Search PubMed⌕ Search

Biomedical subjects

P Vallance

Publications and source records attributed to P Vallance.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease.

Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (NOS 3) influence NO production (as assessed by the plasma levels of nitrogen oxides, NO(x)) in middle-aged men. We also determined whether plasma NO(x) or NOS 3 genotype predicted the risk of is chemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8.1 years of follow-up, and all IHD events were recorded. DNA samples were screened for 4 NOS 3 gene polymorphisms: -786 T/C, -922 A/G, 894 G/T (which predicts a Glu(298)-->Asp amino acid substitution in the mature protein), and a 27-bp tandem repeat in intron 4 (eNOS4a/4b). NO(x) was measured in plasma samples obtained on entry in 1121 participants from North Mymms and Chesterfield general practices, together with an additional 571 recruits selected at random. Genotype frequencies were in Hardy-Weinberg equilibrium, and linkage disequilibrium was detected between all the NOS 3 polymorphismsstudied, with the strongest allelic association being detected between -922 A/G and -786 T/C polymorphisms in the gene promoter (Delta=0.90, P<0.001). Plasma NO(x) was lower in smokers than in nonsmokers in the North Mymms (10.8+/-4.5 versus 11.8+/-4.6 micromol/L, P=0.13), Chesterfield (8.4+/-3.6 versus 9.9+/-4.0 micromol/L, P=0.01), and random samples (10.7+/-5.1 versus 11.7+/-4.7 micromol/L, P=0.03). A weak but significant inverse relationship was detected between plasma NO(x) and serum cholesterol only in the North Mymms data set (r=-0.14, P=0.02). No relationship was detected between plasma NO(x) and any of the NOS 3 polymorphisms, nor was there any association between any NOS 3 polymorphism and risk of an IHD event in either smokers or nonsmokers. These data support the hypothesis that the endothelial dysfunction observed in the blood vessels of smokers is related to reduced NO bioactivity but indicate that NOS 3 genotype does not influence significantly the level of plasma NO(x) or the risk of IHD in this population sample of middle-aged British men.

Blood Pressure↗
PubMed2001

Changes in endothelium-dependent vasodilatation and alpha-adrenergic responses in resistance vessels during the menstrual cycle in healthy women.

During the menstrual cycle, changes in endothelium-dependent vasodilatation have been demonstrated in conduit vessels in vivo, but responses in resistance vessels have not been studied. The aim of this study was to examine endothelium-dependent vasodilatation, the effects of local nitric oxide synthesis, and alpha-adrenergic constriction in resistance vessels during the menstrual cycle in 15 healthy female volunteers (mean age, 28.07 +/- 2.1 yr). Forearm blood flow in response to intrabrachial infusion of bradykinin (10, 30, and 100 pmol/min; endothelium-dependent vasodilator), glyceryl trinitrate (4, 8, and 16 nmol/min; endothelium-independent vasodilator), noradrenaline (60, 120, and 240 pmol/min; alpha-adrenergic receptor agonist), and N(G)-monomethyl-L-arginine (1, 2, and 4 micromol/min; nitric oxide synthase inhibitor) was assessed by venous occlusion plethysmography. All subjects were studied in early menstrual phase (days 1--4) and midcycle (days 10-13). Vasodilator response to bradykinin, expressed as the within-subject mean difference in the area under the dose-response curve between phases, was significantly increased at midcycle compared with that in the early menstrual phase (486.5 +/- 165.0; P = 0.01), whereas there was no significant difference in response to glyceryl trinitrate (185.8 +/- 239.0; P = 0.45). The vasoconstrictor response to noradrenaline was significantly greater at midcycle (97.1 +/- 39.4; P = 0.027), but the response to N(G)-monomethyl-L-arginine was not significantly different (17.5 +/- 35.2; P = 0.63). Serum estradiol was approximately 3-fold higher at midcycle, with a mean difference of 252.3 +/- 56.0 pmol/L (P = 0.0005). Progesterone concentrations were not significantly different (-0.11 +/- 0.1 nmol/L; P = 0.28). Differences in endogenous estrogen levels between menstrual phases may underlie changes in bradykinin and noradrenaline responses. If exogenous estrogens have similar effects, the balance of these two opposing actions may determine whether estrogen replacement in postmenopausal women has beneficial or harmful effects on the vasculature.

Adrenergic alpha-Agonists↗
PubMed2001

Nitric oxide.

Nitric oxide (NO)--a 1:1 combination of the two most abundant gaseous elements--is a biological mediator of complexity, subtlety and protean effects. The history of its discovery as a mediator is fascinating, and its role in mammalian biology and medicine is proving to be of fundamental importance.

Animals↗
PubMed2000

The effect of the nitric oxide donor glyceryl trinitrate on global and regional cerebral blood flow in man.

Despite their potential use as cerebral vasodilatory agents there are few studies of the effect of nitric oxide (NO) donors on the cerebral circulation in non-anaesthetised man. We determined the effect of the NO donor glyceryl trinitrate (GTN) at clinically relevant doses on global and regional cerebral blood flow (CBF) in healthy non-anaesthetised volunteers, using H(2)(15)O PET, ultrasonic colour velocity flow imaging of carotid artery flow, and transcranial Doppler (TCD) of middle cerebral artery velocities (MCAv). Three rates of GTN infusion (0.1, 0.4, 1.0 microg/kg/min) were used. There was no significant change in common or internal carotid artery flow following GTN administration although a dose dependent fall in MCAv post GTN was observed. There was no significant change in either global or regional CBF following GTN. Thus intravenous GTN at therapeutic doses in awake humans does not alter global or regional CBF. However it does produce basal cerebral artery vasodilatation as evidenced by a fall in MCAv in the absence of a change in internal carotid artery flow.

Adult↗
PubMed2000

Acute systemic inflammation impairs endothelium-dependent dilatation in humans.

BACKGROUND: We tested the hypothesis that endothelial dysfunction underlies the association between an acute inflammatory episode and the transiently increased risk of a cardiovascular event by examining the effects of an experimental inflammatory stimulus on endothelium-dependent vasodilation. METHODS AND RESULTS: Salmonella typhi vaccine was used to generate a systemic inflammatory response in healthy volunteers. In 12 subjects, dilatation of the brachial artery to flow and to sublingual nitroglycerin (NTG) was recorded (conduit vessel response), and in 6 subjects, venous occlusion plethysmography was used to measure forearm blood flow during intrabrachial infusion of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent dilators NTG and verapamil (resistance vessel response). Responses were assessed 16 hours before and 8 and 32 hours after vaccination. Vaccination resulted in elevations in white cell count and serum levels of interleukin-6 and interleukin-1 receptor antagonist. Eight hours after vaccination, resistance vessel responses to BK (P:=0.0099) and ACh (P:=0.0414) were markedly attenuated, and brachial artery flow-mediated dilatation was depressed. Resistance vessel responses to verapamil and NTG were unchanged, as was the conduit vessel response to NTG. Thirty-two hours after vaccination, resistance vessel responses to BK and ACh had returned to normal. CONCLUSIONS: S typhi vaccine generates a mild inflammatory reaction associated with temporary but profound dysfunction of the arterial endothelium in both resistance and conduit vessels to both physical and pharmacological dilator stimuli. This finding might explain the association between infection and inflammation and the enhanced risk of an acute cardiovascular event.

Acetylcholine↗
PubMed2000

Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins.

Endogenously produced asymmetrically methylated arginine residues are competitive inhibitors of all three isoforms of nitric oxide synthase (NOS). The enzyme dimethylarginine dimethylaminohydrolase (DDAH) specifically hydrolyzes these asymmetrically methylated arginine residues to citrulline and methylamines. Previously we have proposed that regulation of asymmetric methylarginine concentration by DDAH may provide a novel mechanism for the regulation of NOS activity in vivo. Recently we reported the cloning of human DDAH and identified a novel human DDAH isoform (DDAH I and DDAH II, respectively). Here we report that the DDAH1 gene maps to chromosome 1p22 and confirm that DDAH2 maps to the MHC III region of chromosome 6p21.3. Extensive analysis of the distribution of DDAH1 and DDAH2 mRNA in 50 human tissues indicates differential expression of DDAH isoforms in brain regions, in immune cells, and during development. DDAH2 expression predominates in highly vascularized tissues that express the endothelial NOS isoform and in immune tissues that can express iNOS. Whereas DDAH2 is expressed at relatively high levels in all fetal tissues examined, DDAH1 expression varies little between fetal and adult tissues. The chromosomal localization of the DDAHs is consistent with gene duplication, and consistent with this, comparison of the gene structures indicates that the intron/exon organization is highly conserved. Phylogenetic analysis of DDAH sequences from diverse species suggests that DDAH gene duplication occurred prior to the emergence of bony fish some 400 million years ago. Overall the data suggest that DDAH2 may be the more ancient of the two genes.

Amidohydrolases↗
PubMed2000

Herpesvirus infection accelerates atherosclerosis in the apolipoprotein E-deficient mouse.

BACKGROUND: Human herpesviruses have been implicated but not proven to be involved in the etiology of atherosclerosis. To determine whether there is a causal relationship, the effect of herpesvirus infection on the development of atherosclerosis was assessed in the apolipoprotein E-deficient (apoE-/-) mouse. METHODS AND RESULTS: In the present study, 3- to 4-week-old apoE-/- mice were infected with murine gamma-herpesvirus-68 (MHV-68). Atheroma formation was accelerated over a 24-week period in infected apoE-/- mice compared with control uninfected apoE-/- mice. Acceleration of atherosclerosis was reduced by antiviral drug administration. Histological analysis of the atheromatous plaques showed no difference between lesions of infected and control mice. Viral mRNA was present in the aortas of infected mice before lesion development on day 5 after infection. This suggests that the virus may initiate endothelial injury, which is believed to be an early event in the development of atherosclerosis. Therefore, the virus may play a direct role in atherosclerosis rather than be an "innocent bystander." CONCLUSIONS: These data demonstrate that a gamma-herpesvirus can accelerate atherosclerosis in the apoE-/- mouse. This study provides the first report of a murine model in which to study the causative role of herpesvirus infection in the development of atherosclerosis.

Animals↗
PubMed2000

Nitric oxide and vascular responses in Type I diabetes.

Vascular complications are major causes of morbidity and mortality in patients with diabetes mellitus. The mechanisms underlying the development of microvascular and macrovascular angiopathy in Type I (insulin-dependent) diabetes mellitus are complex and incompletely understood. The discovery of endothelium-derived nitric oxide has greatly improved our understanding of vascular biology. Nitric oxide has an important role in the regulation of vascular tone and impaired nitric oxide activity could be implicated in the development of diabetic vasculopathy. Vascular studies of endothelial function in Type I diabetes have produced conflicting results. The role of nitric oxide in diabetic vasculopathy is still not clear.

Animals↗
PubMed2000

Positive inotropic effects of NO donors in isolated guinea-pig and human cardiomyocytes independent of NO species and cyclic nucleotides.

OBJECTIVE: To characterise the inotropic response of isolated myocytes to a range of structurally unrelated NO donors and to assess the role of NO release kinetics, NO species and cyclic nucleotides in mediating the observed changes. METHOD: Guinea-pig (GP) and human myocytes were prepared by enzymatic digestion. Paced contractile amplitude was recorded at 37 degrees C. NO release was measured by reduction of oxyhaemoglobin and using an NO electrode. Cyclic nucleotides were measured using a tritium labelled competitive binding assay. RESULTS: The NO donors S-nitrosoglutathione (GSNO) and diethylamine/NO (DEA/NO) produced positive inotropic effects in GP myocytes at (10(-5) M) (25 and 111% increases of contraction amplitude). The response to GSNO was significantly enhanced in the presence of a low concentration of isoprenaline (3x10(-10) M). Positive inotropy was observed with a range of both thiol and non-thiol donors, amongst which a fast rate of NO release was associated with positive inotropy. The response to GSNO was abolished by the free NO scavenger oxyhaemoglobin, but not by ODQ (soluble guanylyl cyclase [sGC] inhibitor), Rp-cAMPS (protein kinase A inhibitor) or thapsigargin (sarcoplasmic reticulum Ca(2+) uptake blocker). Direct measurement of cyclic nucleotides showed a rise in cGMP but not cAMP. Human ventricular myocytes showed a significant increase of contraction with GSNO (48+/-15.8%, n=7, P<0. 05) in the presence of isoprenaline and a marked response to DEA/NO alone. CONCLUSIONS: Isolated GP and human myocytes show a positive inotropic effect with certain NO donors. This is independent of sGC and cAMP. The rate of NO release from donors appears important in mediating the effect.

Animals↗
PubMed2000

Impaired vascular sensitivity to nitric oxide in the coronary microvasculature after endotoxaemia.

1. The effects of endotoxaemia on coronary vasodilator responses to bradykinin (BK), sodium nitroprusside (SNP) and nicardipine were investigated in the rat isolated heart perfused at constant flow ex vivo. 2. Dose-dependent reductions in coronary perfusion pressure reaching a maximum of 56+/-3 and 57+/-5 mmHg were observed for BK and SNP respectively. The BK response was biphasic, consisting of a rapid dilator response that was insensitive to N(G)nitro-L-arginine methyl ester (L-NAME, 0.1 mM) and a second slower component whose duration was attenuated by L-NAME. 3. Hearts obtained from rats treated with endotoxin (2.5 mg kg(-1), i.p.) for 2 or 6 h had increased basal coronary perfusion pressure and reduced vasodilator responses to BK or SNP. Dilator responses to nicardipine were not affected by endotoxin treatment. In vitro perfusion of hearts from endotoxin-treated rats with L-NAME (0.1 mM) restored SNP responses to control values. 4. Treatment with dexamethasone (1 mg kg(-1)), 1 h before endotoxin did not alter the endotoxin-induced impairment of dilator responses to BK or SNP. 5. These results show that coronary microvascular responses are altered following endotoxin exposure. Endotoxin results in increased coronary microvascular tone despite induction of NO synthase and inhibits the dilator response to BK and SNP, vasodilators that act via the release of NO. Responses to SNP in endotoxin-treated hearts were restored to control values in the presence of L-NAME suggesting that enhanced endogenous NO synthesis might saturate guanylate cyclase resulting in reduced response to NO donors. The reduced response to vasodilators and increased coronary resistance might be important in determining the response of the coronary circulation to systemic inflammation and infection.

Animals↗
PubMed2000

Intracellular localization of dimethylarginine dimethylaminohydrolase overexpressed in an endothelial cell line.

Methylarginines are endogenous inhibitors of nitric oxide synthase (NOS) and have been implicated in the regulation of the nitric oxide pathway in health and disease. Cellular concentrations of free methylarginines are determined in part by the activity of dimethylarginine dimethylaminohydrolase (DDAH). There are two isoforms of DDAH which have distinct tissue distributions with some relationship to NOS isoforms. We have determined the intracellular localization of both DDAH isoforms by overexpression of epitope-tagged DDAH in an immortalized endothelial cell line. Immunofluorescence confocal microscopy and immunoblotting indicate that both isoforms are predominantly cytosolic with no specific association with organelles or the plasma membrane. These data suggest that the key role for DDAH may be to ensure that under normal conditions the levels of methylarginines are kept low throughout the whole cell.

Amidohydrolases↗
PubMed2000

Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans.

Cerebral blood flow is maintained constant over a range of cerebral perfusion pressures by cerebral autoregulation. Impaired cerebral autoregulation may be important in the pathogenesis of cerebral ischaemia. The mechanisms mediating normal cerebral autoregulation in humans are poorly understood. We used a recently described transcranial Doppler technique, which allows non-invasive measurement of dynamic cerebral autoregulation, to test the hypothesis that nitric oxide mediates cerebral autoregulation. The rate of rise of middle cerebral artery blood flow velocity, compared with that of arterial blood pressure, was determined following a stepwise fall in arterial blood pressure, in order to calculate an autoregulatory index. The effect of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on dynamic autoregulation was compared with that of noradrenaline titrated to result in a similar rise in blood pressure. Six healthy subjects were studied in each group. The mean (S.D.) change in autoregulatory index following noradrenaline at a similar pressor dose was significantly greater than the change following the L-NMMA bolus: 1. 1 (1.2) compared with -0.8 (0.8) for the left middle cerebral artery (P=0.002), and 1.1 (0.8) compared with -0.8 (0.8) for the right middle cerebral artery (P=0.002). There was no difference in the mean (S.D.) blood pressure increase resulting from the two agents: L-NMMA, 19.7 (7.4) mmHg; noradrenaline, 15.5 (4.8) mmHg (P=0.281). These results suggest that nitric oxide mediates at least part of the dynamic phase of cerebral autoregulation in humans. Reduced nitric oxide release may play a role in the impaired cerebral autoregulation seen in patients with, or at risk of, cerebral ischaemia.

Adult↗
PubMed1999

Biochemical characterization of S-nitrosohemoglobin. Mechanisms underlying synthesis, no release, and biological activity.

S-Nitrosohemoglobin (SNO-Hb) has been suggested to act as an endogenous NO donor and physiological regulator of blood pressure. However, the mechanisms responsible for the formation of SNO-Hb and those underlying the release of NO and subsequent biological activity have yet to be elucidated. In the present study, a number of nitrosated oxyhemoglobin (HbO(2)) derivatives have been synthesized and characterized. HbO(2) can be nitrosated at up to three distinct residues, one in the alpha-globin chain and two in the beta-chain. A beta-chain mononitrosated species (designated "SNO-Hb"), generated by the reaction of HbO(2) and S-nitrosoglutathione, released NO via a thiol-dependent mechanism involving nucleophilic attack at the nitrosated thiol functionality of SNO-Hb; in the case of glutathione, this process was associated with the formation of a mixed disulfide. In contrast, multinitrosated hemoglobin species released NO and relaxed vascular smooth muscle by a thiol-independent mechanism. HbO(2) scavenged potently NO released from SNO-Hb and inhibited its vasorelaxant properties. These data show that the predominant vasoactive species released from SNO-Hb is NO, with HNO a putative intermediate; the presence of a low molecular weight thiol is a prerequisite for this process. Such observations have important implications for the generation, metabolic fate, and biological activity of S-nitrosothiols.

2,3-Diphosphoglycerate↗
PubMed1999

Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases.

Methylarginines inhibit nitric oxide synthases (NOS). Cellular concentrations of methylarginines are determined in part by the activity of dimethylarginine dimethylaminohydrolase (DDAH; EC 3.5.3. 18). We have cloned human DDAH and identified and expressed a second novel DDAH isoform (DDAH I and II respectively). DDAH I predominates in tissues that express neuronal NOS. DDAH II predominates in tissues expressing endothelial NOS. These results strengthen the hypothesis that methylarginine concentration is actively regulated and identify molecular targets for the tissue and cell-specific regulation of methylarginine concentration.

Amidohydrolases↗