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Biomedical subjects

D P Nicholls

Publications and source records attributed to D P Nicholls.

At least 19 recordsLinked to original sources
PubMed2000

Exhaled nitric oxide during incremental and constant workload exercise in chronic cardiac failure.

BACKGROUND: Nitric oxide (NO) is present in exhaled breath and produced by the pulmonary vascular endothelium as a potent vasodilator. Exercise is normally associated with pulmonary vasodilatation and a decrease in pulmonary vascular resistance to accommodate the increase in cardiac output. If production of NO is impaired in patients with chronic congestive cardiac failure (CCF), this might contribute to their exercise intolerance. PATIENTS AND METHODS: We quantified NO production (V NO) in 12 patients with chronic stable CCF and 12 controls, at rest and during incremental cardiopulmonary exercise on a treadmill, and at a later date during constant workload exercise. RESULTS: Patients had reduced V NO compared with controls during incremental exercise [381 (180) vs. 777 (275) nL min-1; mean (SD); P < 0.0001] but at constant workload V NO was similar between the two groups [353 (124) vs. 389 (189) nL min-1; P = 0.25]. Plasma levels of nitrate, the stable end-product of NO production, were significantly higher in patients [resting value 46.1 (21.6) vs. 23.0 (10.0) microM; P = 0.004] and were not influenced by exercise. CONCLUSION: Impaired NO-mediated pulmonary vasodilatation does not appear to contribute to exercise limitation in CCF. Alternatively, the lower NO production observed during maximal exercise in the patient group compared with controls may reflect a reduced incremental response of a system that is already abnormally activated in heart failure.

Aged↗
PubMed2000

Is the secretion of atrial natriuretic peptide in man under neural control?

AIMS: Previous work has described short-term variation in the circulating plasma level of atrial natriuretic peptide (ANP), but the mechanism remains unknown. Our aim was to investigate the role of cardiac innervation in this variability. METHODS AND RESULTS: Blood samples were obtained from the right atrium via a pulmonary artery flotation catheter every 2 min over a 90 min period. Seven patients who underwent cardiac transplantation by the standard biatrial technique (partial innervation) and ten patients who underwent transplantation by the bicaval technique (total denervation) were studied. ANP levels were measured by radioimmunoassay. The median ANP levels were somewhat higher in the biatrial group compared to the bicaval group [470 (150-1095) vs. 216 (100-605) pg. ml(-1); median (range); P = ns], and both were much higher than normal levels in the pulmonary artery (40 (24, 56) pg ml(-1); median and interquartile range). In both transplant groups circulating plasma ANP levels showed considerable variability. The median number of 'peaks' and 'troughs', as counted by visual inspection, were not significantly different between the two groups. Computer analysis identified 12-16 and 6-15 'pulses' in the biatrial and bicaval group, respectively. Further analysis revealed that pulse amplitude, height and area were significantly higher in the biatrial compared to the bicaval group. CONCLUSION: It would appear that variability of circulating plasma levels of ANP is preserved despite complete or partial cardiac denervation, and so a neural mechanism does not appear to account for such variation.

Adult↗
PubMed2000

Comparative physiological study of arbutamine with exercise in humans.

Pharmacological stress testing may be used in the diagnosis of coronary artery disease when there are contra-indications to the use of conventional exercise protocols. The responses to such testing using arbutamine and to conventional treadmill exercise were compared in eight patients. Respiratory gas analysis and cardiovascular observations were performed during both tests. For an equivalent increment in heart rate, both protocols increased systolic blood pressure and serum lactate. Minute ventilation and oxygen consumption also rose during both protocols, but much more so with exercise. The end-tidal partial pressure of CO(2) [35.1 (S.D. 3. 1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (V(D)/V(T)) [0.37 (0.09) to 0.33 (0.08)] fell significantly during arbutamine infusion, but the respiratory exchange ratio did not change during either protocol. Oxygen pulse, a marker of stroke volume, did not change significantly after arbutamine, but rose markedly after exercise [arbutamine, 3.9 (1.1) to 3.37 (0.7) ml. min(-1).beat(-1); exercise, 4.7 (1.4) to 16.1 (4.6) ml.min(-1). beat(-1) (P<0.0001 compared with baseline); difference between peak responses: P<0.0001]. We conclude that arbutamine simulates some of the physiological responses to exercise, although a number of these responses are less marked than during conventional exercise, in particular cardiac output (oxygen pulse). An increase in ventilation is produced, possibly due to direct stimulation of arterial chemoreceptors. These data suggest that the main action of arbutamine is to increase central drive rather than to establish peripheral demand.

Adrenergic beta-Agonists↗
PubMed1999

HDL composition and HDL antioxidant capacity in patients on regular haemodialysis.

Recent evidence suggests that HDL can directly inhibit LDL oxidation, a key early stage in atherogenesis. Patients with chronic renal failure are at increased cardiovascular risk, have reduced HDL levels and altered HDL composition. We have therefore investigated whether compositional changes in HDL lead to decreased HDL antioxidant capacity in these patients. In comparison to control subject HDL, patient HDL contained less total cholesterol, cholesterol esters, phospholipids and alpha-tocopherol. LDL, HDL and LDL + HDL were standardised for protein and oxidised in the presence of Cu2+. The rate of propagation during HDL oxidation was reduced in the patient group (3.28+/-0.65 x 10(-5) vs. 4.60+/-0.97 x 10(-5) abs. U/min, P < 0.01). Lipid peroxide generation in patient HDL was decreased: 6.56+4.4 versus 13.42+/-7.0 nmol malondialdehyde (MDA)/mg HDL protein after 90 min and 14.45+/-3.8 versus 20.11+/-7.8 nmol MDA/mg HDL protein after 180 min. This is attributable to reduced HDL polyunsaturated fatty acid content in patients (0.53+/-0.12 vs. 0.72+/-0.16 mmol/g HDL, P < 0.01). The inhibitory effect of HDL on LDL oxidation was similar: 71 and 33% for patient HDL compared to 68 and 31% for control HDL, after 90 and 180 min, respectively. Compositional changes of HDL in patients on haemodialysis did not affect the antioxidant capacity of HDL after standardisation for HDL protein. However, reduced HDL levels in vivo may result in reduced HDL antioxidant capacity in these patients.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1999

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia.

The aim of this study was to develop a mutation screening protocol for familial hypercholesterolaemia (FH) patients and to assess genotype/phenotype effects in terms of pre-treatment lipid profiles and presentation of tendon xanthomata (TX). A total of 158 families with clinical definitions of possible (120) or definite (38) FH were studied using a tiered screening protocol. Mutations were identified in 52 families, 44 families showing 23 different LDLR gene defects and eight families showing the common Apo B100 gene defect R3500Q. LDLR defects were detected in various regions of the gene with 56% in the LDL binding domain (exons 2-6) and 37% in the EGF precursor homology domain (exons 7-14). The most common mutations were D461N(7), C210X(5), 932delA(5), and C163Y(4). Frameshift mutations accounted for 20% with nonsense 13%, mis-sense 35%, splice 3%, Apo B 13% and 2% large deletion, 13% of clinically definite FH remained undefined. In conclusion, DNA based diagnosis is possible in 79% (30/38) of clinically definite FH families and of the 120 possible FH families at the start of the screening program, 18% (22/120) now have defined mutations. Overall 60 families from the original 158 meet the clinical and/or genetic criteria for definite FH. Tendon xanthomata were present in only 58% (30/52) of genetically defined FH families, thus limiting its use as a strict diagnostic criteria. Families with low density lipoprotein receptor (LDLR) defects present with higher total and LDL cholesterol levels and a higher incidence of TX than do those with the common Apo B variant, and frameshift mutations appear to have the most severe presentation.

Electrophoresis, Agar Gel↗
PubMed1999

Calcitonin gene-related peptide, neuropeptide Y and atrial natriuretic peptide distribution in guinea pig heart from paraffin wax-embedded and formalin-cryoprotected tissues.

In this study, the distributions of calcitonin gene-related peptide, neuropeptide Y, and alpha-atrial natriuretic peptide 1-28 immunoreactivity, were investigated within different regions of the guinea pig heart by utilising two different methods of tissue fixation for the immunocytochemistry. The results were compared with data obtained through radioimmunoassays. We observed similar concentrations and distributions of alpha-atrial natriuretic peptide in the right atrium, with results of radioimmunoassay and immunocytochemistry, but there were no myocytes containing alpha-atrial natriuretic peptide in the left atrium or ventricles with immunocytochemistry as opposed to radioimmunoassay. The immunoreaction obtained for neuropeptide Y was more intense in the right ventricle than left. Calcitonin gene-related peptide nerve fibres were about twice as abundant in the left atrium than in the right.

Animals↗
PubMed1999

Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients.

BACKGROUND: Paraoxonase (PON1) gene variants have been identified as risk factors for cardiovascular disease (CVD). There are two common PON1 polymorphisms at position 55 (Leu-Met change) and 192 (Gln-Arg change) of the amino acid chain. Leucine at position 55 and arginine at position 192 have been associated with increased cardiovascular risk. The increased prevalence of CVD in renal transplant recipients can be only partly explained by the increased prevalence of conventional risk factors. METHODS: We therefore investigated PON1 polymorphisms in renal transplant recipients (N = 491) with (N = 103) and without CVD (N = 388) using polymerase chain reaction-restriction fragment length analysis. PON1 polymorphisms and their associated PON1/arylesterase activities were also assessed in a subgroup of patients (N = 165). RESULTS: The genotype distribution and allele frequencies for both polymorphisms were similar in both groups. The frequencies for LL, LM, and MM genotypes for the 55 position in patients with CVD were 0.39, 0.51, and 0.10, respectively, compared with 0.43, 0.43, and 0.14 in patients without CVD (P = 0.31). The distribution for the QQ, QR, and RR genotypes at the 192 position were 0.48, 0.43, and 0.09, respectively, in patients with CVD compared with 0.46, 0.46, and 0.08 in patients without CVD (P = 0.8). There were highly significant differences in serum activities of PON1/arylesterase between genotypes defined by 55 and 192 polymorphisms. Leucine at position 55 and arginine at position 192 were associated with higher activities. CONCLUSION: These data indicate that there is no association between the PON1 gene variants, conferring higher enzyme activity, and the increased cardiovascular risk in renal transplant recipients.

Adult↗
PubMed1999

Regulatory peptides in the heart and major vessels of man and mammals.

Studies on the distribution of peptides in human tissues have been made either by measuring responses to localized stimuli or by subjecting extracts of different regions to radioimmunoassay (RIA). Attempts at isolating regulatory peptides from the mammalian tissues have resulted in the isolation of many bioactive fragments. Later, modification of initial isolation methods led to the identification of the native molecules in various tissues and body fluids. The present study examined atrial natriuretic peptide (ANP) and several other peptides in cardiac tissues of several species of laboratory mammal and human beings; using a sensitive and highly specific radioimmunoassays. In all the species studied, ANP-like immunoreactivity appeared to be highest in the heart tissue of rat. The peptide was highest in the right atrium (RA) of rat and lowest in the RA of guinea pig (P< 0.002). Neuropeptide Y (NPY) another abundant cardiac peptide was present in the cardiac tissues of all species but was more in the left atrium (LA) than the RA of all species (P<0.05). Calcitonin gene-related peptide (CGRP) was present throughout the cardiovascular system of the rat and guinea pig. Small but detectable amount of Neurotensin (NT) immunoreactivity was found in the rat but was consistently negative in the guinea pig cardiac tissues (P< 0.05). Substance P (SP) immunoreactivity was detected in the rat and higher quantities being in the Aorta but no trace of the peptide was detected in the left ventricle, aorta nor the pulmonary vein of post mortem human. Though the structure of most of the species studied has been elucidated, the primary structure of guinea pig ANP has not been fully generated. Thus the data obtained may suggest that in keeping with these mammalian peptides, the primary structures may be variant. With most of the peptides studied (e.g. ANP, Neuropepdide Y), immunoreactivity occurs predominantly in the atrial tissues, but is also present in vessels outside the heart, a finding which may be of functional significance.

Animals↗
PubMed1999

Distributions of VIP, substance P, neurokinin A and neurotensin in rat heart: an immunocytochemical study.

Vasoactive intestinal peptide (VIP) is a peptide amide containing 28 amino acids which was first isolated from the intestine and is distributed over the entire body but primarily in the nervous system. It is released in response to the electrical stimulation of nerve fibres, stimulation of the vagus, prostaglandin E1, oxytocin, operation stress, corticosterone. In the cardiovascular system, VIP has a vasodilation, hypotension, positive chronotropic and inotropic effects.

Animals↗
PubMed1999

Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer.

BACKGROUND: Resection is the treatment of choice for lung cancer, but may cause impaired cardiopulmonary function with an adverse effect on quality of life. Few studies have considered the effects of thoracotomy alone on lung function, and whether the operation itself can impair subsequent exercise capacity. METHODS: Patients being considered for lung resection (n = 106) underwent full static and dynamic pulmonary function testing which was repeated 3-6 months after surgery (n = 53). RESULTS: Thoracotomy alone (n = 13) produced a reduction in forced expiratory volume in one second (FEV1; mean (SE) 2.10 (0.16) versus 1.87 (0.15) l; p<0.05). Wedge resection (n = 13) produced a non-significant reduction in total lung capacity (TLC) only. Lobectomy (n = 14) reduced forced vital capacity (FVC), TLC, and carbon monoxide transfer factor but exercise capacity was unchanged. Only pneumonectomy (n = 13) reduced exercise capacity by 28% (PVO2 23.9 (1.5) versus 17.2 (1.7) ml/min/kg; difference (95% CI) 6.72 (3.15 to 10.28); p<0.01) and three patients changed from a cardiac limitation to exercise before pneumonectomy to pulmonary limitation afterwards. CONCLUSIONS: Neither thoracotomy alone nor limited lung resection has a significant effect on exercise capacity. Only pneumonectomy is associated with impaired exercise performance, and then perhaps not as much as might be expected.

Exercise Test↗
PubMed1999

Lipid metabolism.

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Alcohol Drinking↗
PubMed1998

Extraction of human alpha atrial natriuretic peptide and its physiological validation.

A very sensitive and specific radioimmunoassay for human alpha atrial natriuretic peptide (hANP) and a novel extraction method for hANP, have been developed. Antiserum to hANP showed no cross-reactivity with related analogues (e.g., brain natriuretic peptide). The radioimmunoassay can detect 1.2 fmol ANP/assay tube. Using a commercially available tracer, the antiserum binds 0.7 fmol of radioligand at a final dilution of 1:96,000. Production of ANP tracer, using 125I, Iodogen and reversed-phase HPLC separation, produces two products. The first has identical properties to the commercial reagent resulting in an identical antibody titre. The second, however, is more reactive with the antiserum which can be employed at a final dilution of 1:192K. These products represent oxidised and reduced peptides, respectively, inferring that the commercial tracer is oxidised. The recovery of synthetic hANP from plasma over the range of 0-1000 ng/l through Sep-Pak C18 cartridges, using an extraction method of acetic acid-acetonitrile (4:96) was 89%. Inter- and intra-assay coefficients of variation were 9.5% and 8.2%, respectively. The radioimmunoassay was validated in man by measuring plasma ANP (ng/l) following change of posture and exercise in normal man. Plasma ANP rose from 13.2 (1.0; S.D.) to 20.1 (1.6) from supine to sitting position. Plasma ANP increased to 20.1 (1.6) at rest (sitting) to 34 (2.7) ng/l at peak of exercise, but decreased from 31.2 (2.5) to 21.4 (0.1) ng/l at 3 and 6 min after exercise, respectively. These results confirm that the assay is capable of differentiating changes of concentrations within the physiological range.

Animals↗
PubMed1998

Buccal absorption of enalapril and lisinopril.

OBJECTIVE: The buccal absorption of captopril does not exhibit the classical pH/partition hypothesis, suggesting that mechanisms other than passive diffusion are involved in its absorption; animal studies have suggested that a peptide carrier-mediated transport system may be responsible for its absorption. The present study evaluated the effects of pH on octanol partitioning, and on the buccal absorption of enalapril and lisinopril, using in vitro techniques and buccal partitioning in human volunteer subjects. METHODS: The partitioning of enalapril and lisinopril into n-octanol was examined over the pH range of 3 9 at room temperature. RESULTS: Enalapril exhibited maximal partitioning into the organic phase at pH 4 5; minimal partitioning was recorded at pH values 8 and 9. The partitioning of lisinopril into n-octanol was found to be maximal at pH 9 and minimal at pH 3. Using the buccal absorption technique, the partitioning of enalapril and lisinopril (0.5 mg), was examined in six healthy male volunteers from buffered solutions (pH 3, 4, 5, 6, 7, 8 and 9). In the case of enalapril, lowest buccal partitioning occurred at pH 3, 8 and 9, while maximal partitioning occurred at pH 5; absorption of lisinopril was not extensive at any pH, but was greatest at pH 6. These results, in addition to the n-octanol partition coefficients, indicated that enalapril obeyed the normal lipid partition hypothesis with respect to buccal absorption. The buccal absorption of lisinopril also obeyed the lipid partition hypothesis over the pH range 3-7. These findings are in direct contrast to those for captopril. The buccal partitioning experiments were repeated at the maximal pH for absorption for each angiotensin converting enzyme (ACE) inhibitor, but with the addition of cephradine (0.05 mmol x l(-1)). CONCLUSION: The data indicated that the presence of this peptide transport inhibitor had no effect on the buccal absorption of enalapril (0.06 mmol x l(-1)) and lisinopril (0.057 mmol x l(-1)), which suggests that both drugs do not share a common buccal absorption pathway with cephradine.

Administration, Buccal↗
PubMed1998

Neuropeptide secretion in exercise.

Plasma concentrations of atrial natriuretic peptide immunoreactivity (irANP) and brain natriuretic peptide immunoreactivity (irBNP) in elderly normal subjects (mean age 71.1, range 66-81 years, n = 10) were examined before (rest), during (peak of exercise) and after (3 min, 6 min) a treadmill exercise test (modified Bruce protocol). An attempt was also made to determine the effect of steady state exercise (30% and 50%) and posture (supine, sitting) on circulating levels of atrial natriuretic peptide and calcitonin gene-related peptide (CGRP) in man. The results suggest that exercise gives rise to increased levels of irANP and irCGRP, but not human BNP. The study also demonstrated a >40% rise in irCGRP and irANP levels at 50% steady state exercise compared with 30% steady state exercise. irCGRP was shown to decline in the upright position compared with the supine position, and irCGRP did not rise with exercise. Although ANP is normally stored in large concentration in the atria with much less in the ventricles and BNP is derived to a much greater extent from the ventricles, the differential release rate of these peptides may make BNP concentration a more sensitive indicator of left ventricular dysfunction than ANP. The observations obtained here also raise the possibility that the ANP system may not only help to eliminate intermittent overhydration, but also participate in the postural regulation of diuresis and natriuresis and perhaps even support the maintenance of excretory kidney function in the ageing subjects.

Adult↗
PubMed1998

Body composition and energy expenditure of patients with chronic cardiac failure.

BACKGROUND: Patients with acute cardiac failure have excess body water, and it is commonly assumed that this is also so in patients with stable chronic cardiac failure (CCF). METHODS: To investigate this, we measured total body water (TBW) using stable isotope dilution and single-frequency bioelectrical impedance (BIA), and also extracellular volume (ECV) using bromide dilution in 12 patients with CCF and eight matched control subjects. RESULTS: TBW [kg(-1) bodyweight] was similar in the two groups [median 18O dilution 53.2% (range 46.5-57.1%) in patients vs. 54.8% (47.9-62.7) in control subjects; BIA 56.6% (42.7-73.1) vs. 58.0% (52.0-68.6)]. ECV was also similar in the two groups [0.25 Lkg(-1) (0.20-0.29) vs. 0.25 (0.19-0.35)]. There was a strong correlation between stable isotope and BIA measurements of TBW for all subjects (r = 0.76), but BIA overestimated TBW by a mean difference of 2.4 kg (limits of agreement of -4.1 kg to +8.9 kg). Body fat content was similar in the two groups, whether measured by skinfold anthropometry, whole-body densitometry or by 18O dilution. Resting energy expenditure (REE), calculated from indirect calorimetry, and total energy expenditure (TEE), calculated from the ratio of 2H to 18O elimination rate after drinking doubly labelled water, were also similar in the two groups. CONCLUSION: It is concluded that the patients with stable CCF in this study had normal ECV and TBW, and so excess body water did not account for their persistent symptoms.

Aged↗
PubMed1998

Abnormal vascular responses in human chronic cardiac failure are both endothelium dependent and endothelium independent.

OBJECTIVE: To study underlying vascular responses in chronic heart failure in patients without ACE inhibitor treatment, and to compare them with age matched controls. DESIGN: Forearm blood flow was studied using venous occlusion plethysmography in patients with chronic heart failure (n = 12) and matched controls (n = 13), after infusion of L-NMMA (a nitric oxide synthase inhibitor), glyceryl trinitrate (an endothelium independent vasodilator), and serotonin (an endothelium dependent vasodilator). RESULTS: L-NMMA produced significant vasoconstriction in normal subjects (forearm blood flow reduced by 24%), but not in patients (6%; difference between groups p < 0.03). The vasodilator responses to glyceryl trinitrate were impaired in patients (p < 0.02). In normal controls, serotonin produced initial dilatation, followed by vasoconstriction at high doses. In patients, no vasodilator responses were observed, only late vasoconstriction (p < 0.03). CONCLUSIONS: The vascular responses of patients are confirmed as being abnormal. The lack of response to L-NMMA suggests that nitric oxide does not contribute to basal vascular tone in patients with chronic heart failure. The responses to glyceryl trinitrate and to serotonin suggest that there is both smooth muscle and endothelial dysfunction in patients with chronic heart failure.

Aged↗
PubMed1998

Distribution of calcitonin gene-related peptide, atrial natriuretic peptide and neuropeptide Y in the rat heart.

Calcitonin gene-related peptide (CGRP) is a novel neuropeptide, predicted on the basis of structural analysis of the rat calcitonin gene. It is a neurotransmitter which has been suggested to take part in sensory transmission. In this study, we have examined the distribution of this peptide, alpha-atrial natriuretic peptide immunoreactivity (irANP) and neuropeptide Y (NPY) within different regions of the rat heart. Attempts were also made to compare the distributions of these peptides in the regions examined, through different methods of immunocytochemistry and further comparing these results with those obtained through radioimmunoassay. The distributions of the peptides in the atria were similar to results obtained with radioimmunoassay, but there were no myocytes containing irANP in the ventricles with immunocytochemistry as opposed to radioimmunoassay. While the staining obtained for irANP in the atrium was more intense in the right, CGRP and NPY nerve fibres were two to three times more abundant in the left atrium. The high local concentration of a vasoconstrictor peptide in the region of coronary vessels may suggest that it is involved in the control of vascular smooth muscle tone. The method of choice with the immunocytochemical studies was that of the susa wax technique for irANP. Caution should therefore be observed when interpreting results based only on a single staining technique.

Animals↗