Biomedical subjects

M R Lee

Publications and source records attributed to M R Lee.

At least 19 recordsLinked to original sources

PubMed1992

Distinct promoters direct neuronal and nonneuronal expression of rat aromatic L-amino acid decarboxylase.

Aromatic L-amino acid decarboxylase (AADC, EC 4.1.1.28) catalyzes the decarboxylation of L-dopa to dopamine in catecholamine cells and 5-hydroxytryptophan to serotonin in serotonin-producing neurons. This enzyme is also expressed in relatively large quantities in nonneuronal tissues such as liver and kidney, where its function is unknown. Neuronal and nonneuronal tissues express AADC mRNAs with distinct 5' untranslated regions. To understand how this is accomplished at the genomic level, we have isolated rat genomic DNA encoding AADC. The organization of the AADC gene suggests that there are two separate promoters specific for the transcription of neuronal and nonneuronal forms of the AADC message. A small exon containing 68 bases of the neuronal-specific 5' end is located approximately 9.5 kilobases upstream of the translation start site, which is contained in the third exon. Approximately 7 kilobases upstream from the neuron-specific promoter is another small exon containing 71 bases of the 5' end of the nonneuronal AADC message. These data suggest that transcription initiating at distinct promoters, followed by alternative splicing, is responsible for the expression of the neuronal and nonneuronal forms of the AADC message.

Animals↗

PubMed1992

Isolation and characterization of nuclear proteins that bind to T cell receptor V beta decamer motif.

TCR V beta promoter contains a highly conserved decamer homologous to cAMP response element (CRE). Recent studies have identified this CRE decamer as the dominant transcription-activating element within the TCR V beta promoter. We have isolated cDNA clones, TCR-ATF1 and TCR-ATF2, encoding DNA-binding proteins that recognize this CRE motif. The nucleotide sequence of TCR-ATF1 has not previously been reported, whereas that of TCR-ATF2 was homologous to CRE-BP1, ATF-2, and mXBP. Both TCR-ATF1 and TCR-ATF2 shared a conserved leucine zipper and DNA binding motif with other CRE-binding proteins. TCR-ATF1 and TCR-ATF2 were expressed in all cell lines examined and in mouse embryos as early as 12.5 days. Despite binding to the same CRE motif, TCR-ATF1 and TCR-ATF2 were different from CREB in the fine nucleotide specificity. TCR-ATF bound methylated CRE and CRE mutant M4 (4C----G) that were not recognized by CREB. Additionally, TCR-ATF1 weakly recognized two other single nucleotide mutants of V beta-CRE that were not bound by TCR-ATF2 and CREB. We have further demonstrated that TCR beta-chain expression was immediately activated by cAMP. Such induction is likely mediated through V beta-CRE sequence, because the inclusion of V beta-CRE in a vector with minimum promoter (pBLCAT2) conferred the cAMP inducibility of CAT activity.

Amino Acid Sequence↗

PubMed1992

Lithium pretreatment affects renal and systemic responses to angiotensin II infusion in normal man.

1. Renal and systemic responses to infusion of angiotensin II (1.25 and 2.5 ng min-1 kg-1 body weight) were examined in ten normal males 12 h after single doses of 750 mg of lithium carbonate, 250 mg of lithium carbonate (n = 6) or placebo. 2. Baseline mean arterial pressure [mean (SEM)] was higher after 750 mg of lithium [93.1 (1.7) versus 89.5 (1.9 mmHg, P = 0.014], and the subsequent rise in blood pressure during angiotensin II infusion was lower [8.2 (1.8) versus 12.2 (2.4) mmHg, P less than 0.02]. 3. Lithium at a dose of 750 mg increased overnight urinary sodium excretion before the study. The fall in fractional sodium excretion during angiotensin II infusion was reduced after pretreatment with 750 mg of lithium [750 mg of lithium, 2.73 (0.24) to 1.34 (0.08)%; placebo, 2.69 (0.26) to 1.01 (0.11)%; P = 0.02]. The increases in effective filtration fraction [750 mg of lithium, 5.4 (1.0)%; placebo, 8.6 (0.7)%; P less than 0.05] and total effective renal vascular resistance [750 mg of lithium, 3700 (390) dyn s cm-5; placebo 5100 (460) dyn s cm-5; P = 0.03] during angiotensin II infusion were also attenuated after 750 mg of lithium. Responses after 250 mg of lithium did not differ from those after placebo. 4. The fall in plasma renin activity and the increase in plasma aldosterone concentration during angiotensin II infusion were similar on each study day. 5. Renal responses to exogenous angiotensin II are altered after pretreatment with a 750 mg dose of lithium in normal man. This dose of lithium is not an inert marker of sodium handling.

Adult↗

PubMed1991

A single dose study of the effects of fenoldopam and enalapril in mild hypertension.

To clarify the contribution made by the renin-angiotensin system activation to the short lived hypotensive response to fenoldopam, the haemodynamic effects of a combination of fenoldopam (100 mg) and enalapril (5 mg) were compared with fenoldopam alone, enalapril alone and placebo in a balanced, randomised, double blind, single dose study in eight hypertensive patients. Fenoldopam caused an acute fall in blood pressure which lasted approximately 3 h after dosing and was associated with a reflex tachycardia. Enalapril caused a more gradual fall in blood pressure (onset 2 h) without a reflex tachycardia. The combination of drugs produced greater reductions in blood pressure sustained for a longer period than fenoldopam alone and with a more rapid onset than enalapril alone. In combination the hypotensive effects of fenoldopam and enalapril were clearly additive and not synergistic. Activation of the renin-angiotensin system does not antagonise significantly the hypotensive effect of fenoldopam.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

Oral carbidopa has no effect on the renal response to angiotensin II in normal man.

1. The effect of inhibition of intrarenal dopamine synthesis by carbidopa on the renal response to angiotensin II infusion was studied in six healthy salt-loaded volunteers. 2. Subjects received an infusion of angiotensin II at two doses (0.5 and 1.0 ng min-1 kg-1) on two occasions. Before one study they took a single dose of carbidopa (100 mg) by mouth. 3. The plasma concentrations of angiotensin II produced by the infusion were similar on both study days. Angiotensin II infusion reduced urinary dopamine excretion on the control day. Urinary dopamine excretion was undetectable at all times after carbidopa, but carbidopa did not change the basal excretion rate of sodium. Despite inhibition of renal dopamine synthesis, the reductions in both absolute and fractional sodium excretion during the angiotensin II infusion were not different from those seen in the control study. 4. The reductions in glomerular filtration rate and effective renal plasma flow which occurred during angiotensin II infusion were not modified by pretreatment with carbidopa. 5. The renal response to angiotensin II is not modulated either wholly or in part by endogenous intrarenal dopamine levels. The fall in urinary dopamine excretion which occurs during angiotensin II infusion is consistent with a modulatory role for tubular reabsorptive capacity in the regulation of proximal tubular dopamine synthesis.

Adult↗

PubMed1991

Disposition of gamma-glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg-1 and 100 micrograms kg-1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/- 1.50 ml min-1 kg-1 and 4.92 ml min-1 kg-1 at the higher and lower doses, respectively. Corresponding half-lives were 29.2 +/- 3.7 min and 32.5 +/- 5.6 min, and volumes of distribution were 0.183 +/- 0.052 l kg-1 and 0.235 +/- 0.07/ l kg-1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro-drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.

Adult↗

PubMed1990

A preliminary study of the dopamine DA1 agonist fenoldopam in the treatment of chronic left ventricular failure due to ischaemic heart disease.

The effects of chronic oral fenoldopam in the treatment of NYHA grade II-III heart failure secondary to ischaemic heart disease, were studied in a placebo controlled, double blind, randomised, parallel group fashion in 20 patients. Nine patients taking placebo and six taking fenoldopam completed the study. Adverse events were similar in each group. There were no significant changes in exercise capacity, ejection fraction, body weight or symptom questionnaires with either treatment. This preliminary study has not revealed any benefit of fenoldopam in heart failure due to ischaemic heart disease.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

Effect of lithium on the renal actions of alpha-human atrial natriuretic peptide in normal man.

1. alpha-Human atrial natriuretic peptide (7.5 pmol min-1 kg-1) was infused intravenously into eight healthy men after pretreatment with lithium carbonate (750 mg) or placebo. 2. Baseline sodium excretion was significantly increased after lithium, but the natriuresis during infusion of alpha-human atrial natriuretic peptide was attenuated. 3. Similar decreases in plasma renin activity with infusion of alpha-human atrial natriuretic peptide occurred on both days. 4. Administration of lithium may be associated with pharmacological effects and further work is required to validate the use of lithium clearance as a marker of proximal renal tubular sodium handling.

Adult↗

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↗