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Biomedical subjects

P Vallance

Publications and source records attributed to P Vallance.

At least 91 records · Page 5Linked to original sources
PubMed1996

Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure.

Abstract. NGNG dimethyl-L-arginine (asymmetric dimethyl-L-arginine; ADMA) and NGNG dimethyl-L-arginine (symmetric dimethyl-L-arginine; SDMA) are naturally occurring analogues of L-arginine, the substrate for nitric oxide (NO) synthesis. ADMA is a potent inhibitor of NO synthesis, and accumulates in the plasma of patients with renal failure. However the precise concentration of ADMA and SDMA in renal patients is still controversial. This study was performed to measure plasma ADMA and SDMA concentrations by two different HPLC techniques in nine healthy controls and 10 uraemic subjects, and to investigate the effects of haemodialysis. In controls, the mean (+/-SEM) plasma concentrations of ADMA and SDMA were 0.36 +/- 0.09 and 0.39 +/- 0.05 mumol/l respectively, yielding an ADMA/SDMA ratio of 1.2 +/- 0.17. In uraemic patients, the plasma concentrations of ADMA and SDMA were 0.9 +/- 0.08 mumol/l (P < 0.001 compared to controls) and 3.4 +/- 0.3 mumol/l (P < 0.001 compared to controls) with an ADMA/SDMA ratio of 0.27 +/- 0.015 (P < 0.001). In the course of one 4 h haemodialysis session, ADMA concentrations decreased from 0.99 +/- 0.13 to 0.77 +/- 0.3 mumol/l and SDMA concentrations from 3.38 +/- 0.44 to 2.27 +/- 0.21 mumol/l. The plasma ADMA/creatinine ratio tended to increase from 1.26 +/- 0.20 x 10(-3) to 2.01 +/- 0.41 x 10(-3). It is concluded that there is a modest (3-fold) but definite increase in plasma ADMA concentration in uraemic patients compared to controls. SDMA accumulates to a greater degree (8-fold increase) and more closely parallels creatinine concentration than ADMA. The change in the ADMA/SDMA ratio is not accounted for by greater renal or dialysis clearance of ADMA, and, even though alternative explanations are not excluded, greater metabolism of ADMA than SDMA is the most likely explanation. Although small in magnitude, the increase in ADMA concentration might by biologically significant.

Adult↗
PubMed1996

Nitric oxide and blood pressure: effects of nitric oxide deficiency.

Nitric oxide plays several crucial roles in control of blood pressure and kidney function and in the dietary response to salt in normal humans and animals. Nitric oxide deficiency leads to hypertension and renal damage in experimental animals and may be related to the development of some hypertensive disorders in people.

Animals↗
PubMed1996

Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase.

1. Dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes the endogenous nitric oxide synthase inhibitors NG-monomethyl-arginine and NG,NG-dimethy-L-arginine to citrulline, was identified by Western blotting in rat and human tissue homogenates. 2. S-2-amino-4(3-methylguanidino)butanoic acid (4124W) inhibited the metabolism of [14C]-NG-monomethyl-L-arginine to [14C]-citrulline by rat liver homogenates (IC50 416 +/- 66 microM; n = 9), human cultured endothelial cells (IC50 250 +/- 34 microM; n = 9) and isolated purified dimethylarginine dimethylaminohydrolase. 3. Addition of 4124W to culture medium increased the accumulation of endogenously-generated NG,NG-dimethy-L-arginine in the supernatant of human cultured endothelial cells from 3.1 +/- 0.3 to 5 +/- 0.7 microM (n = 15; P < 0.005). 4. 4124W (1 microM - 1 mM) had no direct effect on endothelial nitric oxide synthase activity but caused endothelium-dependent contraction of rat aortic rings (1 mM 4124W increased tone by 81.5 +/- 9.6% of that caused by phenylephrine 100 nM). This effect was reversed by L-arginine (100 microM). 4124W reversed endothelium-dependent relaxation of human saphenous vein (19.2 +/- 6.7% reversal of bradykinin-induced relaxation at 1 mM 4124W). 5. These data suggest that inhibition of dimethylarginine dimethylaminohydrolase increases the intracellular contraction of NG,NG-dimethyl-L-arginine sufficiently to inhibit nitric oxide synthesis. Inhibiting the activity of DDAH may provide an alternative mechanism for inhibition of nitric oxide synthases and changes in the activity of DDAH could contribute to pathophysiological alterations in NO generation.

Amidohydrolases↗
PubMed1996

Functional effects of econazole on inducible nitric oxide synthase: production of a calmodulin-dependent enzyme.

1. We performed experiments to examine the effects of an anti-fungal imidazole compound, econazole, on the regulation and effects of lipopolysaccharide-inducible nitric oxide synthase (iNOS) activity in rat aortic rings and cultured J774 murine macrophage cells. 2. In endothelium-intact rings of thoracic aorta, phenylephrine caused a concentration-dependent contraction with EC50 of 1.9 +/- 0.15 x 10(-8) M (n = 5). Following incubation with lipopolysaccharide (LPS, 5 micrograms ml-1) for 8 h there was a right-shift in the concentration-response curve (EC50 3.1 +/- 0.28 x 10(-7) M, P < 0.05) with a depression in the maximum contraction from 1.44 +/- 0.25 g to 0.86 +/- 0.26 g (n = 4). Co-incubation of rings with econazole (1 x 10(-5) M) partially inhibited the LPS-induced loss of reactivity to phenylephrine (EC50 6.5 +/- 0.72 x 10(-8) M) and fully inhibited the reduction in maximum tension (1.49 +/- 0.19 g; n = 5). 3. In J774 cells, incubation with LPS (10 micrograms ml-1, 24 h) resulted in significant nitrite production that was inhibited by co-incubation with econazole (IC50 5.0 +/- 0.9 x 10(-6) M; n = 5). In cells stimulated with LPS, production of L-[3H]-citrulline from L-[3H]-arginine was 6.41 +/- 0.22 pmol mg-1 protein min-1 (n = 3). This was inhibited by 92 +/- 6% by addition of NG-monomethyl-L-arginine (L-NMMA, 1 x 10(-3) M; n = 3) to the homogenate but not by econazole (1 x 10(-5) M; n = 3). In contrast pretreatment of cells with econazole (1 x 10(-5) M) markedly reduced the LPS-induced [3H]-citrulline production (0.86 +/- 0.053 pmol mg-1 protein min-1; P < 0.01; n = 3). 4. In cells treated with LPS and econazole, L-[3H]-citrulline production was restored in a concentration-dependent manner by addition of calmodulin (1 x 10(-8)-3 x 10(-7) M) with an IC50 of 4.2 +/- 0.9 x 10(-8) M. 5. We have shown that econazole inhibits the functional and biochemical activity of iNOS in rat aortic rings and cultured J774 cells. Treatment of cells with econazole renders the NO synthase functionally inactive. In econazole-treated cells enzyme activity is restored by calmodulin suggesting that econazole may inhibit the binding of this essential co-factor to the enzyme following its production. These studies may have implications for the design of novel anti-inflammatory agents working through the L-arginine-nitric oxide pathway.

Animals↗
PubMed1996

Interaction between sympathetic and sensory nerves in rat small arteries: involvement of nitric oxide.

The aim of this study was to determine the effects of C-fiber activation on the reactivity of resistance arteries. Rat small mesenteric arteries were mounted in a tension myograph. Electrical field stimulation (EFS) of vessels produced brief contractions that were abolished by tetrodotoxin (1 microM, n = 4) or guanethidine (5 microM, n = 4). Capsaicin caused concentration-related attenuation of the EFS contraction [giving EFS responses of 61.7 +/- 4.3, 39.8 +/- 5.9, and 14.0 +/- 3.9% (n = 13-16) of control EFS contraction in the presence of 1, 3, and 10 microM capsaicin, respectively]. This effect was attenuated by the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) (1 microM, n = 4, P < 0.05), NG-monomethyl-L-arginine (L-NMMA; 100 microM, n = 4, P < 0.01), or endothelial denudation (n = 5, P < 0.001). CGRP concentration-dependent inhibited (n = 5) EFS contraction, but this was unaffected by (L-NMMA (100 microM, n = 4). Capsaicin also relaxed preconstricted vessels (U-46619). This response was attenuated by ruthenium red (30 microM, n = 5, concentration ratio of 3.5 +/- 1.0) and CGRP-(8-37) (1 microM, n = 5, P < 0.05), while L-NMMA (100 microM, n = 6) showed variable effects, and denudation had no effect. These results show directly for the first time responses to activation of capsaicin-sensitive C fibers which modulate reactivity and the responses to sympathetic stimulation of isolated rat small mesenteric arteries, with the latter being an endothelial nitric oxide-dependent effect.

Animals↗
PubMed1996

Endothelial "stunning" following a brief exposure to endotoxin: a mechanism to link infection and infarction?

BACKGROUND: There is an association between infection, inflammation and acute cardiovascular events. In an attempt to explore the mechanism of this association we have developed a model to examine the effects on endothelial function of a brief exposure to endotoxin. METHODS AND RESULTS: Endotoxin was instilled into isolated superficial hand veins of healthy volunteers. The vein was isolated by means of two wedges and endotoxin instilled into the isolated segment. After 1 h the contents of the vein were aspirated and the wedges removed. Dose-response curves to bradykinin (a stimulator of nitric oxide synthesis), arachidonic acid (the precursor of prostanoid production) and GTN (a nitric oxide donor) were constructed before and 1 h after endotoxin. Endotoxin caused a glucocorticoid-inhibitable attenuation in the dose-response curves to bradykinin and arachidonic acid (P < 0.05). This effect persisted for 48 h and took 7 days to recover. Exposure of saphenous vein to endotoxin in vitro also caused selective impairment of endothelium-dependent relaxation (P < 0.05) yet microscopy of the vessels exposed to endotoxin showed no endothelial denudation or structural damage. CONCLUSION: The results demonstrate that a brief local exposure to endotoxin caused endothelial dysfunction that persists for 48 h and takes up to 7 days to recover. The endothelial dysfunction is not due to expression of the inducible isoform of nitric oxide synthase and persists for far longer than the effects of endotoxin on vascular smooth muscle function. We have coined the term endothelial "stunning" to describe the transient endothelial dysfunction and suggest it might provide a mechanism underpinning the association between infection or inflammation and increased cardiovascular risk. Endothelial stunning appears to provide a novel, transient, variable and modifiable potential cardiovascular risk factor.

Adult↗
PubMed1995

Vasodilatation to arachidonic acid in humans. An insight into endogenous prostanoids and effects of aspirin.

BACKGROUND: Human endothelial and vascular smooth muscle cells synthesize prostanoids. Several of these have been implicated in the physiological and pathophysiological regulation of vascular tone; however, there is no direct evidence that human blood vessels synthesize sufficient prostanoid to alter vessel tone. METHODS AND RESULTS: We explored the effects of local infusions of arachidonic acid on the tone of preconstricted superficial hand veins in healthy volunteers. Aspirin was used to assess the contribution of prostanoids to the responses seen. Local infusion of arachidonic acid produced a dose-dependent dilatation of preconstricted veins. This was abolished by local infusion of aspirin. Oral aspirin was also effective: a high (anti-inflammatory) dose of aspirin (1 g) taken 2 hours before the experiment blocked the arachidonic acid-induced venodilatation; however, a low (cardioprotective) dose of aspirin (75 mg) did not. Unlike the responses to arachidonic acid, responses to glyceryltrinitrate and bradykinin were unaltered by aspirin (1 g). Ex vivo platelet aggregation was inhibited by aspirin in both high and low doses. Aspirin (1 g) inhibited arachidonic acid-induced venodilatation for up to 5 days. The time course was similar for vascular and platelet effects. CONCLUSIONS: The present findings demonstrate that local generation of prostanoids in a human vessel in vivo alters vascular tone. The predominant prostanoid synthesized is a dilator and its synthesis can be blocked by an anti-inflammatory but not a cardioprotective dose of aspirin. The results suggest that selective inhibition of platelet aggregation by oral aspirin might be a function of dose rather than the interval between doses.

Acetaminophen↗
PubMed1995

Direct measurement of nitric oxide in human beings.

Nitric oxide is a short-lived radical involved in various biological processes. We have used an electrochemical microsensor to detect nitric oxide signals in blood vessels of healthy volunteers. The sensor was inserted into a hand vein, and the vessel was stimulated with acetylcholine or bradykinin. Dose-dependent signals were detected and were attenuated by an inhibitor of nitric oxide synthase. The results provide further evidence that endothelium-derived relaxing factor is nitric oxide and demonstrate a method for monitoring the L-arginine/nitric-oxide pathway in human beings.

Acetylcholine↗
PubMed1995

Role of thromboxane A2 in the vasoconstrictor response to endothelin-1, angiotensin II and 5-hydroxytryptamine in human placental vessels.

The possibility that the vasoconstrictor agents present in the circulation may mediate their effect on placental blood flow by stimulating local prostanoid production was investigated. Placental cotyledons obtained at term from normal pregnancies were perfused in vitro. The dose-related vasoconstrictor effects of endothelin-1 (ET-1), angiotensin II (A II) and 5-hydroxytryptamine (5 HT) were reduced by graded concentrations of the thromboxane A2 (TXA2) receptor antagonist GR32191 (10(-7)-10(-4)M), aspirin (10(-5)-10(-4)M) and indomethacin (10(-5)M). The effect of the TXA2 receptor agonist U46619 was totally abolished by GR32191 (10(-7)M) but unaffected by the prostanoid synthesis inhibitors, aspirin and indomethacin although they prevented a self-priming effect of U46619. When effluents were collected from perfused placentae, 5-10 min after administration of sub-maximal doses of ET-1 (20 pmol), A II (500 pmol) and 5 HT (15 pmol), there was a significant increase in TXB2, the stable metabolite of TXA2, indicating the vasoconstrictors had induced an increase in local prostanoid production. These findings indicate that the vasoconstrictor effects of ET-1, A II and 5 HT in the placental vascular bed are mediated, at least in part, by vasoconstrictor prostanoids including TXA2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Vascular and hormonal responses to arginine: provision of substrate for nitric oxide or non-specific effect?

1. The vascular and hormonal effects of L- and D-arginine were compared in healthy subjects and in patients with insulin-dependent diabetes mellitus or untreated essential hypertension. 2. Infusion of L- or D-arginine (40 mumol/l) in the forearm vascular bed, sufficient to increase the local concentration approximately 20-fold, had no effect on blood flow or the vasodilator response to acetylcholine (30 and 100 nmol/min) in patients with insulin-dependent diabetes (n = 7) or essential hypertension (n = 7), or in age- and sex-matched control subjects (n = 7 in both groups). 3. Systemic infusion of 10 g of L-arginine (n = 5) or D-arginine (n = 3) increased plasma concentration of arginine approximately 20-fold without altering supine or erect haemodynamics. Increases in plasma insulin, prolactin and glucagon were seen with both enantiomers. The stereopurity of arginine was confirmed in a cell-culture assay system. 4. We conclude that, in healthy subjects and patients with essential hypertension or insulin-dependent diabetes, synthesis of nitric oxide within the vasculature is not limited by substrate availability. At high concentrations of arginine, non-stereospecific effects, including alterations in hormone concentration, occur. It remains to be determined whether these non-stereospecific hormonal changes might contribute to certain haemodynamic effects of arginine.

Adult↗
PubMed1995

Effect of diadenosine phosphates on human umbilical vessels: novel platelet-derived vasoconstrictors.

The responses of human isolated umbilical artery to the novel platelet-derived mediators, diadenosine phosphates, P1,P5-di(adenosine-5')pentaphosphate (AP5A) and P1,P6-di(adenosine-5')hexaphosphate (AP6A) were studied in vitro. AP5A (1 nM-300 microM; n = 7) and AP6A (1 nM-30 microM; n = 5) produced transient concentration-dependent contractions. Responses to AP5A were unaffected by co-incubation with indomethacin (10 microM; n = 4), NGmonomethyl-L-arginine (L-NMMA; 300 microM; n = 4) and theophylline (1 microM; n = 5). These results demonstrate that diadenosine phosphates have constrictor effects on human blood vessels in vitro and are consistent with a role for these platelet-derived mediators in the regulation of blood vessel tone.

Arginine↗