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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 73 records · Page 4Linked to original sources
PubMed1999

DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans.

A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We investigated whether endothelial function was different between different ACE genotypes. We performed a cross-sectional study comparing the endothelial function of the 3 genotypes (II: n=25; ID: n=31; DD: n=12). Mean+/-SD ages of the subjects were 24+/-4 (II), 25+/-6 (ID), and 25+/-6 (DD) years. We assessed the impact of the genotypes on endothelial function and found that the DD genotype was associated with a significant blunting in endothelial-dependent vasodilatation (forearm blood flow data are presented as mean+/-SD ratio of blood flow in response to 3 incrementally increasing doses of each vasoactive agent in the test arm to blood flow in the control arm; the comparison is between DD versus ID versus II; the P value is an expression of an overall difference by ANOVA, and the 95% CIs are of a pairwise comparison between genotypes): acetylcholine, 2.88+/-1.45 versus 3.81+/-1.93 versus 4.23+/-2.37 (P=0.002; 95% CI [II versus ID], -0.19 to 0.91; 95% CI [II versus DD], 0.36 to 1.80; 95% CI [ID versus DD], 0.02 to 1.42). There was also a significant difference with the endothelial-independent vasodilator sodium nitroprusside, with values of 2.11+/-1.00 versus 2.55+/-1.36 versus 2.75+/-1.18 (P<0.05; 95% CI [II versus ID], -0.15 to 0.51; 95% CI [II versus DD], 0.03 to 0.89; 95% CI [ID versus DD], -0.13 to 0.71), but not with verapamil. There was no effect of the ACE genotype on endothelial-dependent or -independent vasoconstrictors NG-monomethyl-L-arginine or norepinephrine. Investigating the effects of cigarette smoking on each genotype demonstrated that for II and DD genotypes, acetylcholine responses were further blunted if subjects smoked. These data demonstrate that the DD ACE genotype in a young population is associated with a blunting of stimulated endothelial NO and donated NO responses but not to non-NO vasodilators or vasoconstrictors.

Acetylcholine↗
PubMed1999

Lisinopril improves arterial function in hyperlipidaemia.

Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n=20), or placebo (n=20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145+/-4 to 128+/-4 mmHg (P<0.001); diastolic: 84+/-2 to 74+/-2 mmHg (P<0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33+/-0.3 (pre) versus 4.45+/-0.48 (post) at 30 microg/ml (P<0.03), and also to nitroprusside, e.g. 3.0+/-0.2 (pre) versus 3.86+/-0.3 (post) at 3.2 microg/ml (P<0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia.

Acetylcholine↗
PubMed1998

Atrial natriuretic peptide increases urinary albumin excretion in men with type 1 diabetes mellitus and established microalbuminuria.

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l-1 in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg-1 plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9% saline), low dose (2.5 pmol kg-1 min-1) or high dose (5.0 pmol kg-1 kg min-1) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) micrograms min-1; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) micrograms min-1, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) micrograms min-1, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM.

Adult↗
PubMed1998

Systemic nitric oxide synthase inhibition increases insulin sensitivity in man.

1. Recent evidence shows that skeletal muscle blood flow is an important determinant of insulin sensitivity and that insulin-mediated vasodilatation is nitric oxide dependent. These results have given rise to the hypothesis that endothelial nitric oxide inhibition may decrease insulin sensitivity in humans. 2. We examined this hypothesis directly by evaluating the effects of systemic nitric oxide synthase inhibition with NG-monomethyl L-arginine (3 mg h-1 kg-1) on whole-body glucose uptake (euglycaemic hyperinsulinaemic clamp) and calf blood flow (bilateral calf venous occlusion plethysmography) in 16 healthy male subjects in a randomized, double-blind, placebo-controlled, crossover study. 3. NG-Monomethyl L-arginine infusion was associated with a pressor effect (119/61 +/- 2/2 compared with 114/58 +/- 2/2 mmHg for placebo; P < 0.001), and a negative chronotropic response (57 +/- 2 compared with 62 +/- 2 beats/min for placebo; P < 0.001). The glucose infusion rate was significantly increased after infusion of NG-monomethyl L-arginine (8.9 +/- 0.9 compared with 7.9 +/- 0.8 mg min-1 kg-1 for placebo; P = 0.002). Whole-body glucose uptake increased during the clamp, with values of 9.4 +/- 0.7 and 10.9 +/- 0.8 mg min-1 kg-1 for placebo and NG-monomethyl L-arginine respectively (P = 0.036; 95% confidence interval 0.2,2.8). NG-Monomethyl L-arginine was associated with increased calf blood flow by comparison with placebo (P < 0.05, area under curve). 4. These data show for the first time that systemic inhibition of nitric oxide synthesis increases rather than decreases whole-body glucose uptake. We suggest that the higher skeletal muscle blood flow seen after NG-monomethyl L-arginine may explain the observed increase in whole-body glucose uptake.

Adult↗
PubMed1998

Aldosterone blunts the baroreflex response in man.

1. Recent animal evidence suggests that aldosterone, like angiotensin II, may possess detrimental autonomic modulating properties. Aldosterone has been shown to impair the baroreflex response in animal models. This study is designed to test the hypothesis that aldosterone directly attenuates the baroreflex in vivo in man.2. Fourteen healthy male volunteers [mean age (S.D.) 25 (9) years] received intravenous d-aldosterone (12 pmol.min-1.kg-1) and 5% dextrose (vehicle) in a double-blind crossover fashion, co-infused with incremental doses of intravenous phenylephrine and sodium nitroprusside. Aldosterone had no significant effect on resting blood pressure, heart rate or baroreflex response to sodium nitroprusside. However, reflex responses to phenylephrine were impaired with aldosterone (P<0.01) while blood pressure responses were unaltered. Baroreflex sensitivity was significantly blunted in the aldosterone group [8.36+/-2.19 versus 10.12+/-2.27 ms/mmHg; P<0. 04].3. This study confirms previous observations from animal models that aldosterone impairs the baroreflex response. High aldosterone levels may contribute to the baroreflex dysfunction in cardiovascular diseases such as hypertension and heart failure.

Adult↗
PubMed1998

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man.

AIMS: The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N(G)-monomethyl-L-arginine (L-NMMA) on systemic and pulmonary haemodynamics. METHODS: Ten normal male volunteers 26 +/- 1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of L-NMMA (4 mg kg(-1) h(-1)) with a front loaded bolus (4 mg kg(-1)) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t0) and after 4, 8, and 12 min (t1, t2 and t3). RESULTS: Infusion of L-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t1 and persisted during the entire infusion period. CONCLUSIONS: These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.

Adult↗
PubMed1998

Endogenous angiotensin II and baroreceptor dysfunction: a comparative study of losartan and enalapril in man.

AIMS: To assess the role of direct ATI receptor antagonism in baroreceptor modulation in man, and to perform a direct comparison of Ang II blockade at the receptor level with that of ACE inhibition. METHODS: Ten healthy male volunteers [mean age (s.d.) 23 (6.9)] pretreated with frusemide therapy (40 mg day(-1) for 3 days prior to each visit) were studied on 3 separate days, 10 days apart, in a placebo-controlled, randomized, double-blind, cross-over fashion. On each study day, subjects were randomly given either a single-dose of enalapril 20 mg, losartan 50 mg or placebo. Baroreceptor function was assessed by measuring changes in blood pressure (BP), pulse interval (RR Int) and heart rate (HR) in response to incremental doses of intravenous phenylephrine infusions (0.2-3.6 microg kg(-1) min(-1)). RESULTS: In response to phenylephrine, no significant differences in BP responses were observed with any of the study medications but reflex heart rate responses were significantly increased with both enalapril and losartan compared with placebo (P<0.05). The (RR/AsBP ratio, taken as a measure of baroreceptor sensitivity (BRS) was significantly increased with enalapril 112.2+4.6 ms mmHg (mean+s.d.)] and losartan [11.9+3.6msmmHg(-1)] compared with placebo [9.2+4.5 ms mmHg(-1)]; i.e. enalapril and losartan increased the (RR/(delta sBP ratio by 3.0 ms mmHg(-1) (95%CI 0.5, 5.6; P<0.05) and 2.8 ms mmHg(-1) (95%CI 0.6, 5.0; P< 0.038), respectively. There were however, no significant differences between losartan and enalapril [mean difference 0.25 (95%CI - 1.6, 2.1)]. CONCLUSIONS: The present study confirms observations from animal models that blocking endogenous angiotensin II in man improves baroreceptor function. Both strategies, ATI receptor antagonism and ACE inhibition appear to be equally effective in restoring baroreceptor function in salt-depleted normotensive subjects.

Adult↗
PubMed1998

Inhaled corticosteroid therapy reduces the early morning peak in cortisol and aldosterone.

1. As mineralocorticoid and adrenocorticoid activity are both under the diurnal control of adrenocorticotropic hormone secretion, we aimed to evaluate whether the normal circadian rhythm of cortisol and aldosterone secretion was suppressed by inhaled corticosteroid therapy.2.Ten normotensive patients with mild-moderate asthma, mean age 24.0 (S.D. 9.8) years and mean arterial pressure 90.7 (9.8) mmHg, were studied in a double-blind, randomized crossover design comparing placebo with fluticasone propionate, 1000 microgram administered twice daily at 08:00 h and 20:00 h. After 5 days of repeated dosing at steady state, measurements were made of plasma cortisol and aldosterone at midnight and 08:00 h.3. With placebo there was a significant (P<0.05) difference between cortisol values at 08:00 h (588.6+/-83.8 nmol/l) and midnight (109.6+/-35.0 nmol/l), whereas after treatment with fluticasone propionate there was no significant difference between levels at 08:00 h (143.3+/-57.4 nmol/l) and midnight (64.3+/-22.3 nmol/l). For cortisol at 08:00 h there was also a significant (P<0.05) difference between placebo and fluticasone propionate. The same pattern was observed for aldosterone. Plasma aldosterone levels at 08:00 h after treatment with placebo (129.6+/-30.9 nmol/l) were significantly different (P<0. 05) to those seen at midnight (40.4+/-6.2 nmol/l). After treatment with fluticasone propionate, there was no significant difference between levels at midnight (55.4+/-11.7 nmol/l) and 08:00 h (64. 8+/-12.7 nmol/l).4. These results show that inhaled corticosteroid therapy abolishes the circadian rhythm of aldosterone and cortisol secretion. This may have possible implications for patients taking inhaled corticosteroids in terms of the beneficial cardiac effects of suppressing early morning aldosterone.

Administration, Inhalation↗
PubMed1997

Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care.

BACKGROUND: The reliability of a clinical diagnosis of heart failure in primary care is poor. Concentrations of natriuretic peptides are high in heart failure. This population-based study examined the predictive value of natriuretic peptides in patients with a new primary-care diagnosis of heart failure. METHODS: Concentrations of plasma atrial (ANP and N-terminal ANP) and B-type (BNP) natriuretic peptides were measured by radioimmunoassay in 122 consecutive patients referred to a rapid-access heart-failure clinic with a new primary-care diagnosis of heart failure. On the basis of clinical assessment, chest radiography, and transthoracic echocardiography, a panel of three cardiologists decided that 35 (29%) patients met the case definition for new heart failure. ANP and NT-ANP results were available for 117 patients (34 with heart failure) and BNP results for 106 (29 with heart failure). FINDINGS: Geometric mean concentrations of natriuretic peptides were much higher in patients with heart failure than in those with other diagnoses (29.2 vs 12.4 pmol/L for ANP; 63.9 vs 13.9 pmol/L for BNP; 1187 vs 410.6 pmol/L for NT-ANP; all p < 0.001). At cut-off values chosen to give negative predictive values for heart failure of 98% (ANP > or = 18.1 pmol/L, NT-ANP > or = 537.6 pmol/L, BNP > or = 22.2 pmol/L), the sensitivity, specificity, and positive predictive value for ANP were 97%, 72%, and 55%; for NT-ANP 97%, 66%, and 54%; and for BNP 97%, 84%, and 70%. Addition of ANP or NT-ANP concentration or both did not improve the predictive power of a logistic regression model containing BNP concentration alone. INTERPRETATION: In patients with symptoms suspected by a general practitioner to be due to heart failure, plasma BNP concentration seems to be a useful indicator of which patients are likely to have heart failure and require further clinical assessment.

Adult↗
PubMed1997

Cross sectional study of contribution of clinical assessment and simple cardiac investigations to diagnosis of left ventricular systolic dysfunction in patients admitted with acute dyspnoea.

OBJECTIVE: To assess the comparative contribution of clinical assessment, electrocardiography, and chest radiography to the diagnosis of left ventricular systolic dysfunction in patients admitted to a general medical ward with acute dyspnoea. DESIGN: Prospective cross sectional study. SETTING: Acute medical admissions ward of a teaching hospital. SUBJECTS: 71 randomly selected patients admitted with acute dyspnoea. MAIN OUTCOME MEASURES: Sensitivity and specificity of each investigation and logistic regression analysis of each variable in identifying left ventricular systolic dysfunction. RESULTS: Clinical assessment in this cohort of patients with severe dyspnoea was generally sensitive (sensitivity 81%). Patients were divided into three groups on the basis of clinical assessment. In the first group (37 patients) the diagnosis of systolic dysfunction was clear, in the second (22) it was in doubt, and in the third (12) it was unlikely. The sensitivity of clinical assessment in identifying left ventricular systolic dysfunction was 81% and the specificity was 47%. The specificity of diagnosis was improved by electrocardiography (69%) and chest radiography (92%). Logistic regression analysis showed that isolated pulmonary crepitations were a comparatively poor predictor of left ventricular systolic dysfunction chi 2 = 10.215, P = 0.0014) but that a full clinical examination had reasonable predictive value (chi 2 = 24.82, P < 0.00001). The combination of clinical assessment and chest radiography improved the accuracy of diagnosis (chi 2 = 28.08, P < 0.00001), as did the combination of clinical assessment and electrocardiography (chi 2 = 32.41, P < 0.00001). CONCLUSION: Clinical assessment in patients admitted with acute dyspnoea is comparatively accurate. Patients with abnormal results on chest radiography, electrocardiography, and clinical examination have a high likelihood of having left ventricular systolic dysfunction. Echocardiography contributes little more to the diagnosis in these patients and may be more efficiently directed towards patients in whom the diagnosis is still in doubt after clinical assessment, chest radiography, and electrocardiography.

Acute Disease↗