.43 mM, derived from this data, approximated the Km of transport of D-3-hydroxybutyrate, suggesting that ketone bodies and monocarboxylic acids compete for transport via the same carrier that is operative for keto acids.

Animals↗
PubMed1985

Recycling of an amino acid label with prolonged isotope infusion: implications for kinetic studies.

To investigate whether recycling of a labeled amino acid would occur after 24 h of infusion, two groups of normal volunteers were infused with [3H]leucine and alpha-[14C]-ketoisocaproate for 4 h and [2H3]leucine for either 4 or 24 h (groups I and II, respectively). Entry of [2H3 )leucine at steady state into the plasma space was indistinguishable from its infusion rate for group I but 30% higher (P less than 0.001) than this rate for group II, demonstrating significant recycling of label. After discontinuation of the infusions, isotope disappearance from the plasma space was followed for 2 h. The 3H and 14C decay data for both groups suggest that plasma leucine and alpha-ketoisocaproate are derived from a single intracellular pool in the postabsorptive state. In group I, the 3H and 2H labels decayed identically; whereas, in group II, the decay of [2H3]-leucine and alpha-[2H3]ketoisocaproate was slower (P less than 0.01) than the decay of [3H]leucine and alpha-[3H]ketoisocaproate, confirming re-entry of label after a 24-h infusion. Therefore kinetic values calculated from models assuming no recycling of labeled amino acids are most likely not quantitative and must be interpreted with care when flux does not change or decreases.

Adult↗
PubMed1987

Effect of endurance training on leucine metabolism in perfused rat skeletal muscle.

An isolated single rat hindlimb muscle preparation was used to examine the influence of exercise training on leucine metabolism during steady-state conditions at rest and during isometric contractions. Treadmill training increased the activity of citrate synthase in the hindlimb muscle by 40-45%. Leucine oxidation, measured as the rate of alpha-decarboxylation, was not different between trained (2.28 +/- 0.15 nmol.min-1.g-1, n = 9) and control (2.57 +/- 0.20, n = 9) muscle at rest. In addition, successive 40-min contraction periods at 15 and 45 tetani/min induced similar increases (50 and 100%, respectively) in leucine oxidation in both groups. However, trained muscle maintained a greater tension output (P less than 0.05) during contractions and exhibited a greater oxygen consumption (VO2) (P less than 0.05) during 45 tetani/min. Thus the rate of leucine oxidation, relative to VO2, was less (P less than 0.05) in the trained group. This response was probably related to differences in intracellular factors modulating branched-chain alpha-keto acid dehydrogenase, the rate-limiting step in leucine oxidation. Although our observed rates of muscle leucine alpha-decarboxylation can reasonably account for the rates of whole-body leucine alpha-decarboxylation of nontrained individuals found during steady-state tracer studies in vivo, this is less reasonably the case for the trained group. This suggests that a greater rate of leucine oxidation by nonmuscle tissues (e.g., liver) may occur in trained compared with nontrained individuals.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1988

Regulation of valine and alpha-ketoisocaproate metabolism in rat kidney mitochondria.

Activities of branched-chain amino acid (BCAA) aminotransferase (BCAT) and alpha-keto acid dehydrogenase (BCKD) were assayed in mitochondria isolated from kidneys of rats. Rates of transamination of valine and oxidation of keto acids alpha-ketoisocaproate (KIC) or alpha-ketoisovalerate (KIV) were estimated using radioactive tracers of the appropriate substrate from amounts of 14C-labeled products formed (14CO2 or [1-14C]-keto acid). Because of the high mitochondrial BCAT activity, an amino acceptor for BCAT, alpha-ketoglutarate (alpha-KG) or KIC, was added to the assay medium when valine was the substrate. Rates of valine transamination and subsequent oxidation of the KIV formed were determined with 0.5 mM alpha-KG as the amino acceptor; these rates were 5- to 50-fold those without added alpha-KG. Rates of CO2 evolution from valine also increased when KIC (0.01-0.10 mM) was present; however, with KIC concentrations above 0.2 mM, rates of CO2 evolution from valine declined although rates of transamination continued to rise. When 0.05 mM KIC was added to the assay medium, oxidation of KIC was suppressed by inclusion of valine or glutamate in the medium. When valine was present KIC was not oxidized preferentially, presumably because it was also serving as an amino acceptor for BCAT. These results indicate that as the supply of amino acceptor, alpha-KG or KIC, is increased in mitochondria not only is the rate of valine transamination stimulated but also the rate of oxidation of the KIV formed from valine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of insulin on whole body and forearm leucine and KIC metabolism in type 1 diabetes.

To investigate whole body rates of appearance (Ra) and forearm metabolism of leucine and alpha-ketoisocaproate (KIC) in type 1 diabetes, before and after insulin administration, seven diabetic subjects were studied in the postabsorptive state with primed-constant infusions of L-[4,5-3H]leucine and [1-14C]KIC, and forearm arterial deep-venous catheterization. This combined technique allowed the selective quantitation of the two processes regulating forearm leucine and KIC metabolism (release and uptake) that may occur simultaneously. Before insulin (arterial plasma glucose, 284 +/- 24 mg/dl; leucine, 215 +/- 24 mumol/l; KIC, 42 +/- 3 mumol/l) forearm leucine and KIC release exceeded uptake slightly but significantly (P less than 0.05). During a 180-min insulin infusion, arterial glucose (144 +/- 27 mg/dl) and leucine concentrations (130 +/- 15 mumol/l) decreased (P less than 0.05 or less vs. base line) toward normal, whereas KIC did not change (33 +/- 4 mumol/l, NS). However, no net uptake of either leucine or KIC across the forearm was detected at any time point. In contrast, a significant net release of these substrates occurred throughout the insulin infusion. By the end of the hormone administration, whole body leucine and KIC Ra decreased 17 and 33%, respectively (P less than 0.01). However, forearm uptake and release of leucine and KIC did not significantly change with respect to base line. The fraction of whole body leucine released from estimated total muscle mass did not change (54 to 48%, NS) before vs. after insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Effect of alpha-ketoacid dehydrogenase phosphorylation on branched-chain amino acid metabolism in muscle.

The regulation of leucine and valine metabolism was evaluated in skeletal muscle of perfused rat hindlimb. Control of the branched-chain alpha-ketoacid dehydrogenase (BCKADH) via phosphorylation was removed with 0.4 mM alpha-chloroisocaproate (CIC). CIC activated the BCKADH complex 13- to 26-fold and led to increased rates of leucine and valine uptake into muscle, transamination to the corresponding alpha-ketoacid, and leucine (3- to 4-fold) and valine (6-fold) decarboxylation but led to decreased rates of alpha-ketoacid efflux from muscle. Although the increased rates of branched-chain amino acid (BCAA) decarboxylation were extensive, they were far below the extent of BCKADH activation as measured in vitro, suggesting that factors other than BCKADH activation become dominant in controlling the flux through alpha-ketoacid decarboxylation in skeletal muscle in situ. When the BCKADH capacity of muscle was increased 70-90% by a training-induced increase in mitochondrial content, the same 13- to 26-fold activation of the complex by CIC led to a rate of BCAA decarboxylation, which was only marginally greater (10-20%; P less than 0.05) than that of normal muscle. In addition, increasing the energy demand via muscle contractions led to a significant increase in leucine decarboxylation in the presence of complete activation of BCKADH by dephosphorylation. Thus BCKADH phosphorylation-dephosphorylation plays an important though not exclusive role in modulating the rates of BCAA metabolism in skeletal muscle. Differences in valine and leucine metabolism were apparent as valine catabolism bolstered citric acid cycle contents by increasing malate in red muscle with high mitochondrial content.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

Pentagastrin increases pepsin secretion without increasing its fractional synthetic rate.

We studied the effects of increasing doses of pentagastrin on gastric secretion of pepsin and on incorporation of L-[1-13C]leucine into gastric aspirate protein as an index of pepsin synthesis. Pentagastrin (0.25-4.0 micrograms.kg-1.h-1) significantly increased pepsin output from basal 76 mg/h to < or = 181 mg/h but did not significantly alter incorporation of L-[1-13C]leucine from the basal fractional synthetic rate of 3.63 +/- 0.05%/h. In four subjects in whom infusion of tracer leucine was continued for > 1 day, aspiration of pepsin between 24 and 27 h demonstrated that plateau 13C labeling of leucine in pepsin had been attained, but at a value that was only 48% of the 13C labeling of plasma alpha-ketoisocaproic acid (alpha-KIC) [0.730 +/- 0.02 (SE) vs. 1.520 +/- 0.14 atoms %excess]. This suggests that actual rates of pepsin synthesis were approximately double those calculated on the basis of alpha-KIC labeling. The results are consistent with an interpretation that increasing doses of pentagastrin cause increased secretion of pepsinogen by recruitment of gastric chief cells, each synthesizing pepsinogen at an unaltered rate. Plateau 13C enrichment of alpha-KIC may not be a valid surrogate for plateau 13C leucine enrichment when fractional synthetic rates of some secreted proteins are calculated.

Adult↗
PubMed1997

Functional heterogeneity of leucine pools in human skeletal muscle.

Current models to measure muscle protein synthesis in humans assume a homogeneous intracellular amino acid pool. This assumption was tested by measuring the isotopic enrichment of leucine and its transamination product alpha-ketoisocaproate (KIC) in plasma and muscle tissue fluid and comparing them with that of leucyl-tRNA during a continuous infusion of L-[1-13C]leucine in 12 healthy subjects. Six subjects were studied twice while drinking a carbohydrate (0.42 kcal/kg) drink every 20 min for 11 h or the same volume of water. Six others took an isocaloric mixed meal providing 14 mg protein/kg every 20 min and water. Enrichment of plasma and tissue fluid KIC and plasma leucine was consistently higher than that of leucyl-tRNA and tissue fluid leucine (P < 0.01), whereas the enrichment of leucyl-tRNA was equivalent to that of tissue fluid leucine in all experiments. Furthermore, the ratio of enrichment of leucyl-tRNA to that of plasma leucine and KIC decreased after the mixed meal, whereas that of leucyl-tRNA to tissue fluid leucine remained constant. The enrichment of KIC was closer (approximately 17% lower) to that of plasma leucine than that of leucyl-tRNA (approximately 43% higher), indicating that the transamination pool derived more leucine from extracellular sources than the acylation pool. We conclude that the use of plasma KIC enrichment as a surrogate measure of leucyl-tRNA enrichment substantially underestimates muscle protein synthetic rates in humans, whereas tissue fluid leucine enrichment is a valid surrogate measure. In addition, the differences in enrichment of leucyl-tRNA and KIC support a regulated cytoplasmic trafficking of leucine in muscle cells.

Adult↗
PubMed1998

Acetogenesis does not replace ketogenesis in fasting piglets infused with hexanoate.

The current studies were performed to better understand the physiological relevance of acetate in the poorly ketogenic piglet and to determine if endogenous acetogenesis rises with increased mitochondrial fatty acid beta-oxidation, analogous to ketogenesis. Plasma acetate concentration values in newborn, fasted, or suckled piglets (230-343 microM) were at least 10-fold higher than the ketone bodies, a pattern opposite to that in 24- to 48-h suckled rats (77-175 microM). Employing continuous infusion techniques with sodium [3H]acetate tracer in fasting approximately 40-h-old piglets, acetate rate of appearance (Ra) was found to be 34 +/- 4 micromol . min-1 . kg body wt-1. This basal Ra was double that observed in animals coinfused with sodium [1-14C]hexanoate (P < 0.001), despite active oxidation of the latter as determined by 14CO2 production. Active acetogenesis in vivo and relatively abundant acetate in piglet blood are consistent with the hypothesis that acetate plays an important physiological role in piglets. However, the negative impact of hexanoate oxidation upon acetate Ra and the lack of significant changes in circulating acetate in newborn, suckled, and fasted piglets draws into question the extent of analogy between acetogenesis and ketogenesis in vivo.

Acetates↗
PubMed1980

Contribution of bile to postprandial intestinal hyperemia.

The role played by bile in postprandial intestinal hyperemia was examined by comparing the vascular effects of luminal placement of various nutrients with and without bile in situ jejunal segments of anesthetized dogs. The bile concentration was either 10 or 33% of that in the gallbladder. At these concentrations, bile per se in the jejunal lumen does not alter local blood flow. In the absence of bile, only glucose increased flow (+5% above control). With 10% bile, glucose and oleic acid increased flow by 10 and 24%, whereas with 33% bile, glucose, oleic acid, caproic acid, and amino acids increased flow by 22, 21, 12, and 12% above control, respectively. Triolein increased flow only after digestion by pancreatic enzymes and mixing with bile. Dipeptides did not alter flow with or without bile. Thus, bile plays an important role in postprandial intestinal hyperemia because it potentiates the glucose-induced hyperemia and because only in its presence can oleic acid, amino acids, caproic acid, and digested triolein increase intestinal blood flow.

Amino Acids↗
PubMed1985

Regulation of jejunal blood flow and oxygenation during glucose and oleic acid absorption.

To differentiate the mechanisms whereby actively absorbed glucose and passively absorbed oleic acid increase blood flow and oxygen uptake during their absorption, the effects of these two nutrients on jejunal blood flow, arteriovenous oxygen difference [(a-v)O2], O2 uptake, absorption, rubidium extraction, and capillary permeability-surface area product (PS) were compared in anesthetized dogs. Oleic acid (37 mM) produced significantly greater hyperemia (+28.2%) than glucose (270 mM) did (+12.5%). As estimated by (a-v)O2, tissue oxygen extraction was decreased by oleic acid (-12%) but increased by glucose (+6.5%); the increases in O2 uptake by these two nutrients did not differ significantly. Glucose absorption was accompanied by an increase in rubidium extraction and capillary PS (+11.3%), whereas oleic acid absorption was not. Unlike glucose, intra-arterial infusion of oleic acid decreased vascular resistance and increased blood flow equally to the mucosa and muscularis layers. A significant relation existed between oleic acid absorption and blood flow but not between glucose absorption and blood flow. The enhancement of glucose-induced hyperemia by bile was not related to glucose absorption. Unmasking of oleic acid-induced hyperemia by bile is unrelated to oleic acid absorption but is related to solubility of oleic acid in aqueous solution. The above findings suggest that glucose absorption affects both resistance and exchange vessels, whereas oleic acid absorption affects primarily resistance vessels.

Animals↗
PubMed2001

Substrate utilization by intestinal mucosal tissue strips from patients with inflammatory bowel disease.

A primary metabolic disorder may be present in the colonic mucosa of patients with ulcerative colitis. Preserving the epithelium in situ, we evaluated the metabolism of the colonic mucosa of control patients and patients with ulcerative colitis and Crohn's disease. Colonic mucosal strips (approximately 500 mg) were incubated with partially 14C-labeled acetate (C2), butyrate (C4), hexanoate (C6), octanoate (C8), and glucose, and the production of CO2 and ketone bodies was quantitated. Metabolism by small intestinal mucosal strips was also evaluated. Compared with controls, no decrease in either CO2 or ketone body production by colonic strips from patients with either ulcerative colitis or Crohn's disease was observed for any substrate. The CO2 production from each of the C2-C8 fatty acids was the same for colonic and small intestinal strips, whereas CO2 production from glucose was higher in small intestinal strips than in colonic strips. The production of ketone bodies was low in small intestinal strips. A primary metabolic disorder in the colonic mucosa of patients with inflammatory bowel disease was not found.

Acetates↗
PubMed2004

Role of hydrogen peroxide in ACh-induced dilation of human submucosal intestinal microvessels.

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several mediators of vasodilation, which include prostacyclin (PGI(2)), nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently defined the role of nitric oxide and PGI(2) in the dilation of submucosal intestinal arterioles from patients with normal bowel function. However, significant endothelium-dependent dilator capacity to ACh remained after inhibiting both these mediators. The current study was designed to examine the potential role of EDHF in human intestinal submucosal arterioles. ACh elicited endothelium-dependent relaxation in the presence of inhibitors of nitric oxide synthase and cyclooxygenase (23 +/- 10%, n = 6). This ACh-induced relaxation was inhibited and converted to constriction by catalase (-53 +/- 10%, n = 6) or KCl (-30 +/- 3%, n = 7), whereas 17-octadecynoic acid and 6-(2-propargylloxyphenyl) hexanoic acid, two inhibitors of cytochrome P450 monooxygenase, had no significant effect (3 +/- 1% and 20 +/- 8%, n = 5, respectively). Exogenous H(2)O(2) elicited dose-dependent relaxation of intact microvessels (52 +/- 10%, n = 7) but caused frank vasoconstriction in arterioles denuded of endothelium (-73 +/- 8%, n = 7). ACh markedly increased the dichlorofluorescein fluorescence in intact arterioles in the presence of nitric oxide synthase and cyclooxygenase inhibitors compared with control and compared with catalase-treated microvessels (363.6 +/- 49, 218.8 +/- 10.6, 221.9 +/- 27.9, respectively, P < 0.05 ANOVA, n = 5 arbitrary units). No changes in the dichlorofluorescein fluorescence were recorded in vessels treated with ACh alone. These results indicate that endothelial production of H(2)O(2) occurs in response to ACh in human gut mucosal arterioles but that H(2)O(2) is not an EDHF in this tissue. Rather, we speculate that it stimulates the release of a chemically distinct EDHF.

Acetylcholine↗