Intrarenal actions of the new adenosine agonist CGS 21680A, selective for the A2 receptor

The purpose of this study was to define the direct intrarenal actions of the new adenosine agonist CGS 21680A (hydrochloride "A" salt of (2-[p-2-carboxyethyl)phenethylamino]5'-N-ethyl-carboxamido adenosine), which is selective for the A2 receptor. CGS 21680A was infused into the left renal artery, while simultaneously measuring blood pressure (BP) and parameters of renal function from both the left and right kidneys. At doses higher than 0.05 micrograms/kg/min, CGS 21680A appeared to leak from the circulation of the infused kidney in pharmacologically significant quantities, inasmuch as BP fell and renal blood flow was increased and renal vascular resistance decreased in the noninfused contralateral kidney. At doses of 0.025 to 0.05 micrograms/kg/min, CGS 21680A appeared localized to the renal circulation, because neither BP nor any measured parameter of contralateral renal function was altered. Intrarenal infusion of 0.025 to 0.05 micrograms/kg/min of CGS 21680A increased renal blood flow but not glomerular filtration rate leading to a fall in the filtration fraction. Urine volume and urinary sodium excretion were unaffected by selective intrarenal infusion of CGS 21680A. Plasma renin activity and renin secretion rate were also not altered significantly by intrarenal infusion of 0.05 micrograms/kg/min of CGS 21680A. In contrast plasma renin activity increased significantly in response to the intrarenal infusion of 0.075 micrograms/kg/min of CGS 21680A, a dose which leaked from the kidney and lowered BP. The results presented suggest that the new adenosine agonist CGS 21680A exerts a direct intrarenal effect on renal hemodynamics, but does not affect urine volume or sodium excretion or directly influence renin release.     

The actions of saralasin on the renal circulation of man and dog; evidence for a sympathetic neural component to vasoconstriction

Abstract. The mechanism of renal vasoconstriction produced by saralasin and its dependence on the sympathetic nervous system was investigated in subjects with mild essential hypertension and in anaesthetized dogs. Fluid or saline was given to maximize agonist vasoconstrictor responses. The changes in renal hae-modynamics produced by intravenously infused saralasin (doses 0.01–10 μg kg^-1 min^-1) were assessed by clearance methods. In the patients, it induced a dose-related renal vasoconstriction which correlated with a rise in plasma noradrenaline levels. In dogs with innervated kidneys it also caused vasoconstriction. But in dogs with denervated kidneys it caused vasodilatation. Infusion at the highest dose directly into the renal artery of denervated kidneys induced only vasodilatation. We conclude that one component of the renal vasoconstriction that occurs with intravenous saralasin infusions is mediated by the renal nerves.     

Effects of different doses of chlorpromazine on renal function in the dog.

This study was carried out to examine the effects of low 'alpha-blocking' and higher 'membrane-stabilizing' doses of chlorpromazine (CPZ) on renal function. CPZ was given at slow infusion rate either intravenously or into the left renal artery at three levels (0.5-1.0, 3-8, and 10-15 mg/kg) to 10 anesthetized dogs. An increase in plasma hemoglobin sometimes occurred within few minutes after infusion of more than 10 mg/kg CPZ, probably due to a hemolytic effect of such high doses. Systemic infusion of 0.5-1 mg/kg CPZ caused an increase in urine volume, sodium excretion, and renal plasma flow, and a decrease in filtration fraction and free water clearance was demonstrated in all dogs. At higher CPZ doses renal plasma flow increased further, whereas urine volume and electrolyte excretion were of the same order at all dose levels. A 21% decrease in tubular maximum para-aminohippurate transport (Tm(PAH)) was observed at the highest CPZ doses. After unilateral renal intra-arterial CPZ infusion the percentage change in urine volume, urinary sodium excretion, and Tm(PAH) were of the same order on the infused side as on the contralateral side. Even though the results at all dose levels can be explained by an 'alpha-blocking' effect of CPZ, possible membrane-stabilizine effects of CPZ cannot be excluded.     

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.     

Pharmacokinetics of cefotiam in normal humans.

Doses of 0.5, 1.0, and 2.0 g of cefotiam were infused intravenously over a 15-min period in a crossover fashion to eight volunteers. Doses of 1.0 and 2.0 g were infused intravenously over periods of 30 and 60 min in a double crossover fashion to another eight volunteers. Serum concentrations fell rapidly from peak levels between 30 and 170 micrograms/ml at the end of the infusion to less than 1.0 micrograms/ml within 6 h after all regimens. The terminal half-life in plasma varied between 0.6 and 1.1 h. The slopes of the time-concentration curves with the different regimens showed different half-life data. The urinary excretion of cefotiam was mostly completed within 4 h of the beginning of drug administration. The pharmacokinetics of cefotiam were dose dependent. With the 2-g dose, the peak plasma concentrations and the values for the area under the curve were more than twice the values observed with 1 g; decreasing values of plasma clearance were observed with higher doses. Injection of cefotiam caused no immediate discomfort or reaction at the infusion site.     

Effects of Different Doses of Chlorpromazine on Renal Function in the Dog

This study was carried out to examine the effects of low ‘alpha-blocking’ and higher ‘membrane-stabilizing’ doses of chlorpromazine (CPZ) on renal function. CPZ was given at slow infusion rate either intravenously or into the left renal artery at three levels (0.5–1.0, 3–8, and 10–15 mg/kg) to 10 anesthetized dogs. An increase in plasma hemoglobin sometimes occurred within few minutes after infusion of more than 10 mg/kg CPZ, probably due to a hemolytic effect of such high doses. Systemic infusion of 0.5–1 mg/kg CPZ caused an increase in urine volume, sodium excretion, and renal plasma flow, and a decrease in filtration fraction and free water clearance was demonstrated in all dogs. At higher CPZ doses renal plasma flow increased further, whereas urine volume and electrolyte excretion were of the same order at all dose levels. A 21 % decrease in tubular maximum para-aminohippurate transport (TmpAH) was observed at the highest CPZ doses. After unilateral renal intra-arterial CPZ infusion the percentage change in urine volume, urinary sodium excretion, and TmPAH were of the same order on the infused side as on the contralateral side. Even though the results at all dose levels can be explained by an ‘alpha-blocking’ effect of CPZ, possible membrane-stabilizing effects of CPZ cannot be excluded.     

Effects of angiotensin II and noradrenaline on intrarenal haemodynamics in the rat.

The haemodynamic effects of angiotensin II and noradrenaline were studied in the rat kidney. These pressors were given by intravenous infusion in stepwise increasing doses. Intrarenal haemodynamics were analyzed by the 133xenon washout technique, 85krypton autoradiography and silastic casting of the renal vascular tree. Angiotensin II induced significant changes in intrarenal haemodynamics before any changes in systemic blood pressure were detected. The decrease in mean renal blood flow (2.91 ml.min-1.g-1 in controls, 1.76 ml.min-1.g-1 in rats given 50 mug of angiotensin II.kg-1.h-1) reflects a reduction in component I blood flow rate (from 3.9 to 2.9 ml.min-1.g-1) as well as a decrease in the fraction of total renal blood flow supplied to component I of the washout curve (from 84% to 62%). With noradrenaline an increase in total renal resistance occurred simultaneously with the elevation of mean arterial blood pressure. The resulting reduction in mean renal blood flow (from 2.76 ml.min-1.g-1 in controls to 1.55 ml.min-1.g-1 in rats given 1000 mug of noradrenaline kg-1.h-1) reflects a decrease in component I blood flow rate with lower infusion rates and a drop in component I flow fraction (from 82% to 52%) whith higher doses. In contrast to canine kidneys, no evidence for a patchy cortical vasoconstriction was found in the rat. Using autoradiography it was possible to attribute component I to the renal cortex and subcortical area of the kidney.     

Intrarenal distribution of vancomycin in endotoxemic rats.

We previously observed that the intrarenal distribution of aminoglycosides was modified by Escherichia coli endotoxin in the absence of any major renal physiological disturbance or histological changes. In the present study, we evaluated the role of E. coli endotoxin on the intrarenal distribution of vancomycin. At the beginning of the experiment, female Sprague-Dawley rats were infused intravenously with saline (control) or endotoxin (0.25 mg/kg) during 15 min. Thereafter, saline was constantly infused for the following 4 h. Two hours after the beginning of the infusion, animals were injected intravenously with a single dose of vancomycin (20 mg/kg). The drug levels in serum; renal cortex, medulla, and papilla; and urine were evaluated from 0.08 to 24 h after injection. Analysis of the area under the curve of the drug concentration in the different kidney components versus time showed a higher accumulation of vancomycin in the renal cortex and medulla in the endotoxin-infused rats than in the normal rats (P less than 0.01). Endotoxin was associated with an increase in the half-life in serum (P less than 0.01) and a lower elimination rate constant. The total clearance of vancomycin from plasma was significantly decreased in endotoxin-treated rats (P less than 0.01). These results demonstrate that endotoxin modifies the renal handling of vancomycin.     

Peptide histidine valine: its haemodynamic actions and pharmacokinetics in man differ from those of vasoactive intestinal peptide and peptide histidine methionine

1. The effects of intravenous and intra-arterial infusion of the peptides derived from prepro-vasoactive intestinal peptide, vasoactive intestinal peptide, peptide histidine methionine and peptide histidine valine, were examined in six healthy volunteers. 2. Vasoactive intestinal peptide given intravenously caused a significant increase in heart rate and a decrease in diastolic, but not systolic, blood pressure, whereas peptide histidine valine caused an increase in heart rate alone, despite higher achieved circulating peptide concentrations. Peptide histidine methionine did not affect heart rate or blood pressure. Forearm blood flow was increased by vasoactive intestinal peptide and peptide histidine valine when infused locally intra-arterially, although vasoactive intestinal peptide was more potent than peptide histidine valine. 3. Plasma concentrations of cardiodilatin (the N-terminal peptide derived from pro-atrial natriuretic peptide) were increased by intravenous infusion of vasoactive intestinal peptide, but were unaffected by peptide histidine methionine or peptide histidine valine. Circulating plasma concentrations of adrenaline and noradrenaline did not change during infusion of vasoactive intestinal peptide, peptide histidine methionine or peptide histidine valine. 4. Peptide histidine valine had a long half-life when compared with peptide histidine methionine and vasoactive intestinal peptide. 5. We conclude that peptide histidine valine is active in the human cardiovascular system and has a similar, though less potent, vasodilating action to vasoactive intestinal peptide. The higher circulating levels of peptide histidine valine found in man suggest that it may be important in modulating vascular tone.     

Vasoactive intestinal peptide: a direct renal natriuretic substance

To establish whether or not vasoactive intestinal peptide (VIP) acts directly on the kidney and also to define the renal responses to it, we compared the natriuretic and haemodynamic responses to VIP (10(-4)-100 pmol min-1 kg-1) infused intravenously with those obtained by direct infusion into the renal artery in seven conscious male rabbits. VIP had significant effects on the renal circulation without changing systemic arterial pressure or pulse rate. There was a significant fall from control in effective renal plasma flow (P less than 0.05 renal infusion, P less than 0.01 intravenous infusion) and glomerular filtration rate (P less than 0.01 renal, P less than 0.05 intravenous). The derived renal vascular resistance rose significantly from control (P less than 0.01 renal, P less than 0.01 intravenous). Despite the significant decline in filtered sodium load (P less than 0.01 renal, P less than 0.001 intravenous), there was a significant log dose-related increase in fractional sodium excretion (P less than 0.005) with intrarenal infusion of VIP. We conclude that the actions of VIP on intrarenal blood vessels and renal tubules are direct, leading to increases in renal vascular resistance and fractional sodium excretion.     

Pharmacokinetics, pharmacodynamics, and minimum effective clinical dose of intravenous nicardipine

Nicardipine hydrochloride was administered intravenously to two groups of hypertensive patients: one group of 37 patients with mild to moderate hypertension and one group of 20 patients with severe hypertension. In the first group, doses of 0.5, 1, 2, and 4 mg/hr, as well as placebo, were infused for 48 hours in a double-blind fashion. Blood pressure and heart rate were monitored for this period and for the 24 hours after the infusion was discontinued. Significant decrements in blood pressure were noted with all doses; 4 mg/hr produced lowering that was greater than all other doses; 1 and 2 mg/hr produced lowering that was greater than 0.5 mg/hr but that were not different from each other. Excellent correlation of blood pressure reduction and plasma level was observed and linear kinetics existed. In the severe hypertensive patients, 1, 2, 4, 5, and 8 mg/hr were infused to established minimal and ineffective doses. One milligram per hour was an ineffective dose; 4, 5, and 8 mg/hr all produced significant reductions over the course of the study that were undistinguishable from each other. Two milligrams per hour produced modest reductions in blood pressure. Blood pressure reduction also correlated with plasma levels in the severe hypertensive group.     

Inhibition of renal vasoconstriction induced by intrarenal hypertonic saline by the nonxanthine adenosine antagonist CGS 15943A

The hypothesis that intrarenal infusions of hypertonic saline induce endogenous release of adenosine to result in renal vasoconstriction has been investigated in salt-deplete dogs using the nonxanthine adenosine receptor antagonist, CGS 15943A. Intrarenal artery infusions of CGS 15943A induced dose-dependent reductions in the renal vasoconstrictor response to bolus doses of adenosine into the renal artery, without altering base-line blood pressure or renal blood flow. Infusion rates of 10 micrograms/min induced an approximate 50% reduction in response, whereas 100 micrograms/min produced a substantially greater response. There was no inhibition of the renal vasoconstrictor response to angiotensin II and norepinephrine by CGS 15943A at a rate of 100 micrograms/min. Changes in RBF after intrarenal infusion of hypertonic saline were compared between further series of salt-deplete dogs receiving intrarenal artery infusions of either vehicle or CGS 15943A (100 micrograms/min). An initial infusion of hypertonic saline to both groups of dogs induced renal vasodilation followed by vasoconstriction. In dogs subsequently infused with CGS 15943A (100 micrograms/min), the initial renal vasodilation response was similar, but there was an abolition of the later vasoconstrictor response. In contrast, the renal blood flow response to hypertonic saline was unchanged in the vehicle-infused dogs. We conclude that CGS 15943A can selectively block the renal blood flow response to exogenous adenosine without altering baseline renal vascular tone and that the ability of CGS 15943A to abolish the renal vasoconstrictor response to intrarenal hypertonic saline is consistent with the hypothesis that endogenous release of adenosine is involved in mediating the reduction in renal blood flow.     

The stimulation of renin secretion by non-vasocontrictor infusions of adrenaline and noradrenaline in the isolated rat kidney.

1. The effect of adrenaline and noradrenaline on renin secretion in the isolated perfuseed rat kidney was examined. The doses of catecholamines used were such that renal vasoconstriction and therefore increases in renal perfusion pressure were avoided. Under these conditions adrenaline and noradrenaline significantly increased renin secretion rates, compared with control experiments in which no catecholamine was infused. 2. Mean renal perfusion pressure during both adrenaline and noradrenaline infusion paralleled the control study by showing a progressive fall. 3. Administration of phenoxybenzamine did not impair the stimulation of renin secretion by adrenaline whereas this was prevented by racemic propranolol. 4. These observations suggest that catecholamines stimulate renin secretion by an intrarenal effect which is largely independent of changes in renal perfusion pressure. It is postulated that the beta-adrenoceptors mediating renin secretion are an integral component of the renin-producing cell.     

Origin of urinary nonconjugated 19-nor-deoxycorticosterone and metabolism of infused radiolabeled 19-nor-deoxycorticosterone in men and women.

It is known that 19-nor-deoxycorticosterone (19-nor-DOC) is a potent mineralocorticosteroid that is present in urine of rats and humans in a free, i.e., nonconjugated, form. In some forms of hypertension in rats, the levels of free 19-nor-DOC in urine are increased compared with those in urine of normotensive animals. Yet, despite the potential importance of this mineralocorticosteroid in the pathogenesis of certain forms of hypertension, little is known of its site of origin or metabolism. In the present investigation, we evaluated the metabolism of intravenously infused [3H]19-nor-DOC and the possibility that 19-nor-DOC was formed from plasma DOC. We found that the metabolism of [3H]19-nor-DOC infused intravenously in men and women was similar to that of DOC with important exceptions. The majority of the radiolabeled urinary metabolites of intravenously infused [3H]19-nor-DOC were excreted in urine as glucuronosides. Little radioactivity, infused as [3H]19-nor-DOC, was recovered in urine as nonconjugated or sulfoconjugated steroids. There was no free radiolabeled 19-nor-DOC in urine after the simultaneous infusion of [3H]19-nor-DOC and [14C]DOC. A major metabolite of [3H]19-nor-DOC in urine was 19-nor-DOC-21-glucuronoside, whereas little or no intravenously infused radiolabeled DOC was excreted as radiolabeled DOC-glucuronoside. We also found that intravenously infused [14C]DOC was not converted to urinary [14C]19-nor-DOC (glucuronoside) and that other tritium-labeled metabolites of infused [3H]19-nor-DOC contained no carbon-14. The production rate of 19-nor-DOC, computed from the specific activity of urinary 19-nor-DOC (glucuronoside), in one normal man was 16 micrograms/d and in the two women of this study, it was 10 micrograms/d. These findings are supportive of the proposition that free urinary 19-nor-DOC is not formed from plasma DOC; it may be formed in kidney from a precursor other than DOC or it may be formed nonenzymatically in kidney or urine from a precursor such as 19-oic-DOC.     

The early effects of intravenous frusemide on central haemodynamics, venous tone and plasma renin activity.

1. Nine paatients with clinically unimportant heart disease or benign essential hypertension were given frusemide intravenously during right-heart catheterization. 2. Pressures in both atria decreased rapidly and in parallel. The magnitude of the pressure decrease was clearly related to decrease in plasma volume loss. 3. Plasma renin activity increased significantly after 5 min (P less than 0-01), but did not correlate with plasma volume loss. 4. Venous tone in the forearm was unchanged. 5. It is concluded that the pressure reduction was secondary to plasma volume depletion through diuresis and that increased plasma renin activity was mainly caused by intrarenal changes.     

Cardiovascular Control in Recently Injured Tetraplegics in Spinal Shock

Cardiovascular control was studied in five tetraplegic patientswith physiologically complete cervical spinal cord transections.All had been injured less than two weeks previously and werein spinal shock. Blood pressure, heart rate, and plasma noradrenalineand adrenaline were measured at rest and during and after bladderstimulation and application of cold stimuli to skin below thelevel of the lesion. In three patients the cardiovascular responsesto intravenously infused 1-noradrenaline and to the Valsalvamanoeuvre were recorded. Measurements were also made in sixchronic tetraplegic patients (in whom reflex spinal cord activityhad returned) at rest, and during and after bladder stimulation,and in six normal subjects at rest. Average resting blood pressure in the recently injured tetraplegicswas 130/57 (mean 81) mmHg, in the chronic tetraplegics 107/55(mean 73) mmHg and in normal subjects 122/82 (mean 95) mmHg.Average resting heart rate was 64, 73 and 77 beats/min in thethree groups respectively. Resting plasma noradrenaline andadrenaline levels in both the recently injured and chronic tetraplegicswere lower than in normal subjects. In the recently injured tetraplegics bladder stimulation causedminimal changes in blood pressure, heart rate and plasma noradrenalineand adrenaline levels. In the chronic tetraplegics simliar stimulationcaused marked hypertension, bradycardia and elevation in plasmanoradrenaline but not adrenaline levels. Cold stimuli in therecently injured tetraplegics did not change blood pressureor heart rate. In the recently injured tetraplegics intravenous infusion of1-noradrenaline resulted in greater elevation in blood pressurethan normal. There was a decrease in heart rate. One patientwas able to perform the Valsalva manoeuvre. His blood pressureresponses were consistently abnormal (‘blocked’Valsalva). It is concluded that recently injured tetraplegics in spinalshock have normal systolic blood pressure but lower diastolicblood pressure than normal subjects. Resting plasma noradrenalineand adrenaline levels are also lower than in normal subjectsand this suggests diminished sympathetic nervous activity atrest. The small cardiovascular and catecholamine responses tocutaneous and visceral stimuli suggest feeble or absent spinalsympathetic cardiovascular reflexes in spinal shock. The abnormalblood pressure responses to infusion of noradrenaline and tothe Valsalva manoeuvre indicate impaired blood pressure homeostaticreflexes.     

Effects of Angiotensin II and Noradrenaline on Intrarenal Haemodynamies in the Rat*

The haemodynamic effects of angiotensin II and noradrenaline were studied in the rat kidney. These pressors were given by intravenous infusion in stepwise increasing doses. Intrarenal haemodynmaics were analyzed by the 13 3enon washout technique, 85krypton autoradiography and silastic casting of the renal vascular tree. Angiotensin II induced significant changes in intrarenal haemodynamies before any changes in systemic blood pressure were detected. The decrease in mean renal blood flow (2.91 ml.min^-1.g^-1 in controls, 1.76 ml.min^-1.g^-1 in rats given 50 μg of angiotensin Il.kg^-1.h^-1) reflects a reduction in component I blood flow rate (from 3.9 to 2.9 ml.min^-1.g^-1) as well as a decrease in the fraction of total renal blood flow supplied to component I of the washout curve (from 84% to 62%). With noradrenaline an increase in total renal resistance occurred simultaneously with the elevation of mean arterial blood pressure. The resulting reduction in mean renal blood flow (from 2.76 ml.min^-1.g^-1 in controls to 1.55 ml.min^-1.g^-1 in rats given 1000 yg of noradrenaline kg^-1. h^-1) reflects a decrease in component I blood flow rate with lower infusion rates and a drop in component I flow fraction (from 82% to 52%) with higher doses. In contrast to canine kidneys, no evidence for a patchy cortical vasoconstriction was found in the rat. Using autoradiography it was possible to attribute component I to the renal cortex and subcortical area of the kidney.     

Plasma dihydroxyphenylglycol for estimation of noradrenaline neuronal re-uptake in the sympathetic nervous system in vivo

1. Neuronal re-uptake is the primary means for terminating the actions of endogenously released noradrenaline. A portion of the recaptured noradrenaline is deaminated to form dihydroxyphenylglycol. The present report describes a technique using plasma dihydroxyphenylglycol for estimation of the rate of neuronal reuptake of endogenous noradrenaline in vivo. 2. Neuronal re-uptake of noradrenaline in the sympathetic nervous system of the rat was estimated from the effects of neuronal uptake blockade with desipramine on three variables: (i) the plasma clearance of intravenously infused 3H-labelled noradrenaline, (ii) the plasma concentration of endogenous dihydroxyphenylglycol, and (iii) the plasma concentration of 3H-labelled dihydroxyphenylglycol formed from infused 3H-labelled noradrenaline. 3. Desipramine decreased plasma dihydroxyphenylglycol by 36%, this representing the fraction of dihydroxyphenylglycol in plasma that was derived from recaptured noradrenaline. After desipramine, the decrease in the rate of neuronal uptake of 3H-labelled noradrenaline was 9.7 times that of the decrease in the plasma spillover of 3H-labelled dihydroxyphenylglycol. Since the appearances in plasma of dihydroxyphenylglycol from unlabelled and 3H-labelled noradrenaline were similar, the neuronal re-uptake of endogenous noradrenaline could be assumed to be 9.7 times as much as the plasma spillover of dihydroxyphenylglycol that was derived from recaptured noradrenaline (0.15 nmol min-1 kg-1). 4. The rate of neuronal re-uptake of endogenous noradrenaline was estimated to be 1.45 nmol min-1 kg-1, whereas the plasma spillover of noradrenaline was 0.127 nmol min-1 kg-1. Thus, only a small fraction (less than 9%) of the noradrenaline released into the synaptic cleft spills over into the circulation.     

Metabolism of intravenously administered prostaglandin E1 in patients with peripheral arterial occlusive disease]

Using high performance liquid chromatography and radioimmunoassay we have investigated the stability of prostaglandin (PG) E1 and its metabolite 13,14-dihydro-PGE1 in human plasma as well as the initial metabolism of PGE1 infused intravenously (80 micrograms/patient/hour) in patients with peripheral arterial occlusive disease. 13,14-dihydro-PGE1 degraded like PGE1 in human plasma at 37 degrees C with a half-life of several hours. During infusion of PGE1 higher plasma concentrations of the major metabolite 15-keto-13,14-dihydro-PGE1 and lower plasma levels of PGE1 and 13,14-dihydro-PGE1 were observed. The metabolite 13,14-dihydro-PGE1 is of interest, since in contrast to 15-keto-13,14-dihydro-PGE1 it is biologically active. The biosynthesis of 13,14-dihydro-PGE1 could contribute to the therapeutic efficacy of PGE1 administered intravenously in patients with peripheral arterial occlusive disease.     

Metabolic and cardiovascular effects of infusions of low doses of isoprenaline in man

1. The cardiovascular and metabolic responses to low doses of isoprenaline (15 and 5 ng min-1 kg-1 body weight infused over 30 min) were determined in six healthy males. The study was performed to investigate whether there were sustained effects after the termination of the isoprenaline infusion, as has been observed previously after the infusion of adrenaline. 2. The isoprenaline infusions produced dose-dependent increases in heart rate, systolic blood pressure and metabolic rate, but similar increases in calf blood flow and decreases in diastolic blood pressure for the two infusion rates. Finger tremor was increased in amplitude by the 15 ng min-1 kg-1 infusion only. The changes in each of these physiological variables largely resolved within a few minutes of discontinuing the isoprenaline infusions. 3. There were no changes in arterialized venous plasma adrenaline or noradrenaline levels during the isoprenaline infusions. Mean peak plasma isoprenaline levels were 0.16 +/- 0.02 nmol/l during the 5 ng min-1 kg-1 infusion and 0.71 +/- 0.05 nmol/l during the 15 ng min-1 kg-1 infusion. 4. Plasma insulin levels increased with isoprenaline but blood glucose concentrations were unchanged, consistent with a direct effect of isoprenaline on beta 2-adrenoceptors mediating insulin release from pancreatic beta-cells. Blood glycerol concentration also increased with isoprenaline but blood lactate concentration was unaltered. 5. The present study demonstrates pronounced cardiovascular and metabolic effects of low dose isoprenaline infusions. Differences in the rate of resolution of the changes induced by isoprenaline and by adrenaline seen in previous studies may result from a significant difference in their metabolism.