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.     

Dose-response study of the redistribution of intravascular volume by angiotensin II in man.

1. The response of systemic and regional haemodynamic indices to increasing infusion rates of angiotensin II (1, 3 or 10 ng min-1 kg-1) or placebo [5% (w/v) D-glucose] was studied in eight normal male subjects. 2. As compared with placebo, angiotensin II infusion caused an incremental rise in the serum angiotensin II level [14.5 +/- 7.7 (placebo) to 187.2 +/- 36.1 (10 ng of angiotensin II min-1 kg-1) pmol/l; mean +/- 95% confidence interval] associated with a stepwise increase in total peripheral resistance [880 +/- 42 (placebo) to 1284 +/- 58 (10 ng of angiotensin II min-1 kg-1) dyn s cm-5] and a progressive reduction in cardiac output [8.3 +/- 0.4 (placebo) to 7.0 +/- 0.4 (10 ng of angiotensin II min-1 kg-1) litres/min]. 3. A stepwise fall in renal blood flow was observed with increasing angiotensin II infusion rate [1302 +/- 65 (placebo) to 913 +/- 64 (10 ng of angiotensin II min-1 kg-1) ml/min]. In contrast, calf blood flow was unaffected by 1 ng or 3 ng of angiotensin II min-1 kg-1 and was significantly increased by 10 ng of angiotensin II min-1 kg-1 (P less than 0.01). 4. Calf venous capacitance was uninfluenced by 1 ng of angiotensin II min-1 kg-1, but was significantly increased by both 3 ng (P less than 0.005) and 10 ng (P less than 0.001) of angiotensin II min-1 kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide inhibits fluid intake in hyperosmolar subjects.

1. The effect of atrial natriuretic peptide on osmotically stimulated thirst appreciation and consequent fluid intake was investigated in healthy man. 2. Six seated male subjects were studied on two occasions: synthetic alpha-human atrial natriuretic peptide (99-126) (2 pmol min-1 kg-1) or placebo (saline, 150 mmol/l NaCl) was infused intravenously for 105 min; 30 min after the start of atrial natriuretic peptide/placebo infusion, hypertonic saline (855 mmol/l NaCl) was infused (0.06 ml min-1 kg-1) for 60 min. Subjects were then allowed free access to water for the next 2 h; infusion of atrial natriuretic peptide/placebo continued for the first 15 min of the drinking period. 3. The plasma atrial natriuretic peptide concentration did not alter significantly during infusion of hypertonic saline and placebo; it rose to a steady state of 12.7 +/- 1.1 pmol/l (mean +/- SEM) during the infusion of atrial natriuretic peptide and hypertonic saline, and remained at this level during the first 15 min of the drinking period. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, similar increases in plasma osmolality (P less than 0.001) and plasma vasopressin concentration (P less than 0.005) occurred. During infusion of hypertonic saline and atrial natriuretic peptide or placebo, thirst increased significantly over the time course of both studies (P less than 0.01), but the effect of atrial natriuretic peptide infusion compared with placebo infusion was to significantly decrease thirst at 60 min. 4. Drinking rapidly abolished thirst and vasopressin secretion before changes in plasma osmolality occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal tubular reabsorption of sodium and water during infusion of low-dose dopamine in normal man

1. Using the renal clearance of lithium (CLi) as an index of proximal tubular outflow of sodium and water, together with simultaneous measurements of effective renal plasma flow, glomerular filtration rate (GFR) and sodium clearance (CNa), renal function and the tubular segmental reabsorption rates of sodium and water during dopamine infusion (3 micrograms min-1 kg-1) were estimated in 12 normal volunteers. 2. CNa increased by 128% (P less than 0.001). Effective renal plasma flow and GFR increased by 43% (P less than 0.001) and 9% (P less than 0.01), respectively. CLi increased in all subjects by, on average, 44% (P less than 0.001). Fractional proximal reabsorption [1-(CLi/GFR)] decreased by 13% after dopamine infusion (P less than 0.001), and estimated absolute proximal reabsorption rate (GFR-CLi) decreased by 8% (P less than 0.01). Absolute distal sodium reabsorption rate [(CLi-CNa) x PNa, where PNa is plasma sodium concentration] increased (P less than 0.001), and fractional distal sodium reabsorption [(CLi-CNa)/CLi] decreased (P less than 0.001). 3. It is concluded that natriuresis during low-dose dopamine infusion is caused by an increased outflow of sodium from the proximal tubules that is not fully compensated for in the distal tubules.     

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.     

Effects of dopamine and dobutamine on the distribution of pulmonary blood flow during lobar ventilation hypoxia and lobar collapse in dogs

Hypoxic pulmonary vasoconstriction was induced in the left lower lobe of fifteen dogs by ventilating the lobe with 7% O2 or by absorption collapse, and the distribution of flow between the lobe and the remainder of the lung was measured with electromagnetic flow probes. The lobar to total blood flow ratio was reduced by lobar ventilation hypoxia and decreased further during lobar collapse. In seven dogs, an infusion of 20 micrograms kg-1 min-1 of dopamine produced an increase in total blood flow, an increase in pulmonary artery pressure (P less than 0.01), and an increase in lobar to total flow ratio (P less than 0.05) during both hypoxic states. There was a significant fall in arterial PO2 (P less than 0.01) during ventilation hypoxia. Similar changes in total and lobar to total flow ratio (P less than 0.01) were observed in eight dogs given 20 micrograms kg-1 min-1 of dobutamine, but there were no changes in pulmonary artery pressure. The greater increase in total flow (+ 111%) resulted in a marked increase in mixed venous PO2 and no significant changes in arterial PO2 in this group of dogs. It is concluded that both drugs produce an increase in lobar to total blood flow ratio and shunt fraction, but that the mechanisms causing the redistribution of flow may differ.     

The infusion of catecholamines in dogs under general anaesthesia with fentanyl. The effects on intrapulmonary shunt

The pulmonary venous admixture, PaO2, and pulmonary and systemic haemodynamics were studied in six mongrel dogs during infusion of dobutamine (infusion rate 7.5 micrograms . kg-1 . min-1), dopamine (7.5 micrograms . kg-1 . min-1) and isoproterenol (0.1 microgram . kg-1 . min-1). Anaesthesia was performed by a single injection of Fentanyl (0.35 mg/kg). The carbon dioxide tension and body temperature were strictly maintained within limits. Only isoproterenol produced a significant change in pulmonary arterial pressure from an average of 1.2 +/- 0.4 kPa to 1.6 +/- 0.2 kPa (P less 0.05). There was no significant change in systemic haemodynamics with any of the three drugs. The use of catecholamines in dogs with healthy lungs does not induce any development in pulmonary venous admixture when haemodynamics are unchanged. Changes in these variables are dependent upon changes in pulmonary blood flow rather than being direct effects of the catecholamine.     

Prostacyclin attenuates both the pressor and adrenocortical response to angiotensin II in human pregnancy

1. The effects of angiotensin II (ANG II) infusion without and with simultaneous infusion of prostacyclin (PGI2; 1.4 pmol min-1 kg-1; 5 ng min-1 kg-1) have been studied in 16 women in second-trimester pregnancy. Ten received one infusion of ANG II alone, followed by its infusion together with PGI2; the remainder received two identical infusions of ANG II alone as controls. 2. PGI2 administration was associated with a small fall in diastolic pressure (P less than 0.01) and a proportionally greater rise in heart rate (P less than 0.001). Small rises in basal plasma renin and ANG II concentrations and a fall in aldosterone concentration were not statistically significant. 3. The diastolic pressor response to ANG II was blunted during PGI2 infusion by comparison with controls (P less than 0.025); this diminution in response was greatest in patients who had initially been most sensitive to ANG II (P less than 0.02). 4. The evoked increment in plasma aldosterone during ANG II infusion was considerably reduced (P less than 0.005) in the presence of PGI2. 5. These data further support the hypothesis of a role for PGI2 in relation to the blunted pressor response to ANG II of normal pregnancy. The apparent inhibitory effects of PGI2 on aldosterone secretion may partly explain the previously described dissociation between the renin-angiotensin system and aldosterone in pregnancy.     

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.     

The independent effect of ketone bodies on forearm glucose metabolism in normal man.

Ketone bodies and non-esterified fatty acids (NEFA) inhibit insulin stimulated glucose uptake in muscle in-vitro. In man the infusion of ketone bodies lowers plasma NEFA levels thus confounding the interpretation of individual effects. The aim of this study was to examine the effect of ketone bodies on insulin mediated forearm glucose metabolism independent of the changes in the plasma NEFA levels. Seven healthy men received sodium 3-hydroxybutyrate (15 mumol kg-1 min-1) or sodium bicarbonate (control) for 240 min. Heparin (0.2 U kg-1 min-1) and insulin (0.01 U kg-1 h-1) were infused for 90 min (pre-clamp), followed by insulin alone (0.025 U kg-1 h-1) and euglycaemia was maintained (clamp). Plasma NEFA levels and rates of forearm NEFA uptake (+23 +/- 14 and +49 +/- 21 [mean +/- SEM] nmol 100 ml forearm [FA]-1 min-1) were comparable during the pre-clamp periods, and were suppressed equally during hyperinsulinaemia. Sodium 3-hydroxybutyrate infusion raised the blood ketone body levels from 70 +/- 4 mumol/l to a plateau of 450 +/- 30 mumol/l, while control levels declined from baseline (ketone body vs control; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of alpha-human atrial natriuretic peptide on proteinuria in patients with primary glomerular diseases

1. The effects of synthetic alpha-human atrial natriuretic peptide (alpha-hANP) on urinary protein excretion were examined in nine healthy subjects and 20 patients with primary glomerular diseases who had proteinuria of 1.0 g or more per day. Synthetic alpha-hANP was intravenously infused into supine subjects at a rate of 8.3 pmol min-1 kg-1 for 40 min. 2. Before alpha-hANP infusion, the plasma concentration of immunoreactive alpha-hANP was significantly higher in the patients with glomerulonephritis than in the normal subjects (44.3 +/- 8.7 vs 19.4 +/- 3.0 pmol/l, mean +/- SEM, P less than 0.01) and it showed a positive correlation with mean arterial pressure (rs = 0.84, P less than 0.001) and a negative correlation with creatinine clearance (rs = -0.50, P less than 0.01). 3. During infusion of alpha-hANP, although the urinary excretion of protein did not change significantly in the normal subjects, it increased from 0.6 +/- 0.2 to 3.0 +/- 0.8 mg min-1 m-2 (P less than 0.001) in the patients with glomerulonephritis. The urinary protein/creatinine ratio did not change significantly in the former (from 0.18 +/- 0.05 to 0.22 +/- 0.06; NS), whereas it rose from 3.25 +/- 0.94 to 7.62 +/- 1.31 (P less than 0.001) in the latter. 4. The urinary excretions of albumin and of alpha 1-, alpha 2-, beta- and gamma-globulins, which were electrophoretically analysed, all increased in eight nephrotic patients during or immediately after infusion of alpha-hANP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered platelet function during mental stress and adrenaline infusion in humans: evidence for an increased aggregability in vivo as measured by filtragometry

1.The effects of mental stress induced by a colour word conflict test (CWT; n = 9) or 3 h infusions of placebo or adrenaline (0.4 nmol min-1 kg-1; n = 9) on platelet function in vivo were studied in 16 healthy male volunteers. 2. Platelet function was assessed by a filtragometry technique, which reflects aggregability in vivo, and by measurements of the plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4). 3. Adrenaline and CWT induced marked cardiovascular responses as expected. Venous plasma adrenaline increased from 0.1-0.2 nmol/l at rest to 4.87 +/- 0.42 nmol/l during adrenaline infusion and to 0.46 +/- 0.10 nmol/l during CWT. 4. Filtragometry measurements were reproducible within individuals with coefficients of variation of 7.9% during placebo infusion and 5.4% for resting measurements between days. 5. Platelet aggregability, as measured by filtragometry, was similarly increased during both adrenaline infusion (P less than 0.05) and CWT (P less than 0.01). 6. The coefficients of variation for beta-TG and PF4 levels were 17.3% for log beta-TG and 27.9% for log PF4 between days, but could not be calculated for within-day variability. Both beta-TG (P less than 0.05) and PF4 (P less than 0.01) levels decreased time-dependently during placebo infusion, indicating that long resting periods (hours) are needed to attain basal levels. Artefactual results could not be identified by evaluating beta TG/PF4 ratios. 7. beta-TG and PF4 levels did not decrease time-dependently during adrenaline infusion. There were no significant changes of beta-TG or PF4 during CWT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of plasma non-esterified fatty acids during and after exercise.

1. The importance of circulating non-esterified fatty acids as a substrate during and after low-grade exercise has been examined by using a nicotinic acid analogue to inhibit lipolysis. Seven healthy men received acipimox or placebo on separate occasions. After 90 min, bicycle exercise was performed for 45 min (40% of pre-determined maximum oxygen uptake), followed by a 60 min recovery period. 2. The plasma concentration of non-esterified fatty acids increased during exercise after placebo (320 +/- 80 to 630 +/- 110 mumol/l) and remained elevated in the post-exercise period. Basal concentrations were lower after acipimox (100 +/- 10 mumol/l; P less than 0.05); they declined to 60 +/- 10 mumol/l during exercise and remained at this level for the rest of the study. 3. Lipid oxidation increased from 0.8 +/- 0.1 to 4.2 +/- 0.5 mg min-1 kg-1 during exercise after placebo (P less than 0.001) and remained elevated in the post-exercise period (1.2 +/- 0.1 mg min-1 kg-1). It was lower after acipimox, but still increased from 0.3 +/- 0.1 to 2.3 +/- 0.2 mg min-1 kg-1 with exercise. Carbohydrate oxidation was increased after acipimox compared with after placebo, but only reached significance during the post-exercise period (P less than 0.05). 4. Although acipimox abolished the rise in the plasma concentration of non-esterified fatty acids during exercise, there was only a 50% decrease in the rate of lipid oxidation. This suggests that an alternative source of non-esterified fatty acids makes an important contribution to the supply of lipid for oxidation during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac and whole-body [3H]noradrenaline kinetics during adrenaline infusion in man.

1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system, the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min-1 kg-1) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization, in whom beta-adrenoceptor antagonists had been discontinued for 72 h. 2. At rest and compared with placebo, infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 +/- 29 pg/ml to 245 +/- 29 pg/ml (P less than 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 +/- 40 ng min-1 m-2 to 358 +/- 41 ng min-1 m-2, P less than 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion, but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease. 3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions. 4. Infusion of adrenaline to produce 'physiological' increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release, as assessed by whole-body noradrenaline spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Effects of pancreatic polypeptide on motilin and circulating metabolites in man

Pancreatic polypeptide was infused intravenously in healthy fasting subjects at 1 pmol kg-1 (n = 7) and 4 pmol kg-1 min-1 (n = 10) producing plasma PP concentrations of 223 +/- 37 pmol/l (mean +/- SEM) and 891 +/- 64 pmol/l respectively. These levels are similar to and four-fold higher than those seen after a normal mixed breakfast in healthy young adults. In a separate study five healthy subjects ingested a small breakfast during infusion of PP on different days at 1 pmol kg-1 min-1 and 2 pmol kg-1 min-1 respectively. PP at 1 pmol kg-1 min-1 caused a marked reduction in fasting plasma motilin concentrations to 20% of the basal level (p less than 0.001). There were, however, no significant changes in plasma concentrations of insulin, glucagon, gastrin, secretin, enteroglucagon, gastric inhibitory peptide or neurotensin. Despite previous reports possibly implicating PP in metabolism, there were no significant effects on blood levels of glucose, alanine lactate, 3-hydroxybutyrate, glycerol or non-esterified fatty acids, either in the fasting state or after the ingestion of food. Although it seems unlikely that PP is a major hormonal regulator of intermediary metabolism in man, its ability to suppress motilin at physiological concentrations suggests the possibility of an indirect influence on digestive motor function.     

Effects of L-arginine on systemic and renal haemodynamics in conscious dogs.

1. The effects of L-arginine on systemic and renal haemodynamics were investigated in conscious dogs. L-Arginine was administered intravenously at doses of 15 and 75 mumol min-1 kg-1 for 20 min. 2. Mean arterial blood pressure, heart rate and cardiac output were not changed significantly by L-arginine infusion. However, L-arginine infusion induced a significant elevation of renal blood flow from 50 +/- 3 to 94 +/- 12 ml/min (means +/- SEM, P less than 0.01). 3. Simultaneous infusion of NG-monomethyl-L-arginine (0.5 mumol min-1 kg-1) significantly inhibited the increase in renal blood flow produced by L-arginine (15 mumol min-1 kg-1) without significant changes in mean arterial blood pressure or heart rate. 4. Pretreatment with atropine completely inhibited the L-arginine-induced increase in renal blood flow, whereas pretreatment with indomethacin attenuated it (63 +/- 4 versus 82 +/- 10 ml/min, P less than 0.05). 5. A continuous infusion of L-arginine increased renal blood flow in the intact kidney (55 +/- 3 versus 85 +/- 9 ml/min, P less than 0.05), but not in the contralateral denervated kidney (58 +/- 3 versus 56 +/- 4 ml/min, P greater than 0.05). 6. These results suggest that intravenously administered L-arginine produces an elevation of renal blood flow, which may be mediated by facilitation of endogenous acetylcholine-induced release of endothelium-derived relaxing factor and vasodilatory prostaglandins.     

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)     

Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man.

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h-1 kg-1) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 +/- 0.20 versus 0.67 +/- 0.10 mmol/l), plasma nonesterified fatty acid (395 +/- 13 versus 51 +/- 1 mumol/l), blood glycerol (152 +/- 2 versus 11 +/- 1 mumol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64-104) versus 4 (3-5) mumol/l] were all significantly higher (all P less than 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 +/- 0.07 versus 0.27 +/- 0.08 mg min-1 kg-1, P less than 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 +/- 0.77 to 6.17 +/- 0.71 mg min-1 kg-1, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)