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Biomedical subjects

M R Lee

Publications and source records attributed to M R Lee.

At least 91 records · Page 5Linked to original sources
PubMed1990

Effect of cardiac tamponade on atrial natriuretic peptide concentrations: influence of stretch and pressure.

1. In order to study the role of atrial pressure and atrial stretch on the release of atrial natriuretic peptide we have measured plasma atrial natriuretic peptide concentration, urine output and haemodynamic variables in eight patients during and 30 min after the relief of cardiac tamponade. This condition is characterized by high atrial pressure with little or no atrial stretch. 2. Relief of tamponade was associated with a rise in urine output (53 +/- 27.9 to 101 +/- 24.5 ml/h, mean +/- SEM; P = 0.09), systolic blood pressure (95 +/- 9.6 to 126 +/- 7.0 mmHg, P less than 0.0001), and plasma atrial natriuretic peptide concentration (369.5 +/- 70.9 to 490.3 +/- 94.7 pg/ml, P less than 0.05) despite a large fall in right atrial pressure (18.6 +/- 1.6 to 9.5 +/- 1.3 mmHg, P less than 0.001). 3. These results suggest, therefore, that an increase in atrial stretch, rather than in atrial pressure, stimulates the release of atrial natriuretic peptide.

Adult↗
PubMed1990

Ethnic differences in the renal sodium dopamine relationship. A possible explanation for regional variations in the prevalence of hypertension?

Over the last three years we have carried out studies on the urine output of both sodium and dopamine in five different ethnic groups: whites, Ghanaians, Zimbabweans, Iranians and Thais. Sodium was measured by ion specific electrode and dopamine by HPLC with electrochemical detection (using epinine as an internal standard). In several groups salt loading studies were also carried out. The five ethnic groups differed substantially with regard to the correlation between their urinary sodium and dopamine outputs. Three groups (whites, Thais and Zimbabweans) showed a strong positive correlation (P less than .001) and this may reflect their traditionally salt rich diet. In two groups (Ghanaians and Iranians) there was no correlation and this may reflect a salt scarce environment. Taken together with our previously reported studies showing that normotensive Ghanaians do not mobilize dopamine on salt loading, this would suggest that certain ethnic groups are predisposed to develop hypertension on salt loading--that is, they are 'salt sensitive.' This genetic trait may have passed from the West Coast of Africa, with the slaves, to America and the Caribbean. Other workers have reported deficiencies in vasodilator systems in the American black, such as dopamine, kallikrein and the renal prostaglandins. These defects may lead to the nosologic entity of 'low renin' hypertension, well described in American blacks, and could open up avenues of therapy based either on DA1 activators (such as fenoldopam) or on renal prodrugs (such as gludopa).

Africa, Western↗
PubMed1990

Effect of prolonged intravenous infusion of gludopa in humans and a preliminary study of its oral bioavailability.

Intravenous infusion of gamma-glutamyl-L-dopa (25 micrograms/kg/min) for 10 h in normal humans caused a natriuresis of 46.5 mmol of sodium without an increase in plasma renin activity and was associated with small but significant falls in blood pressure. In a second study the oral bioavailability of gludopa was estimated in normal subjects and found to be low (less than 2%). The increase in urine dopamine excretion and the natriuretic effect of gludopa were much larger after intravenous infusion than oral dosing.

Absorption↗
PubMed1990

Effects of felodipine on atrial natriuretic peptide in hypertensive non-insulin dependent diabetes mellitus.

Eighteen patients with non-insulin dependent diabetes mellitus and hypertension were treated during two 4 week periods with the calcium antagonist felodipine or placebo in a double-blind, randomised, cross-over study. Mean systemic blood pressure was significantly lower on felodipine, without producing a deleterious effect on diabetic control. Felodipine was associated with an increment in plasma renin concentration but plasma aldosterone and the renal outputs of sodium and dopamine were similar on both treatments. Plasma atrial natriuretic peptide levels were significantly reduced following felodipine treatment.

Aged↗
PubMed1990

Relationship between urinary excretion of sodium and dopamine in type 1 diabetic patients with an without microalbuminuria.

The relationship between urinary sodium and dopamine excretion was investigated in 40 normal males and in 48 normotensive, Type 1 diabetic males, 11 with microalbuminuria and 37 with normal albumin excretion. In all three groups a significant correlation was demonstrated and the regression lines were similar. Thus, no evidence was found that a defect in dopamine mobilization contributes to the early renal pathophysiological changes of Type 1 diabetes.

Adult↗
PubMed1990

Five years' experience with gamma-L-glutamyl-L-dopa: a relatively renally specific dopaminergic prodrug in man.

1. Over the last 5 years we have given intravenous gludopa in man and established its effects on the kidney. 2. At doses of 12.5 to 100 micrograms kg-1 min-1 it is natriuretic and also tends to increase renal blood flow and glomerular filtration. Despite the natriuresis, plasma renin activity is depressed and this effect is blocked by domperidone. The receptors for the tubular natriuretic effect are blocked by d-sulpiride. 3. Four-hour infusions in man do not lower blood pressure; 10-h infusions lower blood pressure and increase pulse rate. 4. The oral bioavailability of gludopa is only 1 to 2% and this rules out the dipeptide as an effective dopaminergic prodrug.

Biological Availability↗
PubMed1990

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg-1. 2. Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 +/- 9.6 ml min-1 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. The mean residence time and half-life were 20.9 +/- 1.4 and 14.4 +/- 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 +/- 0.18 l kg-1. 3. No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4. In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5. These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.

Acute Kidney Injury↗
PubMed1990

Ethnic differences in the renal dopamine response to an oral salt load.

Dopamine is a natriuretic hormone which is synthesised within the kidney. We have previously found that some ethnic groups (e.g. British Caucasians and Thais) show strong positive correlations between 24 h urinary sodium and dopamine outputs. However no such relationship was found in Iranians and black West Africans. We have now studied the effect of oral salt loading (200 mmol) on 24 h urinary sodium and dopamine outputs in individuals from these four ethnic groups. The Caucasians showed a significant increase (35%) in urinary dopamine output after salt loading. However, there was no dopamine response to the salt load in the Ghanaians and the Iranians. The Thais were all vegetarians and fell into two distinct groups with either an increase ('positive responders') or decrease ('negative responders') in dopamine output after salt loading. The negative responders all had a very low mean control sodium output (60 +/- 21 mmol/24 h) compared to the positive responder Thais and the other three ethnic groups which all had mean sodium outputs greater than 115 mmol/24 h. We hypothesize that in some racial groups the uncoupling of the renal sodium-dopamine relationship may be an inherited mechanism to help conserve sodium (as in the Ghanaians and the Iranians) or an adaptive change to being restricted to a low salt diet for a long time (as in the Thai 'negative responders').

Asian People↗
PubMed1989

Ethnic differences in the renal sodium-dopamine relationship: a possible explanation for regional variation in the prevalence of hypertension?

Twenty-four-h urinary sodium and dopamine output by normotensive adults from 5 different ethnic groups have been measured. The groups differed substantially in the correlation between the urinary output to sodium and dopamine. Those with a traditionally salt rich diet (Thais, Caucasians, Zimbabweans) showed a strong positive correlation (p less than 0.001), whereas no such relationship was found in West Africans and Iranians, who come from traditionally salt scarce environments. It is hypothesised that in some races the lack of or uncoupling of the renal sodium-dopamine relationship, possibly as a mechanism to help conserve dietary sodium, predisposes to the development of hypertension when the individuals encounter a salt rich diet.

Adaptation, Physiological↗
PubMed1989

Carbidopa does not affect the renal response to atrial natriuretic factor in man.

1. The dependence of atrial natriuretic factor on renal dopamine for its renal effects in man was examined in 10 healthy volunteers using the dopa decarboxylase inhibitor carbidopa. 2. Each volunteer attended on two occasions, and received an infusion of atrial natriuretic factor (4 pmol min-1 kg-1) for 60 min after pretreatment with either placebo or carbidopa orally. These were administered in random, double-blind fashion. 3. A similar increase in plasma atrial natriuretic factor concentration was seen after atrial natriuretic factor infusion on both visits. 4. Infusion of atrial natriuretic factor produced a small unsustained rise in urinary dopamine excretion. This increase in urinary dopamine excretion was blocked by carbidopa with no effect on the natriuresis. 5. Urinary guanosine 3':5'-cyclic monophosphate excretion increased in response to the atrial natriuretic factor infusion whether placebo or carbidopa was given. Guanosine 3':5'-cyclic monophosphate, but not dopamine, may be a mediator of the renal response to atrial natriuretic factor in man.

Adult↗
PubMed1989

The effect of carbidopa and lithium on the systemic and renal response to acute intravenous saline loading in normal man.

To assess a possible role for endogenous renal dopamine in sodium excretion, the dopa decarboxylase inhibitor carbidopa was given during intravenous salt loading. In addition, the effect of lithium on tubular sodium handling was separately determined. Nine males were studied randomly on three occasions, receiving placebo, lithium carbonate (1000 mg, 11 h prior to study) or carbidopa (100 mg x 2). On each day a baseline period was followed by infusion of isotonic saline (20 ml/kg per hour) over 3 h, and 6 h recovery. With placebo, sodium excretion increased markedly to a peak in the hour after infusion (0.15 +/- 0.03 to 0.73 +/- 0.12 mmol/min, P less than 0.01). Urine dopamine excretion increased modestly (1.33 +/- 0.12 to 1.67 +/- 0.13 mmol/min, P less than 0.01). Carbidopa effectively blocked dopamine output during the study. However, the natriuretic response was comparable to values on placebo at all time points. Fractional lithium clearance, a proposed measure of proximal tubular fluid rejection, increased significantly during saline infusion. However, baseline sodium excretion was greater in the presence of lithium, and plasma renin activity (PRA) was significantly elevated. In addition, the peak natriuretic response was smaller and cumulative sodium excretion reduced by 40% (P less than 0.01) compared to placebo. This study provides no evidence for a facilitatory role for dopamine in the natriuretic response to intravenous salt loading. Lithium, at subtherapeutic levels, cannot be presumed to be an inert marker, and clearance data must be interpreted with caution.

Adult↗
PubMed1989

The renal and haemodynamic effects of a 10 h infusion of glutamyl-L-dopa in normal man.

1. gamma-L-glutamyl-L-dopa (gludopa) and placebo were given by intravenous infusion to 12 healthy salt replete men for 10 h in a single-blind randomised fashion. 2. Gludopa caused a cumulative natriuresis of 46.5 mmol compared with placebo with a biphasic pattern and this was associated with a small reduction in body weight. 3. A small fall in arterial blood pressure and rise in pulse rate was seen with gludopa. 4. Plasma renin activity, atrial natriuretic peptide and urine kallikrein excretion were unchanged by gludopa but a small fall in urine aldosterone excretion, urine flow rate and free water clearance occurred. 5. The renal effects of gludopa are modest and last for only a few hours after the start of infusion.

Adult↗
PubMed1989

The renal effects of atrial natriuretic peptide in man are not attenuated by (+)-sulpiride.

1. Human alpha atrial natriuretic peptide (ANP) was infused intravenously for 1 h in eight healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. ANP increased sodium excretion and urine flow rate but did not alter blood pressure or plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline creatinine clearance, sodium excretion or urine flow rate and did not alter the increases in these parameters with ANP. 4. It is unlikely that the renal effects of ANP are mediated by dopamine DA1-receptors in man.

Adult↗
PubMed1989

Dopamine, the kidney and essential hypertension.

The evidence for dopamine as an intrarenal natriuretic hormone is reviewed. Some patients with essential hypertension may have an uncoupling of the sodium to dopamine relationship in the kidney and their blood pressures may respond particularly well to dopaminergic agonists.

Animals↗
PubMed1988

Quantitative immunoassay of recombinant murine neuroleukin.

A eukaryotic, transient expression system was used to produce recombinant neuroleukin, a growth factor for neurons. Neuroleukin in media conditioned by transfected monkey COS-1 cells was purified to homogeneity in one step by high-performance cation-exchange chromatography. Purified neuroleukin was used to establish a quantitative two-site enzyme-linked immunosorbent assay and the accuracy of the assay was confirmed by analytical high-performance liquid chromatography. The amount of recombinant neuroleukin secreted by the transfected COS-1 cells and the content of endogenous neuroleukin in various murine cell lines was determined. Neuroleukin levels were nearly undetectable in Balb/3T3 embryo cells, intermediate in several leukocytic cell lines and highest in mouse LBRM-33 T lymphoma cells. Maximal survival of sensory neurons was obtained with approximately 10(-9) M recombinant neuroleukin although tissue derived neuroleukin appeared to be significantly more active. Dialysis of the transfected COS-1 cell conditioned medium resulted in increased neuroleukin bioactivity, while binding to the cation-exchange column reduced bioactivity. The expression and purification of the recombinant protein and the detection of natural sources expressing high levels of neuroleukin will greatly facilitate studies of its biological effects.

Amino Acids↗
PubMed1988

A comparison of the renal actions of gamma-L-glutamyl-L-dopa and gamma-L-glutamyl-L-tyrosine in normal man.

1. The renal responses to the dipeptides gamma-L-glutamyl-L-dopa (gludopa) and gamma-L-glutamyl-L-tyrosine (glutyrosine) were compared when given intravenously in six normal male volunteers. 2. Gludopa is natriuretic and diuretic at a dose of 25 micrograms min-1 kg-1. At the same dose, glutyrosine had no effect on the volume or sodium content of the urine. 3. There was a 400-600-fold increase in urine dopamine output after gludopa; there was no conversion of glutyrosine to dopamine. 4. Gludopa significantly inhibited plasma renin activity, whereas with glutyrosine there was a non-significant increase. 5. Gludopa is a potent pro-drug for renal dopamine production and exerts natriuretic and hormonal effects. Glutyrosine appears to be inactive. The results support the contention that circulating L-dopa is the important physiological precursor for renal dopamine.

Adult↗
PubMed1988

Further ethnic differences in the renal sodium-dopamine relationship: its uncoupling in Iranian but not in Thai normotensive subjects.

Dopamine is a natriuretic hormone and is synthesized in the kidney in response to a sodium load. This relationship results in a positive correlation between urinary sodium and dopamine outputs. Uncoupling of the renal sodium-dopamine relationship is reflected in a loss of this correlation and will result in the sluggish excretion of a sodium load. We measured 24-h urinary sodium and dopamine outputs in Thais and Iranians, who traditionally have very different dietary salt environments (salt-rich and salt-scarce, respectively). There was a highly significant positive correlation between sodium and dopamine in the Thais (r = 0.53, P less than 0.001) but no suggestion of such a correlation in the Iranians (r = 0.03). We hypothesize that in some races the uncoupling of the renal sodium-dopamine relationship, possibly as a mechanism to help conserve dietary sodium, predisposes the race to the development of hypertension when the individuals encounter a salt-rich diet.

Dopamine↗