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Biomedical subjects

C C Lang

Publications and source records attributed to C C Lang.

At least 55 records · Page 3Linked to original sources
PubMed1995

Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males.

OBJECTIVE: To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity. DESIGN: A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs. METHODS: Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9. RESULTS: GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P < 0.0001). Cyclosporin-induced hypertension occurred in the absence of any change in urinary sodium output or in plasma endothelin. Cyclosporin did not affect lipoprotein (a) levels during 9 days of cyclosporin therapy. CONCLUSIONS: Cyclosporin-induced hypertension and renal vasoconstriction are well established after 9 days of cyclosporin 5 mg/kg twice a day. We found no evidence to implicate either circulating endothelin or renal sodium retention in the onset of cyclosporin-induced hypertension. Cyclosporin-induced renal vasoconstriction appeared to occur when the protective mechanism of plasma renin activity suppression became exhausted.

Adult↗
PubMed1995

Cyclosporin-induced renal vasoconstriction is augmented by frusemide and by angiotensin II in humans.

OBJECTIVE: To investigate the role of the renin-angiotensin-aldosterone system as a homoeostatic mechanism by examining whether mild activation of the renin-angiotensin-aldosterone system could enhance cyclosporin-induced renal vasoconstriction and hypertension. METHODS: We artificially activated the renin-angiotensin-aldosterone system by two means: by pretreatment with frusemide (40 mg/day orally for 2 days) and by administering exogenous angiotensin II (1 ng/kg per min intravenously). In both cases the levels of renin-angiotensin-aldosterone system activation achieved did not by themselves alter renal blood flow, glomerular filtration rate or blood pressure. We then examined the effect of cyclosporin (10 mg/kg twice a day orally) in the presence of the activated renin-angiotensin-aldosterone system in normal humans. RESULTS: Cyclosporin alone acutely altered neither glomerular filtration rate (760 versus 734ml, NS; area under the curve for placebo versus cyclosporin) nor effective renal plasma flow (4,163 versus 3,915 ml, NS; area under the curve for placebo versus cyclosporin). Co-administration of exogenous angiotensin II with cyclosporin induced a fall in effective renal plasma flow from baseline but no change in glomerular filtration rate. Frusemide pretreatment together with cyclosporin administration induced a fall in glomerular filtration rate and a fall in effective renal plasma flow. Neither exogenous angiotensin II nor frusemide pretreatment influenced the blood pressure rise induced by cyclosporin. The present findings demonstrate that renin-angiotensin-aldosterone system activation augments cyclosporin-induced renal vasoconstriction but not cyclosporin-induced systemic vasoconstriction. We suggest that the renin-angiotensin-aldosterone system suppression, which normally occurs with cyclosporin, may be a homoeostatic mechanism to help prevent cyclosporin-induced renal vasoconstriction. The renin-angiotensin-aldosterone system appears, however, to play little or no role in mediating or preventing the initial increase in blood pressure caused by cyclosporin. Furthermore, frusemide is commonly prescribed together with cyclosporin even though this combination has the potential to cause a marked increase in renal dysfunction.

Adult↗
PubMed1995

Natriuretic response to neutral endopeptidase inhibition is blunted by enalapril in healthy men.

We studied six healthy male subjects in a randomized, placebo-controlled, single-blind fashion to determine the comparative effects on renal hemodynamics and natriuresis of the angiotensin-converting enzyme inhibitor enalapril (5 mg on each of 5 days preceding the study), the neutral endopeptidase inhibitor candoxatrilat (200 mg IV), and the combination of enalapril and candoxatrilat. Enalapril pretreatment alone, compared with placebo, produced slight nonsignificant increments in absolute and fractional sodium excretions and a marked increase in effective renal plasma flow but no change in glomerular filtration rate. Candoxatrilat alone produced marked augmentation of both absolute and fractional sodium excretions. The candoxatrilat-mediated increment in absolute sodium excretion was significantly correlated with increases in urinary cGMP and plasma atrial natriuretic peptide in response to this drug, but neither effective renal plasma flow nor glomerular filtration rate was altered compared with placebo. Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor. Blood pressure was reduced by enalapril alone compared with placebo, whereas candoxatrilat treatment alone led to a marginal but significant enhancement of blood pressure. The combination of enalapril and candoxatrilat abolished any significant blood pressure change compared with placebo. Thus, candoxatrilat-mediated natriuresis occurs via a renal tubular rather than glomerular mechanism and is blunted by enalapril. This attenuation by enalapril may occur by interference with angiotensin II-dependent effects on the renal tubule or on systemic blood pressure.

Adult↗
PubMed1995

The effect of enalapril on tyramine induced changes in renal function in man.

Increasing animal evidence support an important facilitatory interaction between angiotensin II and norepinephrine within the kidney. This angiotensin II/norepinephrine interaction was investigated in man by examining the effect of enalapril pretreatment (5 mg for 5 days) on the renal response to a low non-pressor dose of intravenous tyramine 4 micrograms/kg/min for 120 min in 8 healthy subjects undergoing water diuresis. Tyramine is an indirect sympathomimetic agent which causes neuronal release of norepinephrine. Enalapril and tyramine, alone and in combination, had no effect on glomerular filtration, effective renal plasma flow or sodium excretion. Tyramine caused a significant increase in urinary flow rate (p < 0.05) but this was not influenced by enalapril pretreatment. The lack of effect of enalapril on the renal response to tyramine contrasts with a previous study which examined the effect of enalapril on the renal response to circulating norepinephrine. This may suggest that enalapril affect renal function only when there is renal vasoconstriction (as with norepinephrine) and not when renal blood flow is unchanged (as with tyramine).

Adult↗
PubMed1994

QT dispersion and sudden unexpected death in chronic heart failure.

Death in chronic heart failure (CHF) can be from progression of disease or sudden and unexpected. We have attempted to identify factors that predict sudden death in CHF. We followed up 44 patients with CHF for 12-50 (mean 36) months. 4 patients died of non-cardiovascular causes and were excluded from analysis. There were 7 sudden deaths (symptoms for less than 1 h in a previously stable patient) and 12 from progressive CHF. Patients who died of progressive CHF had lower left-ventricular ejection fractions and higher concentrations of atrial natriuretic factor than the 21 survivors, but there were no differences in these variables between survivors and those who died suddenly. However, the sudden death group had significantly (p < 0.05) greater inter-lead variability in the QT interval on the electrocardiogram (QT dispersion; 98.6 [95% CI 79.1-118] ms1/2) than survivors (53.1 [41.9-64.3] ms1/2) or the group who died from progressive CHF (66.7 [51.8-81.6] ms1/2). QT dispersion is a marker of myocardial electrical instability. The association of increased QT dispersion with sudden death suggests that patients at high risk of such death could be identified by means of this simple, reproducible test. This group might benefit from more intensive treatment.

Aged↗
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

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

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

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↗
PubMed1993

Dose-ranging effects of candoxatril on elimination of exogenous atrial natriuretic peptide in chronic heart failure.

Seven patients with chronic heart failure were treated in single-blind crossover fashion with placebo and 10 mg, 50 mg, and 200 mg doses of the neutral endopeptidase inhibitor candoxatril to determine the effects of candoxatril on the elimination kinetics of exogenously infused atrial natriuretic peptide (ANP). An incremental dose-response effect was observed on the mean maximum observed plasma concentration (Cmax) of the active metabolite candoxatrilat (107.4, 453.5, and 1584 ng/ml in response to 10, 50, and 200 mg candoxatril, respectively). Pooled active versus placebo comparisons showed that candoxatril reduced the clearance (p = 0.021) and elimination rate constant (p = 0.006) and increased Cmax (p = 0.002) and time to reach Cmax (p = 0.01) of exogenous ANP. Individually, both 50 mg and 200 mg but not 10 mg candoxatril significantly altered the elimination kinetics of ANP. The most favorable effects were observed in response to 200 mg candoxatril, although even this dose may not have achieved the maximal modulating effect on elimination of circulating ANP.

Aged↗
PubMed1993

Circulating angiotensin II and renal sodium handling in man: a dose-response study.

1. Animal studies have shown that angiotensin II has a biphasic effect on urinary sodium excretion. To examine whether this is also true in man, we studied seven salt-replete male subjects in a single-blind placebo-controlled manner. 2. While undergoing maximum diuresis, subjects were infused with 0, 1, 2, 5 or 10 ng of angiotensin II min-1 kg-1 over 80 min. Subjects were studied while seated, and stood every 20 min for urine collection. 3. Angiotensin II produced a dose-dependent antidiuretic effect. The urine flow rate, in ml/min expressed as the change from baseline with increasing dose of angiotensin, was: +3.4 +/- 1.77, -1.26 +/- 0.49 (P < 0.05), -2.75 +/- 1.23 (P < 0.05), -4.21 +/- 0.82 (P < 0.05) and -6.51 +/- 1.07 (P < 0.01). 4. In contrast, the effect of angiotensin II on sodium excretion showed a flat dose-response curve beyond 5 ng min-1 kg-1. The urinary sodium excretion, in mumol/min expressed as the change from baseline with increasing dose of angiotensin, was: 9.5 +/- 21.2, -18.9 +/- 29.6, -37.0 +/- 11.6 (P < 0.05), -67.7 +/- 19.6 (P < 0.01) and -63.8 +/- 14.3 (P < 0.01). 5. The fractional distal reabsorption of sodium, determined by using the lithium clearance technique, showed a rise with all doses of angiotensin II used and reached statistical significance with the top two doses. 6. Unlike antidiuresis, antinatriuresis after graded doses of angiotensin II in human subjects showed a flat dose-response curve beyond 5 ng min-1 kg-1. Pressor doses of angiotensin II also have a significant effect on the distal tubule in promoting sodium reabsorption.

Adult↗
PubMed1993

Effect of noradrenaline on renal sodium and water handling in euhydrated and overhydrated man.

1. The renal effects of incremental doses of intravenously infused noradrenaline were evaluated in normal subjects during two different water loads, 5 ml/kg (n = 6) and 20 ml/kg (n = 9), producing conditions of euhydration and overhydration, respectively. 2. Noradrenaline infusion rates ranged from 0.015 to 0.075 microgram min-1 kg-1. In the euhydrated subjects, noradrenaline caused a dose-dependent fall in urinary sodium excretion and an increase in urinary flow rate. During overhydration similar doses of noradrenaline caused a fall in urinary sodium excretion but a decrease in urinary flow rate. 3. Although there was no detectable change in glomerular filtration rate, a dose-dependent fall in effective renal plasma flow was observed in both hydration states during noradrenaline infusion. 4. Noradrenaline infusion was associated with a dose-dependent increase in proximal tubular sodium reabsorption as assessed by the lithium clearance method. Fractional reabsorption of sodium by the distal nephron was, however, unchanged by noradrenaline in both hydration states. 5. Plasma vasopressin concentration was unchanged by noradrenaline in euhydrated subjects. The renin-angiotensin-aldosterone axis was stimulated by noradrenaline in both euhydrated and overhydrated subjects. 6. Thus we conclude that plasma circulating noradrenaline has a dose-dependent antinatriuretic effect in man. The antinatriuretic effect of noradrenaline is mediated mainly at the proximal tubule in man. We have also shown that during overhydration, noradrenaline decreased urinary flow rate. In contrast, in euhydrated subjects, noradrenaline increased urinary flow rate with no accompanying changes in plasma vasopressin concentration, which suggests a direct effect of noradrenaline on the renal tubular permeability to water.

Adult↗
PubMed1993

Renal effects of low dose prazosin in patients with congestive heart failure.

Activation of the sympathetic nervous system may contribute to the renal vasoconstriction and sodium retention seen in congestive heart failure. Previous studies in congestive heart failure patients employing large doses of prazosin that lowered systemic blood pressure have been generally disappointing. The renal haemodynamic and segmental tubular effects of low non-depressor doses of prazosin (0.25 mg and 0.50 mg) were examined in eight female patients with mild to moderate congestive heart failure. Segmental tubular function was assessed by the lithium clearance method. Compared to placebo, prazosin caused a significant increase in urinary sodium excretion (from 56 +/- 7 to 92 +/- 7 mumol.min-1, P < 0.01), paralleled by significant increases in fractional excretion of sodium and lithium. Glomerular filtration rate and effective renal plasma flow were not altered by prazosin. Prazosin pre-treatment did not alter any of the renal responses to frusemide treatment (mean dose 85 +/- 14 mg). This study demonstrates that low non-depressor doses of prazosin have a clear natriuretic effect in congestive heart failure patients, which is predominantly established by interference with tubular reabsorption.

Aged↗
PubMed1993

Enalapril blunts the antinatriuretic effect of circulating noradrenaline in man.

OBJECTIVE: The present study examines the effect of angiotensin converting enzyme inhibition on the renal haemodynamic and sodium excretory responses to noradrenaline in man. DESIGN: We studied the effects of intravenous noradrenaline (0.075 micrograms/kg per min) and enalapril pretreatment (5 mg/day for 5 days), alone and in combination, on urinary sodium excretion, effective renal plasma flow, glomerular filtration rate and segmental tubular function in nine normal subjects. METHODS: The subjects were studied during maximal water diuresis. The clearance of inulin and of para-aminohippurate were used to estimate the glomerular filtration rate and effective renal plasma flow, respectively. Segmental tubule handling of sodium was assessed by the lithium clearance method. RESULTS: Noradrenaline alone decreased urinary sodium excretion (P < 0.01) and the effective renal plasma flow (P < 0.01) without altering the glomerular filtration rate. Enalapril pretreatment significantly attenuated this fall in sodium excretion (P < 0.05) and effective renal plasma flow (P < 0.05), and had a similar attenuating effect on the noradrenaline-induced decrease in the fractional excretion of lithium. The pressor response to noradrenaline infusion was not, however, influenced by the enalapril pretreatment. CONCLUSIONS: Enalapril blunts the renal vasoconstrictive effect and the antinatriuretic effect of noradrenaline in man. Our results indicate that there is an important interaction between the sympathetic nervous system and the renin-angiotensin system in the kidneys in man.

Adult↗