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Biomedical subjects

A D Struthers

Publications and source records attributed to A D Struthers.

At least 163 records · Page 9Linked to original sources
PubMed1994

Sequential effects of cyclosporine therapy on blood pressure, renal function and neurohormones.

We have studied the sequential effects of cyclosporine during the first four days after its initiation in an effort to elucidate the primary and secondary events in the pathogenesis of cyclosporine induced nephrotoxicity and hypertension. Knowledge about the earliest effects of cyclosporine provides a more logical approach for devising therapeutic strategies to counteract nephrotoxicity and hypertension. On day 1, cyclosporine acutely increased systemic BP and decreased urine volume. Plasma renin activity was suppressed by day 2 and remained so thereafter. Renal sodium excretion was not affected until day 4 at which point a natriuresis occurred. Cyclosporine exerted a more marked antidiuretic effect on day 4 compared to day 1, which was augmented by a physiological infusion of vasopressin. Over the first four days of therapy, glomerular filtration rate and effective renal plasma flow were unchanged. Our data show that cyclosporine induced hypertension in the initial stages is not sodium dependent, and that changes in renal water handling were not dependent on alterations in the glomerular filtration rate or effective renal plasma flow. In fact, a natriuresis occurred which was most likely due to a combination of pressure natriuresis and angiotensin II suppression. The cyclosporine induced antidiuresis may indicate a distal nephron effect since cyclosporine augmented the antidiuretic effect of vasopressin, although vasopressin levels per se were not increased by cyclosporine alone.

Adult↗
PubMed1994

Acute haemodynamic and renal effects of cyclosporin and indomethacin in man.

A single oral dose of cyclosporin (12 mg/kg) was given to healthy volunteers (n = 9) on day 2 with or without indomethacin pretreatment (100 mg day 1 + 100 mg day 2). All parameters reported were analysed after a water-loading protocol on day 2. As a peak drug effect within 4 h of drug ingestion on day 2 cyclosporin on its own increased mean arterial pressure by 13% (P < 0.05) without causing any sodium retention or renal vasoconstriction. Indomethacin pretreatment did not accentuate this hypertensive effect of cyclosporin. The earliest renal effect observed with cyclosporin on day 2 was on water handling with a marked antidiuretic effect. Free-water clearance decreased by a maximum of 48% (P < 0.05) following cyclosporin. Indomethacin pretreatment induced a similar antidiuresis on day 2 but cyclosporin did not augment this antidiuresis any further. This suggests that inhibition of vasodilator prostaglandins within the kidneys may mediate the antidiuretic effect of cyclosporin such that in the presence of indomethacin, cyclosporin had no additional effect. The inhibition of intrarenal prostaglandins by a single dose of indomethacin did not, however, produce any acute cyclosporin-induced change in glomerular filtration rate or renal blood flow.

Administration, Oral↗
PubMed1994

Comparison of two methods of determining renal perfusion with and without captopril pretreatment in groups of patients with left ventricular dysfunction.

Methods of effective renal plasma flow measurement by 125I-orthoiodohippurate elimination and para-aminohippurate clearance were compared with and without captopril pretreatment in 10 chronic heart failure patients and in 20 patients after transmural myocardial infarction. In the chronic heart failure group measurements of effective renal plasma flow by the two techniques were strongly correlated (r = 0.92, P < 0.00001), as was the captopril-mediated change in effective renal plasma flow by the two methods (r = 0.85, P = 0.002). However, in absolute terms para-aminohippurate clearance significantly exceeded 125I-orthoiodohippurate clearance by a mean (+/- SD) of 24.8 +/- 43.7 ml.min-1 (P < 0.05) so that only using the former technique was a significant increment in renal perfusion observed in response to converting enzyme inhibition. In the post-myocardial infarction group, correlations between the two methods were variable and much poorer than in the chronic heart failure group (r = 0.54, P = 0.01 and r = 0.74, P = 0.002 on consecutive days). Furthermore, captopril-mediated increments in effective renal plasma flow by the two techniques were unrelated (r = -0.19, P = 0.59). In this group 125I-orthoiodohippurate elimination significantly exceeded para-aminohippurate clearance (P < 0.05). This reversed association and the weaker relationships between methods in post-infarction as compared to chronic heart failure patients may be related to interference by thrombolytic or aspirin treatments.

Aged↗
PubMed1994

Health care delivery for chronic congestive heart failure in the United Kingdom.

Since the United Kingdom has fewer cardiology specialists than other countries, the United Kingdom cardiologist cannot provide direct care for all patients with chronic congestive heart failure (CHF). Most CHF care is provided by general practitioners, physicians or geriatricians. A survey of 100 CHF patients attending a health center revealed that these patients visited their general practitioners 270 times in 1 year, compared with only 34 outpatient visits. The cardiologist mainly provides echocardiography. The accurate diagnosis of mild CHF became imperative with the advent of angiotensin converting enzyme (ACE) inhibitors. Results of a survey showed that although 1.6% of the population are taking diuretics for CHF, only 0.84% of the population have left ventricular systolic dysfunction on echocardiography. An estimated 22 echocardiograms per 1000 population per year are required (10 for structural reasons, three for suspected new CHF, three to identify patients with a low left ventricular ejection fraction and six to identify left ventricular hypertrophy in hypertensive patients). However, district general hospitals in Scotland can only provide 3.3-6 echocardiograms per 1000 population per year. The elderly CHF patient may not receive adequate treatment because of the lack of resources and a dislike of 'overinvestigating' or 'overtreating' the elderly. The benefits of echocardiography and ACE inhibitor therapy for all patients with CHF should be stressed.

Adult↗
PubMed1994

Interactive effects of indomethacin, angiotensin II and frusemide on renal haemodynamics and natriuresis in man.

The responses of renal haemodynamic and natriuretic indices to the oral prostaglandin synthetase inhibitor indomethacin (200 mg), to infused angiotensin II (1 ng min-1 kg-1) and to the combination of the two were studies in placebo-controlled fashion in eight normal male subjects both prior to and following administration of intravenous frusemide (20 mg). As compared with placebo, angiotensin II infusion alone caused significant reductions in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.001 vs placebo) but had no effect on glomerular filtration rate. The only change observed in these parameters with indomethacin alone was a small but significant reduction in urine flow rate (P < 0.005 vs placebo). As compared with the effects of angiotensin II alone, indomethacin pre-treatment followed by angiotensin II infusion led to much greater falls in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.0001 vs placebo) associated with a significant reduction in glomerular filtration rate (P < 0.0001) not observed with angiotensin II alone. Frusemide administration at the midpoint of each study limb resulted in each case in a prompt 15 to 20 fold increase in natriuresis. The renal haemodynamic and natriuretic effects of angiotensin II, indomethacin and their combination were not qualitatively different from those observed in the pre-frusemide phase. Our findings provide a clear demonstration in man of the important homeostatic role of renal prostaglandins in preserving renal function, particularly glomerular filtration, under conditions of elevated circulating angiotensin II.

Adult↗
PubMed1994

Digoxin-specific Fab fragments impair renal function in the rat.

The effect on renal function, and the plasma and urinary disposition, of digoxin-specific antibody fragments (DSFab), were studied using the rat as an experimental model. After 24h, DSFab (2 mg kg-1, i.v.) caused decreases in urine volume and creatinine clearance of 34 and 33%, respectively, when measured in the same rats. However, only the creatinine clearance was significantly changed when compared with a separate saline-treated control group. Plasma and urinary creatinine concentrations were unaffected by DSFab treatment. Since creatinine clearance approximates to glomerular filtration rate (GFR), it appears that a dose of DSFab equivalent to about one-fifth of the usual clinical dose, causes a reduction in GFR of about one-third. In patients undergoing digitalis therapy, a degree of renal impairment is common and it is possible that this may be exacerbated by treatment with DSFab. DSFab had an elimination half-life of 178 min, an apparent volume of distribution (Vd) of 106 mL kg-1 and a plasma clearance of 0.42 mL kg-1 min-1. If it is assumed that the plasma volume of a rat is approximately 35 mL kg-1, the measured Vd suggests appreciable penetration of DSFab into the extracellular fluid at this dose. Seventy-two hours after injection, only 7.6% of the administered dose of DSFab was found in the urine.

Animals↗
PubMed1994

Detection of left ventricular dysfunction after acute myocardial infarction: comparison of clinical, echocardiographic, and neurohormonal methods.

OBJECTIVE: The SAVE study showed that captopril improves mortality in patients with left ventricular dysfunction after myocardial infarction and that this benefit occurred even in patients with no clinically overt heart failure. On the basis of this, it seems important to identify correctly which patients have left ventricular dysfunction after a myocardial infarction. The objective was to compare various methods of identifying patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, < or = 40%) after acute myocardial infarction. The methods compared were echocardiography (quantitative and qualitative visual assessment), clinical evaluation (subjective assessment and three clinical score methods), and measurement of plasma concentrations of cardiac natriuretic peptide hormones (atrial and brain natriuretic peptides, ANP and BNP). DESIGN: Cross sectional study of left ventricular function in patients two to eight days after acute myocardial infarction. SETTING: Coronary care unit of a teaching hospital. PATIENTS: 75 survivors of a recent myocardial infarction aged 40 to 88 with no history of cardiac failure and without cardiogenic shock at the time of entry to the study. MAIN OUTCOME MEASURES: Sensitivities and specificities of the various methods of detecting left ventricular dysfunction were calculated by comparing them with a cross sectional echocardiographic algorithm for LVEF. RESULTS: Clinical impression was poor at identifying LVEF < 40% (sensitivity 46%). Clinical scoring improved this figure somewhat (modified Peel index sensitivity 64%). Qualitative visual assessment echocardiography was a more sensitive method (sensitivity 82%) for detecting LVEF < 40%. Plasma BNP concentration was also a sensitive measure for detecting left ventricular dysfunction (sensitivity 84%) but plasma ANP concentration was much poorer (sensitivity 64%). CONCLUSION: Left ventricular dysfunction is easily and reliably detected by echocardiographic measurement of LVEF and also by a quick qualitative echocardiographic assessment but is likely to be missed by clinical assessment alone. High concentrations of plasma BNP maybe another useful indicator of left ventricular dysfunction, particularly in hospitals where not all patients can be screened by echocardiography or radionuclide ventriculography after myocardial infarction.

Adult↗
PubMed1994

C-type natriuretic peptide levels in cor pulmonale and in congestive heart failure.

BACKGROUND: C-type natriuretic peptide (CNP) is a recent addition to the family of natriuretic peptides which includes atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Whilst the levels of ANP and BNP are increased in conditions such as congestive heart failure and cor pulmonale, abnormal levels of CNP in these conditions have not been reported. METHODS: Plasma levels of CNP were measured by specific radioimmunoassay in 12 young normal controls, 12 elderly normal controls, 12 patients with NYHA grade III-IV congestive heart failure, and in 16 patients with hypoxaemic cor pulmonale. RESULTS: Mean (SE) plasma levels of CNP were similar in young normal controls (0.46(0.03) pmol/l), elderly normal controls (0.43(0.05) pmol/l), and in patients with congestive heart failure (0.33(0.2) pmol/l). In patients with cor pulmonale, however, plasma levels of CNP were raised (1.39(0.27) pmol/l) 3.2-fold compared with age-matched controls. CONCLUSIONS: In cor pulmonale the increased plasma levels of CNP were not as great as the previously observed increases in levels of ANP (5.6-fold) or BNP (18.5-fold) in comparable patients. CNP may therefore be less important than ANP or BNP as a circulating counter-regulatory peptide in conditions of overactivity of the renin angiotensin system.

Adult↗
PubMed1994

Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans.

OBJECTIVE: To test the hypothesis that an imbalance in intrarenal prostaglandins plays a role in cyclosporin-induced nephrotoxicity. METHODS AND RESULTS: Indomethacin was given in combination with cyclosporin to healthy volunteers. Cyclosporin alone (10 mg/kg twice a day) for 4 days had no effect on effective renal plasma flow (ERPF) and glomerular filtration rate but 4 days of therapy with cyclosporin (10 mg/kg twice a day) and indomethacin (50 mg twice a day) in combination resulted in a 37% fall in glomerular filtration rate and a 32% fall in ERPF. This suggests that autoregulatory mechanisms, possibly involving renal prostaglandins, may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans. Cyclosporin increased systemic blood pressure acutely, and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention. This suggests that, in contrast to the renal vasculature, the systemic vascular response to cyclosporin is neither augmented nor buffered by prostaglandins. CONCLUSION: The reduction in intrarenal prostaglandins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction, but we could not demonstrate a role for prostaglandins or for sodium retention in the initiation of cyclosporin-induced hypertension.

Adult↗
PubMed1993

Plasma brain natriuretic peptide as an indicator for angiotensin-converting-enzyme inhibition after myocardial infarction.

Brain natriuretic peptide (BNP) is a cardiac ventricular hormone that may be a sensitive and specific marker of changes in ventricular function. In a prospective, randomised open trial with 16 patients followed for 6 months after first Q wave anterior myocardial infarction we set out to determine: whether BNP concentrations are raised acutely, the effect on circulating BNP of angiotensin-converting enzyme (ACE) inhibition, how BNP and atrial natriuretic peptide (ANP) concentrations compared as correlates of left-ventricular ejection fraction, and whether plasma BNP concentrations could distinguish patients with low (< 40%) and relatively preserved (> 40%) ejection fractions. Plasma concentrations of BNP measured on days 2, 7, 8, 42, and 180 postinfarction were significantly raised in patients compared with normal controls and to a proportionately greater degree than ANP concentrations. Treatment with placebo (n = 8) or oral captopril (n = 8) from day 8 resulted in significantly lower BNP concentrations at days 42 (p = 0.05) and 180 (p < 0.05) in the captopril-treated group. Compared with ANP, BNP concentrations were much more strongly correlated with radionuclide-measured left-ventricular ejection fraction at days 2, 42, and 180. All 8 patients with baseline (day 2) ejection fractions of 40% or above had plasma BNP concentrations less than 10 pmol/L, whereas the 8 patients with ejection fractions less than 40% had BNP concentrations greater than 10 pmol/L. Our findings suggest that measurements of circulating BNP may identify those patients with significant left-ventricular dysfunction who have been highlighted by the Survival and Ventricular Enlargement study as likely to benefit from long-term ACE inhibition after myocardial infarction.

Adult↗
PubMed1993

Effectiveness of captopril in reversing renal vasoconstriction after Q-wave acute myocardial infarction.

The purpose of this investigation was to study whether favorable renal effects might contribute to the influence of captopril in offsetting ventricular dilatation after infarction. Effective renal plasma flow and glomerular filtration rate were estimated by isotope injection methods in 20 patients on days 2, 7, 8, 42 and 180 after a first transmural anterior myocardial infarction. After measurements on day 7, patients were randomized to receive either captopril 25 mg 3 times daily (n = 10) or placebo (n = 10) for the remainder of the study. At baseline (day 7) there were no differences between the 2 treatment groups in radionuclide left ventricular ejection fraction, effective renal plasma flow, glomerular filtration rate or neurohormones. Left ventricular ejection fractions (40 +/- 4% [mean +/- 2 SD] at baseline) were higher in the captopril- than the placebo-treated patients on days 42 (p < 0.05) and 180 (p < 0.01) after infarction. Effective renal plasma flow became significantly higher at all time points after randomization in the captopril-treated group than in the placebo group (p < 0.001). A similar but lesser trend was observed for glomerular filtration rate. Plasma atrial natriuretic factor and aldosterone were significantly higher in the placebo group (p < 0.05). Renal hemodynamic indexes were directly correlated with and neurohumoral indexes inversely correlated with ejection fractions. In a second group of 12 patients with higher baseline ejection fractions (48 +/- 4%) after an inferior infarction, none of these beneficial effects of captopril were demonstrable. It is proposed that in the setting of left ventricular dysfunction after infarction, a prompt and sustained improvement in renal hemodynamics, by reducing inappropriate fluid retention and thus ventricular preload, may be one contributory mechanism by which captopril prevents progression of left ventricular dilatation.

Aged↗
PubMed1993

Acute effects of captopril on the renal actions of furosemide in patients with chronic heart failure.

This study examined the effects of conventional doses of oral captopril on the renal responses to oral furosemide in ambulant patients with stable chronic heart failure. Twenty-five men (mean age 63 years) were randomized to one of two groups. Group 1 received placebo on days 1 and 2 before furosemide. Group 2 received placebo on day 1 before furosemide and captopril thereafter (i.e., captopril before furosemide on day 2). Urine was collected after either placebo or captopril and after furosemide (taken after placebo or captopril pretreatment). Captopril by itself did not affect renal function. Captopril did, however, significantly affect the renal response to furosemide. The increase in urine flow rate after furosemide in group 2 was decreased from 225% with placebo to 128% with captopril (p < 0.02). The increase in sodium excretion after furosemide was decreased from 623% with placebo to 242% with captopril (p < 0.001). Pretreatment with captopril abolished the increase in creatine clearance after furosemide. The increase in urinary albumin excretion (used as a marker of glomerular function) after furosemide was also significantly blunted by captopril. Conventional doses of captopril acutely inhibit the natriuretic and diuretic responses to furosemide at the glomerular level in ambulant patients with stable chronic heart failure.

Administration, Oral↗
PubMed1993

The differential effects of circulating norepinephrine and neuronally released norepinephrine on sodium excretion in humans.

The renal effects of incremental infusions of norepinephrine (placebo, 0.025 mu/kg/min), 0.075 micrograms/kg/min, phenylephrine (placebo, 0.5 micrograms/kg/min, 2.5 micrograms/kg/min), and tyramine (placebo, 2 micrograms/kg/min, 15 micrograms/kg/min) were examined in three respective groups (n = 9, 8, and 8) of normotensive male subjects undergoing water diuresis. Tyramine is an indirect sympathetic agent that causes neuronal release of endogenous norepinephrine. Increases in mean arterial pressure during each high-dose infusion were comparable in all three groups. Both norepinephrine and phenylephrine caused a decrease in urinary sodium excretion and effective renal plasma flow, with no changes in glomerular filtration rate. Proximal tubular sodium reabsorption, as assessed by both lithium clearance and solute-free water clearance methods, was increased by pressor doses of norepinephrine and phenylephrine. In contrast, a similar pressor dose of tyramine was associated with a pressure natriuresis, an increase in effective renal plasma flow, and a decrease in proximal tubular sodium reabsorption. Our data indicate that, in normotensive humans, circulating catecholamines (norepinephrine and phenylephrine) have opposite effects on renal sodium handling from neuronally released norepinephrine (tyramine).

Adult↗