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Biomedical subjects

P Vallance

Publications and source records attributed to P Vallance.

At least 19 recordsLinked to original sources
PubMed1999

A simple computer program for guiding management of cardiovascular risk factors and prescribing.

OBJECTIVE: To describe, and to test against trial data, a simple and flexible computer program for calculating cardiovascular risk in individual patients as an aid to managing risk factors and prescribing drugs to lower cholesterol concentration and blood pressure. DESIGN: Descriptive comparison of actual cardiovascular risk in randomised controlled trials of cholesterol reduction with risk predicted by a computer program based on the Framingham risk equation. Comparison of the program's performance with that of tables and guidelines by means of hypothetical case examples. MAIN OUTCOME MEASURES: Average risk of coronary heart disease and myocardial infarction. RESULTS: The computer program accurately predicted baseline absolute risk in a UK population as well as the relative and absolute reduction in risk from cholesterol lowering for primary prevention of coronary heart disease. The program also allowed a more refined estimate of absolute risk of coronary heart disease than some existing tables and enabled the impact of prescribing decisions to be quantified and costed. CONCLUSIONS: This simple computer program to estimate individuals' cardiovascular disease risk and display the benefits of intervention should help clinicians and patients decide on the most effective packages of risk reduction and identify those most likely to benefit from modulation of risk factors.

Anticholesteremic Agents↗
PubMed1999

Effects of cytokines on nitric oxide pathways in human vasculature.

Proinflammatory cytokines exert a number of important effects on vascular reactivity. At one end of the spectrum, certain cytokines may induce vascular paresis leading to profound vasodilatation and hyporesponsiveness to constrictor stimuli. This may be relevant to the pathogenesis of septic shock and other types of inflammatory vasodilatation. At the other end of the spectrum, inflammatory cytokines can impair endothelium-dependent dilatation and the endothelium may lose its ability to respond to circulating hormones or autacoids. This effect may case a predisposition to vessel spasm, thrombosis or atherogenesis. Studies in human vessels suggest that interleukin-1 is particularly important as a mediator of inflammatory dilatation; the underlying mechanisms include induction of the inducible isoform of nitric oxide synthase in vascular smooth muscle, or over-production of nitric oxide from the endothelial isoform of nitric oxide synthase. Induction of the enzyme GTP cyclohydrolase 1 and consequent production of tetrahydrobiopterin contributes to the increase in the activity of endothelial nitric oxide synthase. In contrast, tumour necrosis factor-alpha considerably impairs endothelium-dependent relaxation. The mechanisms of these effects are not yet fully understood, but tumour necrosis factor can induce endothelial dysfunction in human endothelial cells in culture, and human blood vessels in vitro and in vivo. The implications of these observations for cardiovascular disease are discussed.

Animals↗
PubMed1998

Endothelium-dependent sensory NANC vasodilatation: involvement of ATP, CGRP and a possible NO store.

1 Non-adrenergic non-cholinergic (NANC) vasodilator nerves regulate tone in certain vascular beds. We have investigated the mechanisms of the NANC dilator response in the isolated small mesenteric artery of the rabbit by use of the tension myograph. 2 Small second or third order (150-300 microm in diameter) arteries of the rabbit mesenteric bed were mounted in a Mulvany tension myograph. Responses to electrical field stimulation (EFS) and exogenous vasodilators were investigated. 3 EFS (0.5-16 Hz, 10 V, 0.3 ms for 5 s), in the presence of guanethidine (5 microM) and atropine (1 microM) produced frequency-dependent relaxation of small arteries. Pretreatment with tetrodotoxin (1 microM) abolished the relaxation and desensitization with capsaicin (10 microM) strongly inhibited the relaxation. 4 Pretreatment with a P2Y-purinoceptor antagonist, basilen blue (3 microM) or a human calcitonin gene-related peptide (hCGRP) receptor antagonist, hCGRP8-37 (1 microM) suppressed the NANC relaxation by approximately 40-60 % in each case and combined pretreatment almost abolished the relaxation. 5 The EFS-induced relaxation was suppressed by endothelium-removal, pretreatment with the soluble guanylyl cyclase inhibitor ODQ (1 microM) and the NO scavenger oxyhaemoglobin (OxyHb; 20 microM) but not by NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME; 300 microM) or NG-nitro-L-arginine (L-NOARG; 300 microM). Combined pretreatment with ODQ and CGRP8-37 almost abolished the relaxation. 6 A P2Y-purinoceptor agonist, 2-methylthio ATP, produced endothelium-dependent relaxation which was inhibited by L-NAME and ODQ (1 microM), whilst hCGRP produced endothelium-independent and ODQ-insensitive relaxation. 7 Ultraviolet light (320 nm, 5 shots over 20 s) produced relaxation that was blocked by both OxyHb and ODQ but not by NG-monomethyl-L-arginine (L-NMMA, 300 microM). 8 The present study suggests that EFS-induced NANC relaxation of the mesenteric small artery of the rabbit is mediated mainly by capsaicin-sensitive sensory C-fibres and that both ATP and CGRP are involved. The action of ATP released by EFS appears to be endothelium-dependent and involve activation of soluble guanylyl cyclase, but is resistant to inhibitors of NO synthase. The response to CGRP is endothelium-independent. These results show that ATP and CGRP account fully for the NANC relaxation of this vessel type and that the endothelium is involved in NANC-induced relaxation. The endothelium-dependent part of the response is consistent with the release of NO, either from NO synthase, incompletely inhibited by the NO synthase inhibitors, or by some preformed stores.

Adenosine Triphosphate↗
PubMed1998

Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hypercapnia.

BACKGROUND AND PURPOSE: Animal studies suggest that nitric oxide (NO) is important in basal cerebral blood flow (CBF) regulation and that it may mediate the vasodilatory response to carbon dioxide. We investigated its role in the human circulation using the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). METHODS: L-NMMA was administered as an intravenous bolus at three doses (1, 3, and 10 mg/kg). CBF was assessed by color velocity ultrasonic imaging of internal and common carotid artery volume flow (ICA flow and CCA flow) and transcranial Doppler ultrasound measurement of middle cerebral artery flow velocity (MCAv). The pressor effect of L-NMMA was controlled for by comparison with noradrenaline titrated to effect an equivalent blood pressure elevation. RESULTS: L-NMMA produced a dose-dependent reduction in basal mean+/-SD CCA flow from 415.2+/-51.9 to 294+/-56.2 mL/min (at 10 mg/kg) and ICA flow from 268.8+/-59.4 to 226.2+/-72.6 mL/min (P<.005 and P<.05, respectively, comparing areas under the dose-response curve). This was reversed by L-arginine. Mean+/-SD systemic blood pressure rose from 85.2+/-6.4 to 100.8+/-9.6 mm Hg (P<.01). There was no significant reduction in MCAv. There was no significant change in the CBF response to either 6% or 8% carbon dioxide after L-NMMA. Noradrenaline produced a lesser fall in basal CCA flow (12.0%) but had a similar effect on the hypercapnic response. CONCLUSIONS: Basal NO release is important in controlling human CBF, but intravenously administered L-NMMA does not inhibit the hypercapnic hyperemic response in humans. The discrepancy between CBF and MCAv after L-NMMA administration is consistent with MCA vasoconstriction. Neuronal NO synthase inhibition may be protective in stroke. However, our results suggest that nonselective NO synthase inhibitors such as L-NMMA should be used with caution because they reduce CBF.

Adult↗
PubMed1997

Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo.

BACKGROUND: Endothelial dysfunction occurs in many diseases associated with increased cardiovascular risk. We examined the effects of pro-inflammatory cytokines on endothelial function. METHODS AND RESULTS: Subjects lay with one hand placed on an angled support. The diameter of a vein was recorded by measuring the linear displacement of a probe placed on the skin overlying the vein when the pressure in a congesting cuff placed around the upper arm was deflated from 40 to 0 mm Hg. A length of the vein was isolated by two wedges. TNF-alpha (1 ng), IL-1beta (1 ng), or IL-6 (100 pg) were instilled for 1 hour, either individually or together. At the end of the hour, the wedges were removed and the vein reconnected with the circulation. Dose-response curves (bradykinin: 2, 4, and 8 pmol/min; arachidonic acid: 0.2, 2, and 20 nmol/min; and glyceryl trinitrate 1, 2, and 4 pmol/min) were constructed before and 1, 6, 24, and 48 hours after instillation. In another study, hydrocortisone (100 mg) was given 2 hours before the study. In a different study, subjects were given oral aspirin (75 mg or 1 g) 2 hours before the study. TNF-alpha and IL-1beta alone but not IL-6 attenuated the dilatation to bradykinin and arachidonic acid; the response was greatest at 1 hour with recovery occurring by 6 hours. Combination of IL-1beta and TNF-alpha prolonged the endothelial dysfunction, resulting in recovery at 24 hours. Hydrocortisone and high-dose aspirin prevented endothelial dysfunction. CONCLUSIONS: The results demonstrate that pro-inflammatory cytokines induce transient and reversible endothelial dysfunction and indicate that cyclooxygenase activity may contribute to the genesis of the effect. If other vessels behave similarly, this may provide further insight into the mechanisms precipitating acute cardiovascular events after inflammatory disorders.

Adult↗
PubMed1997

Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney.

NG-monomethylarginine (L-NMA) and asymmetric NG, NG-dimethylarginines (ADMA) are endogenous inhibitors of cellular L-arginine uptake and/or nitric oxide (NO) synthesis that are implicated in renal parenchymal and Dahl salt-sensitive hypertension. Since the L-arginine:(L-NMA + ADMA) ratio determines NO synthase (NOS) activity, we compared the immunohistochemical distribution of NOS with NG, NG-dimethylarginine dimethylaminohydrolase (DDAH), which inactivates dimethylarginines (DMA) and L-NMA by hydrolysis to L-citrulline. Neuronal NOS (nNOS) was expressed predominantly in tubular epithelial cells of macula densa (MD), endothelial NOS (eNOS) in vascular endothelial cells (EC), and inducible NOS (iNOS) quite widely in tubular epithelium, including proximal tubules (PT), thick ascending limbs of Henle (TAL), distal convoluted tubule and intercalated cells (IC) of the collecting duct. Immunostaining for DDAH was present in PT, TAL, MD, and IC, and was also present in the glomerulus, Bowman's capsule, and endothelium of blood vessels. DDAH was detected in small vesicles of TAL and PT by electron microscopic (EM) immunocytochemistry. To study the effects of methylarginines on tubuloglomerular feedback (TGF) response, vehicle or methylarginines (10(-3) M) were added to artificial tubular fluid (ATF) perfused orthogradely from the late PT at 40 nl. min-1 while assessing changes in glomerular capillary pressure from proximal stop flow pressure (PSF). Whereas the maximal TGF responses were unchanged by vehicle (delta TGF 0 +/- 0%) or symmetric DMA (SDMA; +1 +/- 2%, NS), they were enhanced by L-NMA (+22 +/- 4%, P < 0.001) and asymmetric DMA (ADMA; +28 +/- 3%, P < 0.001). Since L-arginine transport can regulate renal epithelial NO generation, methylarginines (10(-3) M) or vehicle were co-perfused orthogradely with [3H]-L-arginine from the late PT and collected at the early distal tubule to study arginine uptake from the perfused loop of Henle. All methylarginines reduced fractional loop [3H] absorption significantly (P < 0.001; vehicle, 84 +/- 6; ADMA, 49 +/- 6; SDMA, 56 +/- 6; L-NMA, 41 +/- 6%). In conclusion, sites of DDAH expression in the vasculature or nephron are all sites of expression of an isoform of NOS. L-NMA, ADMA, and SDMA all inhibit renal tubular L-arginine uptake, whereas L-NMA and ADMA, but not SDMA, enhance TGF responses. Therefore, DDAH may regulate the cellular L-arginine: methylarginine levels in specific renal cells, thereby governing cell-specific L-arginine uptake and NO generation in renal tubular epithelium.

Amidohydrolases↗
PubMed1997

Dose- and time-dependency of the dilator effects of the endothelin antagonist, BQ-123, in the human forearm.

AIMS: Endothelin-1 is a potent endogenous vasoconstrictor that acts on the endothelin A (ET[A]) receptor. The dose-response and time-course of the dilator effect of the ET(A) receptor antagonist, BQ-123, was investigated in the forearm of healthy volunteers. METHODS: Forearm blood flow was measured using mercury-in rubber strain gauge venous occlusion plethysmography. RESULTS: Following intra-arterial infusion of BQ-123 (50 nmol min-1) for 5 min, forearm blood flow increased by approximately 60% over the next 60 minutes; lower doses were without significant effect. The degree of dilatation was similar to that observed in previous studies using 20-fold larger doses. CONCLUSIONS: This study confirms that basal endothelin-1 has a role in the physiological regulation of vascular tone. It is possible that at low doses, BQ-123 might be a more sensitive pharmacological tool for the detection of abnormal endothelin-1 mediated constriction.

Adult↗
PubMed1997

Flow associated or flow mediated dilatation? More than just semantics.

Dilatation of the brachial artery occurs after flow is increased, and an attenuation in this response is seen in subjects with cardiovascular risk factors, and in those with established coronary artery disease. The mechanisms linking ischaemia, flow changes, and brachial artery dilatation are unclear, and it is not known how these are affected by arterial disease. For the present it might be more appropriate to refer to flow associated rather than flow mediated dilatation, to describe the phenomenon in the brachial artery. Despite these caveats, the non-invasive measurement of brachial artery following ischaemic dilatation represents a significant advance, and its suitability as a surrogate marker for coronary artery dysfunction appears promising. The technique has potential as a tool for screening those at high risk of vascular disease, and as a surrogate endpoint in intervention studies. Further research should clarify the mechanisms involved, and lead to greater insights into the nature of endothelial dysfunction and cardiovascular disease.

Brachial Artery↗