Metabolic effects of low-dose dopamine infusion in normal volunteers

1. Dopamine in 5% (w/v) D-glucose was infused into five healthy male volunteers at doses of 2, 5 and 10 micrograms min-1 kg-1 over three sequential periods of 45 min each. 2. Oxygen consumption, respiratory exchange ratio, blood glucose concentration and plasma levels of free fatty acids, glycerol, lactate, dopamine, adrenaline and noradrenaline were measured. The results were compared with values obtained during infusion over the same time period of the corresponding volumes of 5% (w/v) D-glucose alone. 3. Energy expenditure calculated from the oxygen consumption and the respiratory exchange ratio was higher than control values during infusion of dopamine (P less than 0.001, analysis of variance) specifically at a rate of 10 micrograms min-1 kg-1 (P less than 0.05) when it was 14% higher, but not at a rate 2 of or 5 micrograms min-1 kg-1. The plasma noradrenaline concentration was 74 and 230% and the blood glucose concentration was 21 and 36% higher than control values at 5 and 10 micrograms of dopamine min-1 kg-1, respectively (P less than 0.01). At 10 micrograms of dopamine min-1 kg-1 the plasma free fatty acid concentration was 70% and the plasma glycerol concentration was 80% higher than during the control infusion (P less than 0.01). The respiratory exchange ratio and the plasma lactate concentration were the same in the two groups and did not alter during the dopamine infusion. The plasma adrenaline concentration rose significantly (P less than 0.01), but only transiently, during dopamine infusion at a rate of 2 micrograms min-1 kg-1. 4. Dopamine at low doses has metabolic effects. It increases the blood glucose concentration and the circulating noradrenaline level at an infusion rate of 5 micrograms min-1 kg-1. It increases energy expenditure and circulating free fatty acid and glycerol levels at an infusion rate of 10 micrograms min-1 kg-1, presumably due to stimulation of lipolysis.     

Effect of metoclopramide on dopamine-induced changes in renal function in healthy controls and in patients with renal disease

1. The effects of intravenous metoclopramide on baseline values and dopamine dose-response curves for renal haemodynamics and natriuresis were investigated in healthy volunteers and patients with renal disease. 2. Dopamine infusion alone, in doses ranging from 0.25 to 8 micrograms min-1 kg-1, resulted in a dose-dependent increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) with a fall in filtration fraction (FF) in eight hydrated healthy volunteers and, to a lesser degree, in 12 patients with renal disease. An increase in natriuresis (urinary excretion of sodium, UNa+V), fractional excretion of sodium (FENa+) and diuresis (urine flow rate, UV) was found in both groups for doses of 2 micrograms min-1 kg-1 and higher. 3. Metoclopramide infusion did not alter baseline values of GFR, ERPF or FF, but shifted the dopamine dose-response curve for ERPF and FF in the healthy volunteers. Metoclopramide induced a fall in UNa+V and FENa+ in both groups (fall in baseline FENa+ from 1.52 to 0.71 during metoclopramide in healthy volunteers and from 1.23 to 0.56 in patients; P less than 0.01) and blunted the natriuretic response to subsequent dopamine infusion. The fall in UNa+V during metoclopramide infusion showed a strong correlation with baseline GFR (r = -0.944). In the patients, the response for the fractional excretions of beta 2-microglobulin and gamma-glutamyltransferase was comparable with that of FENa+. 4. Dopamine infusion induced a fall, and metoclopramide led to rise, in plasma aldosterone concentration. 5. We conclude that metoclopramide acts as a dopamine antagonist at the renal level in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Metabolic effects of dobutamine in normal man.

1. Dobutamine in 5% (w/v) D-glucose was infused at sequential doses of 2, 5 and 10 micrograms min-1 kg-1, 45 min at each dose, into eight healthy male subjects, and the effects were compared with those produced by infusion of the corresponding volumes of 5% (w/v) D-glucose alone. 2. The energy expenditure increased and was 33% higher than control (P less than 0.001) at 10 micrograms of dobutamine min-1 kg-1. The respiratory exchange ratio decreased from 0.85 (SEM 0.02) before infusion to 0.80 (SEM 0.01) at 10 micrograms of dobutamine min-1 kg-1, but did not alter during the placebo infusion (P less than 0.001). 3. Plasma noradrenaline concentrations were lower during the dobutamine infusion compared with during the infusion of D-glucose alone (P less than 0.025). Plasma dopamine concentrations remained below 0.1 nmol/l throughout both infusions. 4. Compared with during the placebo infusion, the blood glucose concentration decreased (P less than 0.001), the plasma glycerol and free fatty acid concentrations increased by 150 and 225%, respectively (both P less than 0.001), and the plasma potassium concentration decreased from 3.8 (SEM 0.07) to 3.6 (SEM 0.04) mmol/l (P less than 0.01) during dobutamine infusion. The plasma insulin concentration increased at 2 and 5 micrograms of dobutamine min-1 kg-1 (P less than 0.001) with no further rise at 10 micrograms of dobutamine min-1 kg-1. 5. Compared with during the placebo infusion, the systolic and diastolic blood pressures and the heart rate increased during dobutamine infusion (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative analysis of the contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines

The contribution of pulmonary and hind limb circulation to the clearance of exogenous catecholamines was analyzed quantitatively. During infusion of clinical doses of norepinephrine, epinephrine and dopamine in dogs, the plasma level of catecholamine and the plasma flow were measured simultaneously. Percentage of contribution was calculated from the following equation; transorgan difference of plasma catecholamine (nanograms per milliliter) X plasma flow (milliliters per minute) X 100/dose (nanograms per minute). This value means the percentage of the amount of catecholamine cleared by an organ to the amount of catecholamine administered into the body. Small but significant transpulmonary gradients of plasma levels of norepinephrine, epinephrine and dopamine and large translimb gradients of plasma levels of these catecholamines were observed. The plasma flow of pulmonary circulation was increased by infusion of epinephrine and dopamine, whereas it remained unchanged by infusion of norepinephrine. The plasma flow of hind limb circulation showed no significant change by infusion of catecholamines. The calculated contribution values indicate that pulmonary circulation clears 35.7% of norepinephrine (at 0.2 ng X kg-1 X min-1), 27.1% of epinephrine (0.2 ng X kg-1 X min-1) and 21.5% of dopamine (10 micrograms X kg-1 X min-1) administered exogenously, and that the corresponding figures for hind limb circulation are 8.2, 7.8 and 4.5%.     

Subcutaneous and muscle blood flow during dopamine infusion in man

Subcutaneous fat tissue and skeletal-muscle blood flow was measured in six male volunteers using the local 133Xe-washout method. Measurements were obtained before and during intravenous dopamine infusion in non-pressor (1 microgram kg-1 min-1) and pressor infusion rates (3-6 micrograms kg-1 min-1). During non-pressor infusion rate the systolic and diastolic arterial pressure and heart rate remained unchanged. When pressor dose dopamine was infused the systolic and mean arterial pressures increased significantly, whereas the diastolic pressure and the heart rate were left unchanged. The blood flow increased progressively from control values in both subcutis (control: 2.9 +/- 0.2, non-pressor: 5.0 +/- 1.6, pressor: 9.1 +/- 0.4 ml min-1 100 g-1, mean +/- SEM) and in skeletal muscle (control: 1.2 +/- 0.2, non-pressor: 1.5 +/- 0.2, pressor: 1.9 +/- 0.4 ml min-1 100 g-1, mean +/- SEM) and was significantly different from baseline values at any dopamine infusion rate. Side-effects were observed only at pressor dose infusion. It is concluded that dopamine in humans seems to possess vasodilatoric properties in subcutaneous fat tissue, and in skeletal muscles.     

Atrial natriuretic peptide inhibits osmolality-induced arginine vasopressin release in man

1. Eight normal volunteers were infused with 5% saline (5 g of NaCl/100 ml) at a rate of 0.06 ml min-1 kg-1 for 120 min to increase plasma osmolality and plasma arginine vasopressin. Human atrial natriuretic peptide (alpha-hANP; 100 micrograms) or placebo was given in random order in a double-blind cross-over design for the last 20 min of the saline infusion. 2. Compared with the placebo infusion, atrial natriuretic peptide (ANP) produced a 43% greater sodium excretion and a 34% greater urinary volume in the subsequent hour. 3. Mean plasma immunoreactive ANP did not increase in response to changes in osmolality and rose to a peak of 118 pg/ml during the alpha-hANP infusion. alpha-hANP produced significant suppression of mean plasma arginine vasopressin over the 60 min after the infusions. 4. We conclude that ANP is not released in response to increased osmolality in vivo, and that it inhibits osmolality-induced arginine vasopressin release in man.     

The effect of low-dose dopamine infusion on anterior pituitary hormone secretion in normal female subjects

The effect of low-dose dopamine infusion on anterior pituitary hormone secretion in a group of seven healthy female subjects is reported. Subjects were infused with NaCl solution (154 mmol/l) (control) or dopamine (0.01 and 0.1 micrograms min-1 kg-1 for 120 min at each rate) on separate days in the early follicular phase of consecutive menstrual cycles. Serum prolactin decreased during infusion of dopamine at 0.01 micrograms min-1 kg-1 but a similar fall was found in the control group. When the rate of dopamine infusion was increased to 0.1 micrograms min-1 kg-1 a further substantial decrease in prolactin concentration occurred, whereas prolactin in the control group showed no change. At the end of the period of dopamine infusion at 0.1 micrograms min-1 kg-1 serum prolactin remained significantly (P less than 0.025) lower than in the control group (85 +/- 12 vs 180 +/- 21 m-units/1). No change in thyrotrophin (TSH), growth hormone (GH) or luteinizing hormone (LH) was seen during either rate of dopamine infusion compared with control. While dopamine infusion at 0.1 micrograms min-1 kg-1 caused significant inhibition of prolactin secretion in normal female subjects, other pituitary hormone secretion was not affected: it is suggested that under the conditions of this study dopamine in hypophysial portal blood is not of primary importance in the control of basal TSH, GH and LH release.     

Distribution of free and conjugated catecholamines between plasma, platelets and erythrocytes: different effects of intravenous and oral catecholamine administrations

Plasma, platelet and erythrocyte contents of free and conjugated norepinephrine, epinephrine and dopamine were determined by radioenzymatic assay in 12 resting healthy volunteers. Mean platelet/plasma concentration ratios were 533 for free norepinephrine, 502 for free epinephrine and 149 for free dopamine. Corresponding erythrocyte/plasma ratios were 1.04, 1.13 and 4.5, respectively. The presence of conjugated catecholamines in platelets and erythrocytes could be confirmed; however, their relative proportion within these cells, particularly in platelets, was lower than that in plasma. Upon intravenous infusion of dopamine for 3 hr at 5 micrograms kg-1 min-1, concentrations of free dopamine in plasma increased rapidly (280-970-fold), whereas conjugated dopamine only reached maximal values (14-19-fold increase) at 30 to 60 min after cessation of the infusion. The relative distribution of unconjugated dopamine in whole blood between plasma, platelets and erythrocytes changed from mean values of 1:0.33:3.7 at rest to 1:1.1:0.5 at the end of the infusion. As a result of the subsequent rapid decrease of dopamine in plasma and erythrocytes, this distribution was 1:17:1 shortly thereafter and remained constant up to the end of the investigation period. The relative distribution for conjugated dopamine of 1:0.001:0.5 at rest changed to about 1:0.2:0.1 at the termination of the infusion. Oral administration of norepinephrine and dopamine led to increases in the plasma concentrations of these amines in their conjugated forms only, whereas epinephrine concentrations remained constant. These elevations were not accompanied by corresponding increases in platelet and erythrocyte norepinephrine, epinephrine and dopamine contents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide increases albuminuria in type I diabetic patients: evidence for blockade of tubular protein reabsorption

BACKGROUND: It has been suggested that atrial natriuretic peptide (ANP) contributes to the glomerular hyperfiltration of diabetes mellitus. Infusion of ANP increases the urinary excretion of albumin in patients with type I diabetes mellitus (IDDM). Although the increased albuminuria is attributed to a rise in glomerular pressure, alterations in tubular protein handling might be involved. PATIENTS AND METHODS: We have studied the effects of ANP in nine microalbuminuric IDDM patients. After obtaining baseline parameters, ANP was infused over a 1-h period (bolus 0.05 microgram kg-1, infusion rate 0.01 microgram kg-1 min-1). Renal haemodynamics, sodium and water clearance and tubular protein handling were studied. RESULTS: The glomerular filtration rate (GFR) increased from 116.4 +/- 8.9 to 128.3 +/- 8.8 mL min-1 1.73 m-2, whereas the effective renal plasma flow (ERPF) decreased from 534.3 +/- 44.3 to 484.9 +/- 33.3 mL min-1 1.73 m-2 (P < 0.05). As a result, the filtration fraction was significantly higher during infusion of ANP. ANP attenuated proximal tubular sodium reabsorption. Urinary albumin excretion rose from 87.57 +/- 21.03 to 291.40 +/- 67.86 micrograms min-1 (P < 0.01). Changes in the urinary excretion of beta 2-microglobulin and free kappa light chains were more marked, the excretion of beta 2-microglobulin increasing from 0.28 +/- 0.21 to 51.87 +/- 10.51 micrograms min-1 (P < 0.01), and of free kappa-light chains from 4.73 +/- 1.74 to 46.14 +/- 6.19 micrograms min-1 (P < 0.01). CONCLUSIONS: The observed rise in albuminuria during infusion of ANP does not simply reflect a change in glomerular pressure, but might at least partly result from an attenuation of tubular protein reabsorption.     

Haemodynamic effects of vasopressin in man are related to posture

Ten healthy volunteers received intravenous infusions of arginine vasopressin (AVP) at 0.1 m-unit min-1 kg-1 and 5% D-glucose on separate days. AVP caused a small fall in forearm blood flow and small rises in mean arterial pressure and systemic vascular resistance. Cardiac output was unaffected. When subjects were tilted to 50 degrees the fall in forearm blood flow was much greater, mean fall being 44.8% with AVP compared with 18.2% with D-glucose. Cardiac output also fell significantly more with AVP, and diastolic pressure, mean arterial pressure and systemic vascular resistance rose significantly more on tilting during AVP infusion than with D-glucose. Six of the same volunteers were given sequential infusions of 'low dose' (0.0125 m-unit min-1 kg-1) and 'high dose' (0.3 m-unit min-1 kg-1) AVP on a third occasion. Tilting still produced a mean fall in forearm blood flow of 41.2% during low dose infusion, despite a mean plasma AVP level of only 1.9 pg/ml, which is well within the physiological range. When the AVP concentration was increased 24-fold to the high dose, forearm blood flow fell only a further 8.8%. The low dose infusion was also associated with a marked fall in cardiac output on tilting and a rise in systemic vascular resistance. We conclude that AVP has profound haemodynamic effects in man at physiological concentrations. Although these effects are modest in the supine position, they become marked on tilting, suggesting a possible role for AVP in the postural control of blood pressure.     

Lithium clearance in dogs: effects of water loading, amiloride and lithium dosage.

1. The influences of lithium dosage, urine flow rate and acute administration of amiloride on the renal handling of lithium in normal conscious dogs were investigated. 2. Lithium was administered in the diet at daily doses of 100 mg or 2 mg of lithium carbonate for the 2 days preceding the investigation. Urine flow rate was altered by water loading with and without arginine vasopressin infusion (5 pg min-1 kg-1). Amiloride was administered as an intravenous bolus (130 micrograms/kg) followed by a continuous infusion (1.22 micrograms h-1 kg-1). 3. Glomerular filtration rate (exogenous creatinine clearance) did not change within series and was not different between series; it averaged 3.27 ml min-1 kg-1. Control levels of fractional lithium excretion (12.4 +/- 1.2%, mean +/- SEM) were not influenced by hydration, hydration plus arginine vasopressin administration or the lithium dosage. However, in hydrated dogs having a plasma lithium concentration of 130-140 mumol/l, amiloride administration was associated with a 5% increase in fractional lithium excretion (P less than or equal to 0.01). 4. It is concluded that distal tubular lithium reabsorption may take place in sodium-replete conscious dogs undergoing water diuresis. The low fractional lithium excretion even during amiloride infusion (14.1-16.8%) may well be due to a high fractional reabsorption of lithium in the proximal tubules; however, a significant reabsorption of lithium distal to the proximal straight tubules by amiloride-insensitive pathways cannot be excluded.     

Atrial natriuretic peptide: an endogenous factor enhancing sodium excretion in man

For many years experimental evidence has suggested the existence of a circulating factor able to enhance sodium excretion. Very recently peptides with natriuretic activity in experimental animals have been isolated from mammalian and human cardiac tissue. In order to determine whether this natriuretic activity has relevance to man we have studied the effects of an infusion of alpha-human atrial natriuretic peptide (alpha-h-ANP) in normal subjects. Sodium excretion trebled (P = less than 0.005) during the infusion of a calculated dose of 15 pmol of alpha-h-ANP min-1 kg-1 and there was an accompanying diuresis; radioimmunoassay of plasma alpha-h-ANP during the natriuresis indicated a mean peak incremental concentration of 203 +/- 78 (SEM) pmol/l. The infusion of a calculated dose of 1.5 pmol min-1 kg-1 did not affect sodium excretion. There were no haemodynamic changes and no side effects were noted.     

Enhanced urinary excretion of albumin and beta 2 microglobulin in essential hypertension induced by atrial natriuretic peptide.

Atrial natriuretic peptide (ANP) was given as an intravenous bolus injection (2.0 micrograms kg-1) to 12 essential hypertensive patients (EH) and 10 normotensive control subjects (C) in order to study the effect of ANP on urinary excretion of albumin and beta 2-microglobulin, and on glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF). After the ANP injection, urinary excretion of albumin increased significantly (p less than 0.01) in EH from 7.3 micrograms min to 125 micrograms min (medians) and in C from 2.9 micrograms min-1 to 8.1 micrograms min-1 (p less than 0.05). Urinary excretion of beta 2-microglobulin increased in EH from 70 ng min-1 to 1022 ng min-1 (p less than 0.01) and in C from 118 ng min-1 to 170 ng min-1 (p less than 0.01). The increase in urinary excretion of both albumin (p less than 0.01) and B2-microglobulin (p less than 0.01) was significantly more pronounced in EH than in C. GFR and RPF were almost unchanged in both groups. FF rose to the same degree in the two groups. The increase in fractional excretion of sodium and in urine volume after ANP was enhanced in EH. It is concluded that ANP in pharmacological doses increased urinary excretion of albumin and beta 2-microglobulin to a considerably larger extent in essential hypertensive patients than in normotensive control subjects.     

Biokinetic characterization of human glycerin utilization

23 patients received controlled infusions of 10% glycerol solution using an "Infusomat". During various rates of infusion biokinetic parameters and renal excretion were measured. The concentration of glycerol in the serum rises over-proportional with increasing rates of infusion. The extrapolated maximal metabolic turnover capacity is 54 micronmol.kg-1.min-1. Halb-maximal turnover rate is reached at a serum level of 0,56 micronmol.ml-1. After an infusion of 0,3 g.kg-1.min-1 glycerol disappears from the blood with an elimination constant of 0,024 min-1 and a half life of 28,9 minutes. Renal excretion increases with the dose but remains below 10% of the dose in the investigated range. From the data it can be concluded that glycerol cannot be applicated in higher doses than other polyols. No adverse reactions have been observed in the range up to 0,3 g.kg-1.min-1.     

Renal haemodynamics and tubular sodium handling following volume expansion with sodium chloride (NaCl) and glucose in healthy humans.

Renal haemodynamics estimated using inulin- and para-aminohippuric acid-(PAH) clearances and segmental tubular handling of sodium as estimated using lithium clearance where studied in fourteen healthy men. Volume expansion was induced by a 2 h (25 ml kg-1) infusion of 0.9% sodium chloride (NaCl) load. Eight of the 14 subjects were rechallenged with a 2 h infusion of 5% glucose (25 ml kg-1). In addition, ten healthy subjects were investigated with inulin and PAH-clearances during water diuresis. When NaCl was infused glomerular filtration rate (GFR) decreased from 115 to 103 ml min-1 (p < 0.002) and fractional sodium excretion increased by 85%. The fall in GFR could be due to tubuloglomerular feedback as a result of inhibition of proximal tubular sodium reabsorption. The fall in GFR raises doubt about the usefulness of NaCl as an inert control infusion in metabolic studies. During glucose infusion blood glucose rose from 4.3 to 10.9 mmol l-1 with no significant change in GFR, but fractional sodium excretion was reduced by almost 40%. The etiology of the acute antinatriuretic effect of volume expansion with glucose infusion in healthy humans is not known but a blunted decrease in plasma renin activity and erythrocyte volume fraction in conjunction with a failure to mobilize renal dopamine and an increase in plasma levels of antinatriuretic factors such as insulin and norepinephrine are all factors that may contribute to the antinatriuretic effect of a glucose infusion.     

The effect of indomethacin on the renal response to arginine vasopressin in man

The renal response to graded intravenous infusions of arginine vasopressin (AVP) was investigated in a two part study in six volunteers. First, under maximal water diuresis, seven control incremental infusions of AVP were given from zero to 12 fmol min-1 kg-1. Second, the AVP infusions were repeated after pretreatment with indomethacin, 150 mg daily for 36 h. After the AVP infusions, plasma AVP concentrations did not change significantly and remained within the physiological range; in contrast, urinary AVP excretion rate increased steadily. Indomethacin did not alter the plasma or urinary concentrations of AVP. AVP caused a fall in urine flow rate from a state of maximal diuresis to one of maximal antidiuresis. After indomethacin, fractional free water clearance was reduced by an average of 26% at the zero, 2 and 4 fmol min-1 kg-1 infusion rates of AVP. A significant increase in fractional sodium clearance of approximately 50% occurred during the AVP infusions, which was abolished after pretreatment with indomethacin. After indomethacin, urinary prostaglandin E2 (PGE2) excretion rate was reduced by an average of 40% at the zero and 2 fmol min-1 kg-1 infusion rates of AVP. At higher AVP infusion rates, no significant inhibition of PGE2 was observed. Urinary kallikrein excretion rate decreased steadily to one-third of its original value after AVP and this change remained unaltered by indomethacin. The findings show that infusions of AVP, resulting in plasma concentrations in the physiological range, evoke a maximal antidiuretic response, which is accompanied by natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circadian variation of thyrotrophin, determined by ultrasensitive immunoradiometric assay, and the effect of low dose nocturnal dopamine infusion

The effect of low dose dopamine infusion on the circadian rhythm of thyrotrophin (TSH), prolactin and cortisol in a group of six healthy male volunteers is reported. Subjects were infused in random order with either saline (154 mmol/l NaCl solution; control) or dopamine (0.1 and 1 microgram min-1 kg-1) between 21.00 and 01.00 hours, in random order. The serum TSH profile was characterized by a maximal peak occurring at 23.00 hours and higher nocturnal than diurnal values. Superimposed on this are short term oscillations in serum TSH levels, typical of an ultradian rhythm. The maximal peak in TSH, occurring at 23.00 hours, was abolished by dopamine infused at a rate of 1 microgram min-1 kg-1, and was unaffected by the lower rate of dopamine infusion (0.1 microgram min-1 kg-1). The serum prolactin profile was characterized by a peak occurring soon after the onset of sleep (23.30-00.30 hours), which fell during the morning, and began to rise in late evening. Low dose dopamine (0.1 microgram min-1 kg-1) had a slight but insignificant effect with decreased prolactin levels at the end of the infusion whereas the higher dopamine dose was associated with significantly lower prolactin levels during and throughout the infusion. There was a rebound to levels significantly higher than control on cessation of the infusion. Cortisol levels were unaffected by dopamine.     

Pressor effect of arginine vasopressin in progressive autonomic failure

The blood pressure (BP) and heart rate (HR) responses to 5 min incremental intravenous infusions of noradrenaline (NA) and arginine vasopressin (AVP) were investigated both in patients with progressive autonomic failure (PAF) and in normal volunteers. Stepwise infusion of NA at rates of 300-3000 pmol min-1 kg-1 produced a bradycardia and a dose related increase in BP in normal subjects. In subjects with PAF there was no significant HR response but the dose-BP response was shifted to the left with significant pressor responses at infusion rates of 60-300 pmol min-1 kg-1. Stepwise infusion of AVP at 0.2-5.0 pmol min-1 kg-1 caused transient bradycardia but no pressor response in seven normal volunteers. Further increases in AVP infusion in three other subjects achieved plasma AVP levels as high as 3000-4000 pmol/l, and still no significant pressor response was observed. Stepwise infusion of AVP at 0.05-2.0 pmol min-1 kg-1 in the eight subjects with PAF resulted in a pressor response without any change in HR. During this infusion plasma AVP increased from 0.8 +/- 0.2 (mean +/- SEM) to 30 +/- 2 pmol/l. A significant pressor response was already apparent at a plasma AVP level of 5.5 +/- 1.8 pmol/l.