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J R Vane

Publications and source records attributed to J R Vane.

At least 163 records · Page 9Linked to original sources
PubMed1990

Endothelin-1 and U46619 potentiate selectively the venous responses to nerve stimulation within the perfused superior mesenteric vascular bed of the rat.

The effects were examined of endothelin-1 and U46619 on the responses to perivascular nerve stimulation of the simultaneously perfused arterial and venous vessels of the superior mesenteric arterial bed of the rat. Stimulation of the nerves at 4-16 Hz for 30 s caused frequency dependent constrictions of both the arterial and venous vessels similar to those produced by bolus doses of exogenous noradrenaline (0.1-10 nmol). Infusion of either endothelin-1 (0.1 nM) or U46619 (1-3 nM) caused small (less than or equal to 5 mmHg) increases in arterial and venous perfusion pressures and selectively potentiated the venous, but not arterial, responses to nerve stimulation. Conversely, endothelin-1 and U46619 potentiated the responses of both the arterial and venous vessels to exogenous noradrenaline. Thus, as reported previously for the arterial vessels of the rat mesentery, the isolated venous vessels constrict to perivascular nerve stimulation in a frequency dependent manner. In addition, endothelin-1 and U46619 potentiate selectively the effects of nerve stimulation on the veins.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

L-glutamine inhibits the release of endothelium-derived relaxing factor from the rabbit aorta.

The present study investigates the effect of the amino acid L-glutamine (L-Gln) on the release of endothelium-derived relaxing factor (EDRF) from the luminally perfused rabbit aorta and on endothelium-dependent relaxations of rabbit aortic strips. L-Gln (200 microM) had no effect on the acetylcholine (Ach)-induced release of EDRF from freshly prepared aortic tissues. The concentration of L-arginine (L-Arg) in endothelial cells isolated from these aortae was approximately 4 mM, as determined by HPLC analysis. After an initial equilibration period of 2 h and two consecutive infusions of Ach (55 microM for 15 min) at 2 and 3 h, L-Arg levels fell by 62 +/- 14% (n = 4). Under these conditions, L-Gln (200 microM) but not D-Gln (200 microM) inhibited the release of EDRF by 50 +/- 4% (n = 7). This effect of L-Gln was partially reversed by infusions of L-Arg (500 microM) but not D-Arg (500 microM). L-Gln (200 microM) but not D-Gln (200 microM) potentiated the inhibitory effect of N omega-nitro-L-arginine (30 microM), an inhibitor of EDRF biosynthesis, on Ach-induced relaxations of rabbit aortic strips, whereas L-Gln alone had no effect. Thus, L-Gln inhibits the release of EDRF from intact blood vessels presumably by interfering with the generation of L-Arg by the endothelium.

Acetylcholine↗
PubMed1990

Endothelium-derived relaxing factor participates in the increased blood flow in response to pentagastrin in the rat stomach mucosa.

The stimulation of gastric-acid secretion by pentagastrin, a synthetic analogue of the endogenous peptide gastrin, is associated with an increased blood flow to the stomach mucosa, commonly referred to as functional hyperaemia. There are at least two potent vasodilator substances, the local release of which from endothelial cells could contribute to this hyperaemia, endothelium-derived relaxing factor (EDRF) and prostacyclin. EDRF has been identified as nitric oxide, released enzymatically from the guanidino group of L-arginine. In the present studies, the involvement of prostacyclin in the pentagastrin-induced increase in stomach blood flow was eliminated by using the cyclo-oxygenase inhibitor indomethacin. Thus this work was designed to elucidate the participation of EDRF/NO in the pentagastrin-induced hyperaemia and not its relative importance to prostacyclin. The increase in blood flow to the gastric mucosa in response to pentagastrin was measured by laser Doppler flowmetry in situ. Inhibition of EDRF/NO biosynthesis with the L-arginine analogues NG-monomethyl-L-arginine (MeArg) or N omega-nitro-L-arginine (NO2Arg) significantly attenuated (by more than 80%) the increase in mucosal blood flow in response to pentagastrin. However, infusions of the natural substrate L-arginine reversed the inhibitor effect of MeArg on pentagastrin-induced increase in mucosal blood flow. Local intra-arterial injections of the endothelium-independent vasodilator glyceryl trinitrate produced a dose-related increase in blood flow to the rat stomach mucosa that was unaffected by infusion of MeArg. Thus, in the absence of prostacyclin, EDRF/NO participates in the pentagastrin-induced increase in blood flow to the rat stomach mucosa.

Animals↗
PubMed1990

Endothelins release tissue plasminogen activator and prostanoids.

Endothelin (ET)-1 (0.1-1 nmol/kg), ET-2 (0.1-1 nmol/kg) or ET-3 (0.3-3 nmol/kg) dose dependently inhibited platelet aggregation induced by adenosine di-phosphate (ADP) ex vivo in anaesthetised rabbits, while having no effect on aggregations induced by ADP, collagen or arachidonic acid in vitro. This anti-aggregatory effect of the peptides is most likely due to the release of prostacyclin into the circulation, for the inhibition was abolished by an injection of indomethacin (5 mg/ml). All three peptides produced a significant, bi-phasic reduction of the euglobulin clot lysis time. This ET-induced enhancement of plasma fibrinolytic activity was associated with a release of tissue plasminogen activator into the circulation. ET-1 or ET-2 caused a transient decrease in left ventricular systolic pressure (LVSP) followed by a prolonged pressor response. However, ET-3, while inducing a similar transient fall in LVSP caused a second, more prolonged, decrease in LVSP. The haemodynamic responses to all three peptides were modulated by the release of prostanoids, as evidenced by the elevation of the pressure responses by indomethacin.

Adenosine Diphosphate↗
PubMed1990

Cultured endothelial cells maintain their L-arginine level despite the continuous release of EDRF.

Endothelial cells cultured from bovine aorta and grown on microcarrier beads contain 107 +/- 9 microM L-arginine (Arg; n = 11). When packed into a jacketed chromatography column and perfused with Krebs solution, the cells showed a substantial and sustained release of endothelium-derived relaxing factor (EDRF) for up to 2 h, which was further enhanced by infusions of adenosine diphosphate (4 microM). In contrast to other amino acids, such as L-alanine, L-aspartate, L-glutamine, L-glutamate or L-serine, which showed a time-dependent decrease to less than 30% of their original level within 2 h, Arg remained at control levels for 30 min and decreased only by 25% after 2 h. Thus endothelial cells can generate Arg from an intracellular source to maintain their Arg level despite the continuous formation of EDRF.

Amino Acids↗
PubMed1990

Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine.

NG-monomethyl-L-arginine (MeArg) inhibits the release of endothelium-derived relaxing factor (EDRF) from endothelial cells (EC) and the formation of nitric oxide (NO) from L-arginine (Arg) in EC and activated macrophages. We have compared the inhibitory potency of MeArg to that of N omega-nitro-L-arginine (NO2Arg), a more potent inhibitor of EDRF synthesis in vitro. NO2Arg (100 microM) was significantly more potent than MeArg in inhibiting the endothelium-dependent relaxation of rabbit aorta induced by acetylcholine. MeArg and NO2Arg (10 and 30 microM) also inhibited the release of EDRF from bovine aortic cultured EC. In the anaesthetized rat in vivo, the pressor effect of NO2Arg (3 and 10 mg kg-1) was significantly larger and longer lasting than that of MeArg. These differences in potency could be due to the extensive metabolism of MeArg but not NO2Arg to L-citrulline (Cit) and subsequently to Arg by EC. The enzyme responsible for the conversion of MeArg to Cit had the characteristics of a novel deiminase, NG,NG-dimethylarginine dimethylaminohydrolase, recently isolated from rat kidney.

Acetylcholine↗
PubMed1990

The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells.

The mechanism by which L-glutamine (L-Gln) inhibits the release of endothelium-derived relaxing factor from bovine aortic cultured endothelial cells was investigated. The intracellular concentration of L-arginine (L-Arg) in Arg-depleted endothelial cells was inversely related to the level of L-Gln. Removal of L-Gln from the culture medium (usually containing L-Gln at 2 mM) abolished the inhibitory effect of the culture medium on L-Arg generation. L-Gln (0.2 and 2 mM) but not D-Gln inhibited the generation of L-Arg by both Arg-depleted and nondepleted endothelial cells. L-Gln did not interfere with the uptake of L-Arg or the metabolism of L-Arg-L-Phe to L-Arg but inhibited the formation of L-Arg from L-citrulline (L-Cit), L-Cit-L-Phe, and NG-monomethyl-L-arginine. L-Gln also inhibited the conversion of L-[14C]Cit to L-[14C]Arg by Arg-depleted endothelial cells. However, L-Gln did not inhibit the conversion of L-argininosuccinic acid to L-Arg by endothelial cell homogenates. Thus, L-Gln interferes with the conversion of L-Cit to L-Arg probably by acting on argininosuccinate synthetase rather than argininosuccinate lyase. L-Gln also inhibited the generation of L-Arg by the monocyte-macrophage cell line J774 but had no effect on the conversion of L-Cit to L-Arg by these cells. As the release of endothelium-derived relaxing factor from cultured and non-cultured endothelial cells is limited by the availability of L-Arg, endogenous L-Gln may play a regulatory role in the biosynthesis of endothelium-derived relaxing factor.

Animals↗
PubMed1990

The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine.

We have investigated the mechanism by which cultured endothelial cells generate L-arginine (L-Arg), the substrate for the biosynthesis of endothelium-derived relaxing factor. When Arg-depleted endothelial cells were incubated in Krebs' solution for 60 min, L-Arg levels were significantly (9.7-fold) elevated. The generation of L-Arg coincided with a substantial decrease (90%) in intracellular L-glutamine (L-Gln), whereas all other amino acids were virtually unaffected. Changes in calcium, pH, or oxygen tension had no effect on L-Arg generation, which was, however, prevented when the cells were incubated in culture medium containing L-Gln. L-Arg generated by endothelial cells labeled with L-[14C]Arg was derived from an unlabeled intracellular source, for the specific activity of the intracellular L-Arg pool decreased substantially (8.8-fold) over 60 min. Arg-depleted endothelial cells did not form urea or metabolize L-ornithine but converted L-citrulline (L-Cit) to L-Arg possibly via formation of L-argininosuccinic acid. Nondepleted cells stimulated with the calcium ionophore A23187 showed only a transient accumulation of L-Cit, indicating that L-Cit is recycled to L-Arg during the biosynthesis of endothelium-derived relaxing factor. The generation of L-Arg by Arg-depleted endothelial cells was partially (45%) blocked by protease inhibitors, and various Arg-containing dipeptides were rapidly cleaved to yield L-Arg. Thus, cultured endothelial cells recycle L-Cit to L-Arg and possibly liberate peptidyl L-Arg. The Arg-Cit cycle appears to be the equivalent in the endothelial cell to the formation of urea by the liver. The biosynthesis of endothelium-derived relaxing factor may, therefore, not only produce a powerful vasodilator but also relieve the endothelial cell of excess nitrogen.

Animals↗
PubMed1990

Regional vascular resistance and haemodynamics in the spontaneously hypertensive rat: the effects of bradykinin.

To identify those vascular beds that contribute to the elevated peripheral resistance (TPR) seen in spontaneously hypertensive rats (SHR) as compared to Wistar-Kyoto rats (WKY), the distribution of cardiac output, organ blood flow, and regional vascular resistance were measured using radiolabelled microspheres. WKY and SHR had similar heart rates, cardiac outputs, and cardiac stroke volumes, whereas SHR had significantly elevated TPR. This increased TPR was the cumulative effect of significant elevations in vascular resistance in the brain, testes, epididymides, gastrointestinal tract, pancreas/mesentery, skin, kidneys, and skeletal muscle. Only in the renal and skeletal muscle vasculature was this elevation in resistance associated with reduced blood flow. Haemodynamic responses to bradykinin [thought to act through a release of endothelium-derived relaxing factor (EDRF)] were similar in both WKY and SHR with the exception of the liver where no reduction of hepatic arterial resistance was seen in the SHR. We suggest that the increase in resistance in the renal and skeletal muscle vasculature is due to active vasoconstriction in these beds. This vasoconstriction diverts a significant proportion of the cardiac output through other vascular beds, especially the brain, liver, and coronary circulation. This will result in increased shear-stress and consequent damage to endothelial cells.

Animals↗
PubMed1990

Inhibition by L-glutamine of the release of endothelium-derived relaxing factor from cultured endothelial cells.

L-Glutamine (0.02-2 mM) but not D-glutamine (0.2 mM and 2 mM) inhibited the release of endothelium-derived relaxing factor (EDRF) from bovine aortic endothelial cells cultured in the presence or absence of L-arginine. Inhibition was maximal at a concentration of 200 microns, and was reversed by L-arginine (50 microns) but not D-arginine (100 microns). L-Glutamic acid (2 mM) or ammonium chloride (1 mM), putative products of the metabolism of L-glutamine in endothelial cells, had no effect on EDRF release. L-Glutamine (0.2 mM and 2 mM) but not D-glutamine (2 mM), L-glutamic acid (2 mM) or ammonium chloride (1 mM) also inhibited the generation of L-arginine in endothelial cells. Thus, L-glutamine inhibits EDRF release by preventing the generation of L-arginine.

Animals↗