Haemodynamic and renal effects of urodilatin in healthy volunteers

Urodilatin (ANF(95-126)), an analogue of the atrial natriuretic factor (ANF(99-126)), has recently been isolated from human urine. To study haemodynamic and renal effects of synthetic urodilatin, 18 healthy male volunteers (age 26.1 +/- 0.8 years; X +/- SEM) received i.v. bolus injections of urodilatin at doses of 1, 2 or 4 micrograms kg-1 body weight (bw) (n = 6 per dosage group). Urodilatin dose-dependently increased heart rate and cardiac index. A dose-dependent increase in plasma cyclic GMP levels was also observed. Urinary cyclic GMP excretion, urine flow and natriuresis increased 7-fold, 5-fold and 4-fold, respectively. Renal effects were not different between dosage groups. Compared with ANF(99-126), after urodilatin the reduction in mean pulmonary arterial pressure (PAP) was more pronounced (2 micrograms kg-1, n = 6; ANF -1.8 +/- 0.5, URO: -5.5 +/- 1.1 mmHg, P less than 0.05). Furthermore, after urodilatin the reduction of PAP lasted continuously from 2 up to 90 min after injection, while ANF(99-126) produced only a transient decrease of PAP. Similarly the reduction of pulmonary capillary wedge pressure (PCWP) by urodilatin from 9.3 +/- 1.2 to 3.8 +/- 0.9 mmHg (P less than 0.05) was also sustained up to 90 min post administration. These data in healthy volunteers suggest that, due to prolonged reduction of PAP and PCWP with increases of cardiac index and reduction of systemic vascular resistance, urodilatin might exhibit beneficial effects in cardiovascular disease.     

Disposition and dynamics of atrial natriuretic factor in conscious rabbits

The kinetics and dynamics of atrial natriuretic factor (ANF), rat ANF(99-126), were documented in conscious rabbits. The kinetics of immunoreactive ANF (IR-ANF) were first-order after a bolus of up to 300 ng/kg. Compared to the bolus, prolonged infusion of ANF produced a significant reduction in the systemic clearance of IR-ANF, from 132 to 59 and 70 ml/min/kg (P less than .0001) for the 81 +/- 8 ng/min/kg (x140 min) and 126 +/- 6 ng/min/kg (x480 min) infusion rates, respectively; however, the distribution of ANF was not affected. During the infusion of ANF, there was a marked decrease in mean arterial pressure and renal plasma flow, whereas the effects on renal excretion of water and sodium parameters were minimal. The change in hemodynamics was accompanied by a rebound increase in plasma renin activity. It is concluded that the kinetics of IR-ANF are zero-order after a prolonged infusion, secondary to a fall in the systemic clearance of ANF and that in this animal model, and at the doses used, this peptide only elicited hemodynamic effects, possibly related to the activation of counter-regulatory mechanisms.     

SCH 39370, a neutral metalloendopeptidase inhibitor, potentiates biological responses to atrial natriuretic factor and lowers blood pressure in desoxycorticosterone acetate-sodium hypertensive rats

SCH 39370 (N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl]-(S)-isoserin e) is a potent and specific inhibitor of neutral metalloendopeptidase (NEP) from rabbit kidney (IC50 = 11.2 +/- 1.9 nM) and is devoid of angiotensin-converting enzyme inhibitory activity at 1 microM. We evaluated the effect of NEP inhibition with SCH 39370 on the inactivation of atrial natriuretic factor (ANF) and on cardiovascular function in rats. SCH 39370 effectively prevented in vitro degradation of ANF (99-126) by a purified rabbit kidney NEP. SCH 39370 (30 mg/kg s.c) significantly delayed the disappearance of immunoreactive (ir) ANF from plasma in rats after an i.v. infusion of ANF (1 microgram/kg/min for 30 min): the plasma ir ANF level at 15 min postinfusion was 1.5 +/- 0.3 ng/ml vs. 0.3 +/- 0.04 ng/ml in the control. SCH 39370 also delayed the disappearance of ir ANF after infusion of the peptide (0.1 microgram/kg/min for 30 min) which increased plasma levels to those observed during volume expansion. This effect was accentuated markedly in rats with bilateral nephrectomy. The hypotensive response to injection of ANF (30 micrograms/kg i.v.) in spontaneously hypertensive rats (-38 +/- 6 mm Hg vs. -13 +/- 2 mm Hg in the control) and the diuretic and natriuretic responses to ANF in normal rats were potentiated by SCH 39370 (30 mg/kg s.c.), respectively. The results suggest that NEP can play a role in ANF disposition in vivo and that potentiation of the biological activities of high doses of ANF by SCH 39370 may be consequent to its inhibitory effect on ANF degradation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentrations of atrial peptides ANF(l-98) and ANF(99–126) after intravenous infusion: effect of infusate temperature

Summary. Atrial peptides ANF(l-98) and ANF(99–126) were measured in plasma before and after infusion of Ringer-Acetate solution in healthy volunteers. The solution was infused over a 45 min period in an amount equal to 20 per cent of estimated extra-cellular volume. We found that the increase in atrial peptide immuno-reactivity after infusion depended on the temperature of the infusate. The molar increase in ANF(l-98) was much larger than the increase in ANF(99–126). We speculate that plasma levels of ANF(l-98) may be a clinically useful parameter of atrial distension secondary to hypervolaemia.     

Renal tubular responsiveness to atrial natriuretic peptide in sodium-retaining chronic caval dogs. A possible role for kinins and luminal actions of the peptide.

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng.kg-1.min-1) with a natriuresis (TIVC-NR; delta UNaV = 2 +/- 0.8 mu eq/min) whereas the remaining 40% responded normally (TIVC-R; delta UNaV = 216 +/- 50 mu eq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (delta UNaV = 67 +/- 2 mu eq/min) and permitted a natriuresis in the presence of ANP (delta UNaV = 97 +/- 18 mu eq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased UNaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in delta UNaV (62 mu eq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.     

Evidence for direct estrogen regulation of the human gonadotropin-releasing hormone gene.

Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin elevated in acute congestive heart failure (CHF), which is degraded by the enzyme neutral endopeptidase 24.11 (NEP). This study was designed to investigate the pulmonary and urinary clearance of ANF before and after the initiation of acute experimental CHF in dogs, and to assess the contribution of enzymatic degradation to these clearances in CHF. This study demonstrated a significant clearance of plasma ANF across the pulmonary circulation at baseline, and a tendency for pulmonary clearance to decrease in CHF (1115 +/- 268 to 498 +/- 173 ml/min, NS). The pulmonary extraction of ANF present at baseline was not altered with acute CHF (36.0 +/- 7.8 to 34.9 +/- 12.1%, NS). NEP inhibition (NEPI) abolished both the clearance and extraction of plasma ANF across the lung in CHF. Similarly, significant urinary clearance of ANF was present at baseline, and in acute CHF the urinary clearance of ANF decreased (0.14 +/- 0.02 to 0.02 +/- 0.01 ml/min, P less than 0.05). NEPI prevented the decrease in the urinary clearance of ANF, and enhanced the renal response to endogenous ANF, independent of further increases in plasma ANF during CHF. This study supports an important role for NEP in the pulmonary and urinary metabolism of endogenous ANF during acute CHF.     

Effects of a bolus dose of atrial natriuretic factor in young and elderly volunteers

We assessed the haemodynamic and renal effects as well as the effects on plasma cGMP levels of a small i.v. dose (33 micrograms) of human atrial natriuretic factor (99-126; hANF) in two age groups of healthy volunteers. Binding properties of platelet ANF receptors were also measured. The elderly (four males, eight females, mean age 52.3 years) showed increased haemodynamic (decrease in blood pressure) and renal responses (diuresis, natriuresis, calciuresis) as well as greater increases in plasma cGMP levels and urinary cGMP excretion than the young subjects (four males, 12 females, mean age 26 years). Binding capacities and affinities of platelet ANF receptors were identical in both groups. These data indicate that the sensitivity to ANF increases with age and that this increased sensitivity is reflected in the reactivity of plasma cGMP levels but not in the properties of platelet ANF receptors. The data may be important for the therapeutic use of ANF, for the understanding of the physiological regulation of ANF action and may underline the necessity of using age-matched control subjects for clinical studies on the possible therapeutic effectiveness of ANF.     

Urodilatin: a new approach for the treatment of therapy-resistant acute renal failure after liver transplantation

Abstract A pilot study was performed in patients after liver transplantation (Ltx) to examine the effect of continuous intravenous urodilatin (URO, CDD/ANP-95–126)-infusion as an alternative therapy of acute renal failure (ARF) resistant to conventional therapy. Eight patients who developed ARF after liver transplantation and fulfilled requirements for haemo-dialysis/haemofiltration were treated. After URO infusion was started, renal function improved and all patients developed a strong diuresis and natriuresis within 2–4h. The extracellular expansion due to sodium and water retention in anuric/oliguric ARF lead to an increased central venous pressure (CVP) and elevated blood pressure. During the URO infusion CVP declined and systolic, as well as diastolic, blood pressure were stable. In six patients where haemodialysis/haemofiltration could be avoided, serum creatinine (SC) and blood urea nitrogen (BUN) declined during URO treatment and creatinine clearance (CC) also improved significantly. Fluid and electrolyte disturbances changed promptly and normalized. This was in concordance with renal excretion of electrolytes. Two patients still required haemodialysis/haemofiltration. The six patients who did not require haemodialysis/haemofiltration after URO treatment normalized concerning their renal function and did well in a control period of 12 weeks. The study shows that continuous low dose URO infusion may present a new concept for treatment of postoperative acute renal failure resistant to conventional therapy.     

Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion.

We investigated atrial natriuretic factor (ANF) in humans, measuring plasma immunoreactive (ir) ANF (in femtomoles per milliliter), and renal, hormonal, and hemodynamic responses to ANF infusion, in normal subjects (NL) and congestive heart failure patients (CHF). Plasma irANF was 11 +/- 0.9 fmol/ml in NL and 71 +/- 9.9 in CHF (P less than 0.01); the latter with twofold right ventricular increment (P less than 0.05). In NL, ANF infusion of 0.10 microgram/kg per min (40 pmol/kg per min) induced increases (P less than 0.05) of absolute (from 160 +/- 23 to 725 +/- 198 mueq/min) and fractional (1-4%) sodium excretion, urine flow rate (from 10 +/- 1.6 to 20 +/- 2.6 ml/min), osmolar (from 3.2 +/- 0.6 to 6.8 +/- 1.2 ml/min) and free water (from 6.8 +/- 1.6 to 13.6 +/- 1.6 ml/min) clearances, and filtration fraction (from 20 +/- 1 to 26 +/- 2%). Plasma renin and aldosterone decreased 33% and 40%, respectively (P less than 0.01). Systolic blood pressure fell (from 112 +/- 3 to 104 +/- 5 mmHg, P less than 0.05) in seated NL; but in supine NL, the only hemodynamic response was decreased pulmonary wedge pressure (from 11 +/- 1 to 7 +/- 1 mmHg, P less than 0.05). In CHF, ANF induced changes in aldosterone and pulmonary wedge pressure, cardiac index, and systemic vascular resistance (all P less than 0.05); however, responses of renin and renal excretion were attenuated. ANF infusion increased hematocrit and serum protein concentration by 5-7% in NL (P less than 0.05) but not in CHF.     

Effects of dichloroacetate and bicarbonate on haemodynamic parameters in healthy volunteers.

1. It has been shown that sodium bicarbonate has no effect or could even be detrimental in various forms of metabolic acidosis. Dichloroacetate, a stimulator of the pyruvate dehydrogenase complex, might offer an alternative treatment. The present study therefore examines the metabolic and haemodynamic effects of dichloroacetate and sodium bicarbonate in healthy volunteers. 2. On 2 different days, sodium dichloroacetate (50 mg/kg body weight) or sodium bicarbonate (1.5 mmol/kg body weight) was given intravenously as a single bolus in 10 healthy volunteers. Haemodynamic parameters were measured using a microprocessor-controlled system. Measurements were performed before and 30 and 60 min after infusion. 3. After administration of dichloroacetate, cardiac index increased from 2.3 +/- 0.03 to 2.7 +/- 0.1 1 min-1 m-2 (P less than 0.05), peripheral vascular resistance decreased from 266 +/- 9.7 to 240 +/- 1.7 kPa s l-1 (2662 +/- 97 to 2398 +/- 169 dyn s cm-5, P less than 0.05), oxygen availability increased from 442 +/- 16 to 535 +/- 30 ml min-1 m-2 (P less than 0.05) and serum lactate concentration fell from 1.4 +/- 0.14 to 0.6 +/- 0.1 mmol/l (P less than 0.05). With infusion of sodium bicarbonate there were no significant effects on any of these variables. 4. Our results show that dichloroacetate administered intravenously reduces the serum lactate concentration. The main effects of dichloroacetate itself are on the haemodynamic variables. Dichloroacetate increases cardiac index and oxygen availability and decreases peripheral vascular resistance, whereas sodium bicarbonate has no effect on haemodynamic or metabolic parameters. These data give some further insights in the actions of dichloroacetate and support the use of dichloroacetate as alternative therapy in various forms of metabolic acidosis.     

Pharmacokinetics, hemodynamic, renal, and neurohormonal effects of atrial natriuretic factor in experimental heart failure

The hemodynamic, renal, neurohormonal effects and pharmacokinetics of synthetic atrial natriuretic factor (ANF) were studied in six conscious dogs with severe heart failure induced by right ventricular pacing at 250 beats/min for 5.0 +/- 0.6 weeks. Severe heart failure was characterized by a low cardiac output (2.1 +/- 0.1 L/min, elevated pulmonary capillary wedge pressure (26.8 +/- 2.8 mmHg) and right atrial pressure (14.5 +/- 2.2 mmHg). Synthetic ANF (human 99ser-126tyr ANF) was administered intravenously as 2 consecutive 30 min infusions (0.02 and 0.10 microgram/kg.min respectively); and each infusion was preceded by a priming dose of 1 microgram/kg. In contrast to the potent vasorelaxant, natriuretic and renin-lowering effects previously reported in normal dogs, these effects were not observed in the dogs with heart failure with either dose of ANF. The plasma half-life was 10.0 +/- 2.6 min, significantly longer than that reported previously in normal dogs. These data suggest that in this model of heart failure, the pharmacokinetics of ANF are altered and there is generalized target organ resistance to the actions of ANF.     

Hemodynamic effects of atrial natriuretic factor in young and elderly subjects

Because levels of plasma atrial natriuretic factor (ANF) increase with advancing age, a diminished hemodynamic responsiveness to ANF in the elderly has been hypothesized in the literature. Therefore hemodynamic effects after two infusion rates (0.25 and 2.0 micrograms/min) of atrial natriuretic factor (99-126) were investigated in young (n = 8) and elderly (n = 9) volunteers in a double-blind, randomized, and placebo-controlled protocol. After low-rate infusion, ANF concentrations increased to the upper normal range, and only minor effects were observed. In contrast, high-rate infusion resulted in a decrease in blood pressure and forearm vascular resistance, whereas an increase in heart rate was observed in both groups. Between young and elderly subjects, a significant difference was observed in the ANF-induced decrease in systolic blood pressure (mean +/- SD, -4% +/- 4% versus -12% +/- 7%, p less than 0.05) and mean arterial pressure (-6% +/- 5% versus -11% +/- 4%, p less than 0.05) during the high rate infusion. When compared with the concentrations of the young subjects, the ANF concentrations reached at both ANF dosages were higher in the elderly subjects; this was the result of a diminished ANF clearance in the elderly subjects. After correction of the changes of systolic blood pressure and mean arterial pressure for the higher ANF levels reached within this elderly group, no difference between young and elderly subjects remained. We conclude that a diminished cardiovascular responsiveness to ANF with advancing age could not be demonstrated. In contrast, the high-rate infusion of ANF induced an increased hemodynamic response in the elderly subjects, but this seems to be the result of the higher ANF levels reached within this group.     

Development and validation of a two-site immunoradiometric assay for human atrial natriuretic factor in unextracted plasma

This two-site immunoradiometric assay (IRMA) for human atrial natriuretic factor (ANF)99-126 in plasma utilizes a mouse monoclonal antibody raised against rat (r) ANF103-125 with specificity directed towards the ring structure of ANF, and a rabbit antiserum to human (h) ANF99-126. The monoclonal antibody is radioiodinated, and the IgG fraction of the antiserum is coated onto wells of a microtiter plate. Plasma or standard hANF99-126 (150 microL) is incubated with the radioligand in coated wells for 24 h. The detection limit is 0.9 pg per well, corresponding to 2 pmol/L, with a working range (CV less than 10%) from 4.5 to 540 pmol/L. Intra- and interassay precision are 7% and 9%, respectively, and the assay is unaffected by plasma matrix. In humans, the IRMA is specific for hANF99-126, the major circulating form of ANF, and does not cross-react with metabolites having deletions at the carboxy terminus. Plasma IRMA values in normal seated subjects were 6.6 +/- 1.5 (SEM) pmol/L and results correlated with those of an extraction RIA (r = 0.81, P less than 0.001).     

Effects of hyperglycaemia on kidney function, atrial natriuretic factor and plasma renin in patients with insulin-dependent diabetes mellitus.

In normoalbuminuric patients with insulin-dependent diabetes mellitus, plasma atrial natriuretic factor (ANF), cyclic GMP and active renin and the renal clearances of [99Tcm]-diethylenetriaminepentaacetic acid (DTPA) lithium and sodium were studied on a hyperglycaemia day and a euglycaemia day. Baseline euglycaemia was achieved by an overnight variable insulin infusion, which during study days was fixed at the rate necessary to maintain euglycaemia in the morning. After a baseline euglycaemic clearance period of 90 min, measurements were repeated in a new 90-min period beginning 150 min later. On the hyperglycaemia day i.v. infusion of 20% glucose was started at the end of the euglycaemic baseline period, increasing blood glucose (5.3 +/- 1.3 vs 12.1 +/- 1.2 mmol l-1, p less than 0.01). On the euglycaemia day blood glucose declined (5.1 +/- 1.0 vs 4.2 +/- 1.0 mmol l-1, p less than 0.02). Glomerular filtration rate (GFR) was unchanged by acute hyperglycaemia (127 +/- 16 vs 129 +/- 24 ml min-1, NS), but nearly normalized during maintained euglycaemia on the euglycaemia day (124 +/- 17 vs 105 +/- 16 ml min-1, p less than 0.01). When comparing the hyperglycaemic study period with the similarly timed period on the euglycaemia day, GFR was elevated by hyperglycaemia (129 +/- 24 vs 105 +/- 16 ml min-1, p less than 0.01), while the renal clearances of lithium and sodium were similar. Consequently, the calculated absolute proximal reabsorption rate of sodium and water was elevated during hyperglycaemia. Hyperglycaemia reduced the slight decline in plasma concentrations of ANF and cyclic GMP observed on the euglycaemia day. Active renin, glucagon and plasma osmolality were unchanged. In conclusion, marked changes in glomerular filtration rate are induced by changes in blood glucose concentration, but the effect is delayed and thus not directly related to renal tubular transport of glucose. Hyperglycaemia does not affect renal clearances of lithium and sodium, while proximal tubular reabsorption is markedly stimulated. These changes are not related to changes in ANF, renin, glucagon or plasma osmolality.     

Relationship of increased plasma atrial natriuretic factor and renal sodium handling during immersion-induced central hypervolemia in normal humans.

Although maneuvers augmenting atrial volume and/or stretch also augment plasma levels of atrial natriuretic factor (ANF), the role of ANF in modulating renal sodium and water handling has not been defined. Water immersion to the neck (NI) was employed to assess the ANF response to acute volume expansion in 13 seated sodium-replete normal subjects. ANF increased promptly and markedly from 7.8 +/- 1.8 to 19.4 +/- 3.8 fmol/ml, then declined to 6.3 +/- 1.4 fmol/ml after 60 min recovery. Concomitantly, NI increased urine flow rate (V) (2.0 +/- 0.6 to 7.0 +/- 0.9 ml/min; P less than 0.001) and sodium excretion (UNaV) (92 +/- 12 to 191 +/- 15 mu eq/min; P less than 0.001), and decreased PRA (-66 +/- 3%) and plasma aldosterone (-57 +/- 6%). Increases of plasma ANF ranged from less than 20% to over 12-fold. Similarly, the natriuretic response to NI varied markedly from none to 500%. There was a strong correlation between peak ANF and peak UNaV (r = 0.67; P less than 0.025), but none between peak V and peak plasma ANF (r = -0.10; P greater than 0.5). These findings suggest that an increase in plasma ANF contributes to the natriuretic response to NI, implying a physiological role for ANF in modulating volume homeostasis in humans.     

Optimization of atrial natriuretic factor radioimmunoassay

The development and long-term performance of a radioimmunoassay method for cardionatrin (C I = ANF 99-126) is described. The method was evaluated for accuracy, specificity and precision using different protocols and in various species. The antiserum raised against C I cross-reacts 100% with both human and rat C I and 122% with cardionatrin IV (C IV = ANF 1-126). Dextran-coated charcoal (DCC) and double antibody (DA) disequilibrium protocols were used for the separation of free from antibody-bound radioactivity. The sensitivity, coefficient of variation within assay and between assay for DCC was 4.6 pg/tube, 3.1% and 13.8% respectively, and 1.5 pg/tube, 3.8% and 9.1% for the DA. The mean normal plasma C I levels in human, rat and dog after plasma acidification and extraction using the DA method was 49.7 +/- 4.0; 253.6 +/- 19.6 and 59.9 +/- 3.4 pg/mL respectively.     

Severe hypotension and bradycardia after continuous intravenous infusion of urodilatin (ANP 95–126) in a patient with congestive heart failure

Abstract. The effects of a continuous i.v. infusion of urodilatin at a dose of 30 ng kg^-1 min^-1 were studied in a patient with congestive heart failure. After 30 min, urodilatin had induced a marked stimulation of plasma cyclic GMP concentrations. In parallel haematocrit increased. No significant diuresis and no change of invasive haemodynamics was observed. After 2 h the patient developed a profuse perspiration. Eighty minutes later he suffered from dizziness due to hypotension (blood pressure 80/40 mmHg) and a sudden bradycardia (50bpm). Urodilatin was discontinued and symtoms were relieved by bed tilt and rapid infusion of isotonic saline solution. Mechanisms contributing to these adverse effects may be fluid extravasation to the third space and sympathoinhibitory effects known to occur with natriuretic peptide infusion.     

Effect of exercise on plasma atrial natriuretic factor and cardiac function in men and women

In order to provide an integrated view of the physiology of atrial natriuretic factor (ANF) during exercise, we studied changes of its plasma concentrations in 13 normal subjects (seven males, six females) during three graded exercise levels and two periods of recovery (5 and 30 min), concomitantly with an assessment of cardiac function and ventricular volumes by multigated radionuclide angiography. Mean ANF levels (+/- SEM) increased in all patients at the second (P less than 0.002) and third (P less than 0.002) exercise levels, and after 5-min recovery (P less than 0.01): in males from 16 +/- 7 to 30 +/- 11 pg ml-1 at the third level, in females from 27 +/- 12 to 61 +/- 33 pg ml-1. Normal values were observed after 30-min recovery. Even if mean ANF levels were all higher in females, this difference did not reach statistical significance (P = 0.06). Significant decreases of ventricular volumes, as well as increases of ejection fraction and rate pressure product, were noted during exercise and were similar in both sexes. The kinetics of plasma ANF concentrations, compared with the increase of rate pressure product, was characterized by a latency and a remanence in recovery. This remanence, also present in the changes of ventricular volumes, supports the hypothesis that other factor(s) like catecholamines might still exert their influence after the exercise stops.     

The immediate haemodynamic response to the initiation of extracorporeal membrane oxygenation in a piglet model of infant hypoxic respiratory failure

There is evidence that haemodynamic fluctuations on extracorporeal membrane oxygenation (ECMO) increase the risk of cerebral damage. We hypothesized that initiation of venovenous (VV) or venoarterial (VA) ECMO itself causes haemodynamic fluctuations and, thus, established an infant animal ECMO model in order to discuss this hypothesis. Five piglets were cannulated using the jugular and femoral veins (VV group) and five using the jugular vein and carotid artery (VA group). All animals were subjected to hypoxic ventilation (FiO2 8%) for 10 min, leading to a PaO2 of < 40 mmHg, and subsequently rescued by ECMO. The heart rate (HR) and mean arterial blood pressure (MAP) were recorded at 5-min intervals; the arterial blood lactate was measured prior to and after 5 and 10 min of hypoxia, as well as 30, 60 and 120 min after initiation of ECMO. The response to initiation of ECMO was similar in the VV and VA groups with regard to HR and lactate, but differed significantly in MAP. HR decreased significantly from 135 +/- 7 to 103 +/- 6 beats/min (p < 0.05) and from 132 +/- 8 to 84 +/- 9 beats/min (p < 0.01) at 5 min (p = NS) after installation; lactate increased from 1.4 +/- 0.1 to 1.8 +/- 0.2 mmol/l (p = NS) and from 1.4 +/- 0.2 to 1.6 +/- 0.5 mmol/l (p = NS) after 30 min (p = NS); MAP decreased from 80 +/- 5 to 63 +/- 3 mmHg (p = NS) and increased from 75 +/- 4 to 84 +/- 3 mmHg (p = NS) at 5 min (p = 0.001), respectively. The initiation of ECMO is associated with haemodynamic fluctuations in both modalities, which differ with regard to blood pressure reaction.     

Insulin sensitivity and secretion in healthy elderly human subjects with ''abnormal'' glucose tolerance

Glucose tolerance deteriorates dramatically with advancing age. It is not known whether the underlying pathophysiology is different in older subjects. We employed a two step hyperinsulinaemic euglycaemic glucose clamp with [6(14)C] glucose infusion to compare peripheral and hepatic insulin sensitivity in eight elderly (EAGT) with eight young (YAGT) subjects with abnormal (matched) glucose tolerance and nine elderly subjects with normal glucose tolerance (ENGT). There was no difference in basal HGO (EAGT 14.5 +/- 0.9, YAGT 15.3 +/- 1.1 mumol kg-1 min-1). Glucose turnover was similar in both groups at step 1 (EAGT 13.2 +/- 0.8, YAGT 13.4 +/- 0.8 mumol kg-1 min-1) and step 2 (EAGT 25.1 +/- 3.1, YAGT 27.2 +/- 2.7 mumol kg-1 min-1). HGO was lower in the EAGT subjects at step 1 (2.3 +/- 0.4 vs. 4.3 +/- 0.6 mumol kg-1 min-1 P = 0.01). Incremental serum insulin response to oral glucose was comparable (EAGT 66.8 +/- 11.6 YAGT 57.8 +/- 12.2 mU l-1.h). Compared to the ENGT group the EAGT group was insulin resistant with a lower MCR of glucose at step 1 (2.03 +/- 0.28 vs. 3.23 +/- 0.44 ml kg-1 min-1 P = 0.04) and at step 2 (6.18 +/- 0.83 vs. 9.64 +/- 0.38 ml kg-1 min-1 P = 0.004) and had a lower early insulin response (AUC 0-30 min 5.9 +/- 1.1 vs. 9.8 +/- 1.4 mU l-1.h P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)