Adrienne Korn

Oral glucose tolerance test: Effect of different glucose loads on splanchnic carbohydrate and substrate metabolism in healthy man

Abstract To evaluate the role of splanchnic metabolism in the disposal of orally ingested glucose and thereby to define the optimal glucose load for glucose tolerance testing, splanchnic glucose output (SGO), as determined by the hepatic-venous catheter technique, was estimated in 16 healthy male volunteers in the basal state and after different glucose loads. Following glucose ingestion of 12.5, 25, 50, 75, and 100 g glucose, mean SGO over 2 hours was 9, 10, 12.3, 20, and 24.7 g above basal hepatic glucose production or 72, 40, 25, 26, and 25 percent of the respective glucose load. Increasing glucose doses represented a greater and more prolonged insulinogenic stimulus as determined by insulin concentrations in hepatic venous plasma. Splanchnic lactate uptake decreased and finally reverted to a net output in most of the subjects studied, whereas pyruvate production increased with rising glucose loads. It is concluded that (1) maximal stimulation of insulin release by administration of 50 to 100 g glucose results in maximal splanchnic extraction (75%) of an ingested glucose load, whereas smaller amounts of glucose are retained to a lesser extent; (2) 100 g of glucose provide optimal conditions for performing an oral glucose tolerance test (OGTT), thereby provoking a relative as well as an absolute maximum of splanchnic glucose extraction; and (3) splanchnic uptake of pyruvate and lactate following ingestion of small amounts of glucose revert to a net output with utilization of increasing glucose loads.

In vivo clearance of antibody-sensitized human drug carrier erythrocytes.

Antibody coating of resealed drug carrier erythrocytes may be useful for drug targeting to the reticuloendothelial system. We have investigated the survival in the circulation of anti‐Rh antibody (IgG anti‐D)–coated autologous erythrocytes loaded with gentamicin by hypoosmotic dialysis. Five subjects were injected with 15.2 ± 0.4 ml and five additional subjects with 62.8 ± 1.5 ml carrier cells. Survival of the cells was monitored by intraerythrocytic gentamicin concentration in blood. In the first subject group initial t1/2 was 0.21 ± 0.06 hours and terminal t1/2 was 1.71 ± 0.36 hours. In the second group initial t1/2 was 0.59 ± 0.21 hours followed by a slow phase with a t1/2 of 89 ± 28 hours. Results indicate that rapid drug delivery to the reticuloendothelial system by antibody—sensitized carrier erythrocytes is possible, but small volumes of erythrocytes seem more efficient.

Primary defect in α‐adrenergic responsiveness in patients with varicose veins

Responsiveness of superficial hand veins to local infusions of noradrenaline was compared in patients with primary varicose veins and in healthy volunteers by use of the dorsal hand vein technique. Patients with varicose veins required significantly higher doses of noradrenaline for half‐maximal venoconstriction than the dose required by control subjects (geometric mean, 11.6 ng/min in patients compared with 4.8 ng/min in control subjects; p = 0.006). Noradrenaline responsiveness in varicose veins was not significantly different from hand vein responsiveness in the same patients. Our findings indicate a constitutional decrease in venous a‐adrenergic receptor responsiveness in patients with varicosities. Dilation of varicose veins does not further affect noradrenaline‐induced venoconstriction.

Survival of gentamicin‐loaded carrier erythrocytes in healthy human volunteers

Abstract. Resealed erythrocytes are potential slow release carriers for drugs and enzymes. We have investigated carrier erythrocyte survival in human volunteers using gentamicin (G) as encapsulated cell marker; G was readily incorporated into red cells by hypo‐osmotic dialysis (87% efficiency of incorporation) and did not exit from carrier cells in vitro. Six healthy young volunteers were injected with 59 ± 7 ml carrier erythrocytes containing 56 ± 13 mg G. G levels were measured in plasma and haemolysed whole blood by RIA. After an initial phase of cell loss (up to 4·5 h post‐injection) the carrier erythrocytes survived in circulation with a half‐life of 22 days, as was indicated by intracellular G concentration. G levels were detectable in plasma during the first 90 min after injection. This indicates haemolysis of some carrier cells. In conclusion, carrier erythrocytes appear to circulate longer than any other drug carrier under investigation and may well serve as innocuous slow release system.

In vivo studies on alpha-adrenergic receptor subtypes in human veins

SummaryWe studied in vivo responsiveness of venous α1 and α2-adrenoceptors, measuring the diameter changes in superficial veins in response to α-adrenergic agonists and antagonists in healthy human volunteers. The dorsal hand vein technique was used because it permits complete dose-response studies of venous constriction without confounding reflex alterations.Local infusions of all agonists studied induced dose-dependent contraction of the hand vein; the maximal effects (Emax) were: norepinephrine (88% ± 10%), methox amine (97% ± 5%), phenylephrine (95% ± 6%), clonidine (54% ± 12%), and azepexole (68% ± 26%). Clonidine reduced the norepinephrine-induced venoconstriction by 11% ± 10%. Oral doses of 1 mg prazosin antagonized the venoconstriction induced by norepinephrine, methoxamine, and clonidine, but not by azepexole. Yohimbineantagonism was observed against all agonists studied. Inhibition by yohimbine of clonidine-induced venoconstriction was irreversible over 60–180 min.Results show that the in vivo effects on veins of α-adrenergic agonists are in good agreement with results from in vitro experiments. Agonists with α1- and α2-adrenoceptor subtype selectivity cause venoconstriction in vivo, but α2-receptor mediated constriction is intrinsically weaker. Clonidine acts as a partial antagonist against norepinephrine, presumably on postsynaptic α2-receptors. At high doses, α2-adrenoceptor subtype selectivity of clonidine and yohimbine appear to be partially lost in vivo.

Plasma concentrations of free and sulfoconjugated dopamine, epinephrine, and norepinephrine in healthy infants and children

SummaryPlasma concentrations of free and sulfoconjugated catecholamines were measured in healthy infants and children under resting conditions. Free norepinephrine and epinephrine levels were up to three times higher in healthy children under 2 years than in adults, even under true resting conditions. In contrast, free dopamine concentrations of all age groups fell within the normal range for adults. The levels of sulfoconjugation were in the adult range.

Effect of buformin on splanchnic carbohydrate and substrate metabolism in healthy man

The effect of buformin (100 mg b.i.d. for 5 days) on carbohydrate metabolism, both splanchnic glucose output (SGO) and net substrate exchange were studied in 6 healthy male volunteers in the basal state and following glucose ingestion (100 g). Control studies without buformin were also performed in 5 men. Splanchnic glucose and substrate exchange was determined by means of the hepatic venous catheter technique. SGO was 154 +/- 18 (SEM) mg/min in the postabsorptive state and increased 33.3 +/- 2.8 g above the basal level during the 150 min period following glucose ingestion. Buformin administration did not alter basal SGO (157 +/- 26 mg/min), nor the splanchnic exchange of pyruvate, alanine, glycerol, OH-butyrate and acetoacetate. Splanchnic lactate balance was altered by buformin and net lactate output occurred. Following glucose ingestion the rise in splanchnic lactate output was increased, whereas no change in SGO (32.9 +/- 3.5 g/150 min) and splanchnic exchange of the other substrates was observed. The increase in arterial blood glucose concentration following oral glucose loading was reduced by buformin pretreatment (p less than 0.005). The insulin production rate (basal, 16 +/- 2 mU/min; following oral glucose, 13 +/- 2 U/150 min) as calculated from C-peptide release from the splanchnic area was unchanged by buformin. Except for a marked rise in splanchnic lactate production, buformin did not alter splanchnic carbohydrate metabolism after orally ingested glucose in healthy man. The diminished increase in arterial blood glucose concentration associated with unaltered insulin production suggests that buformin facilitates glucose utilization by peripheral tissues.

Impaired plasma amino-acid clearance in patients with cirrhosis of the liver and portocaval shunt--its relation to insulin resistance.

Abstract. To study the interdependence of utilization of branched chain amino acids and glucose and of hyperinsulinaemia in patients with liver cirrhosis the plasma disappearance of glucose and amino acids was estimated in seven patients with cirrhosis and portocaval shunt and in seven healthy controls following infusion of glucose and essential amino acids during suppression of endogenous hormone release by somatostatin. Exogenous insulin was infused by means of an automated glucose controlled insulin infusion system. The data demonstrate that (i) insulin requirement almost doubled in patients as compared to controls to obtain similar blood glucose responses to i.v. glucose, and (ii) the plasma disappearance rates of the infused amino acids were reduced in the patients as compared to controls despite hyperinsulinaemia sufficient to achieve normal glucose assimilation. Thus, in cirrhotic patients insulin resistance may be overcome by excess insulin as far as glucose homeostasis is concerned, whereas amino‐acid metabolism still remains impaired.

The role of adrenergic mechanisms in the blood pressure regulation of leg-amputees

SummaryAn increased occurrence of hypertension has been reported among legamputees. In order to investigate whether leg amputation is followed by an elevation of sympathetic tone, possibly enhanced by continuous mechanical irritation of the amputation stump by wearing a prosthesis, blood pressure (BP), pulse-rate (PR) and plasma catecholamines (norepinephrine, NE, and epinephrine, E) were measured in six hypertensive leg-amputees during prosthesis walking as well as during irritation of the amputation stump by vacuum suction in the supine position. Six patients suffering from essential hypertension and six normotensive subjects served as control groups.Basal levels of plasma NE and E did not differ in the three investigated groups. Mechanical stump(limb) irritation as well as walking induced a rise of NE but not of E, accompanied by a rise of BP and PR in amputees as well as in the control subjects. Elevation of NE and BP was most accentuated in hypertensive amputees when walking with prosthesis. Within each investigated group there was a positive correlation between NE and mean arterial blood pressure (MAP), (p<0.001 in hypertensive amputees and non-amputees, p<0.05 in normotensives). We conclude that mechanical limb irritation induces a rise of BP by sympathetic nervous stimulation. Thus wearing of a vacuum-prosthesis may support a consistent rise in BP.ZusammenfassungDie Entstehung von Bluthochdruck als Spätfolge der Beinamputation wurde vielfach diskutiert. Um festzustellen, ob es nach Beinamputation zu einer verstärkten Aktivität des sympathischen Nervensystems kommt, die möglicherweise durch kontinuierliche mechanische Irritation des Amputationsstumpfes durch das Tragen einer Prothese intensiviert wird, wurden bei sechs beinamputierten Hypertonikern Blutdruck, Puls und Plasmakatecholamine (Noradrenalin und Adrenalin) sowohl während des Gehens auf Prothesen als auch im Liegen während mechanischer Reizung des Amputationsstumpfes durch Vakuumapplikation gemessen. Sechs nichtamputierte, essentielle Hypertoniker und sechs gesunde Personen wurden als Kontrollgruppen verwendet. Die basalen Plasmakatecholaminspiegel Beinamputierter unterscheiden sich nicht von denen nichtamputierter Kontrollpersonen. Die mechanische Reizung des Amputationsstumpfes bzw. Oberschenkels im Liegen führte bei Amputierten und Kontrollpersonen zu einem Anstieg von Plasmanoradrenalin, Blutdruck und Puls. Gehen bewirkte ebenfalls eine Erhöhung von Plasmanoradrenalin, Blutdruck und Puls. Das Ausmaß dieser Veränderungen war in den drei Gruppen vergleichbar, vorausgesetzt, daß die Amputierten keine Prothesen, sondern Krücken benützten, wohingegen Plasmanoradrenalin und Blutdruckanstieg beim Gehen mit Prothesen deutlich verstärkt waren. Innerhalb jeder der drei untersuchten Gruppen bestand eine positive Korrelation zwischenNor-adrenalin und mittlerem arteriellem Blutdruck.

Effect of calcium antagonists on basal and digitalis-dependent changes in splanchnic and systemic hemodynamics

We investigated the effects of the calcium antagonists verapamil and tiapamil on basal splanchnic and systemic hemodynamics and digoxin‐induced vasoconstriction in 16 healthy men, using the hepatic venous catheter technique, the thermodilution method, and systolic time intervals. After a baseline period, verapamil or tiapamil were given by a primed‐constant infusion in six of 16 subjects each, and hemodynamic changes were determined. Thereafter digoxin (1 mg) was concomitantly infused and hemodynamic changes were observed over 105 minutes. Control trials with digoxin alone were performed in seven of 16 subjects. Four of 16 subjects received only placebo. Digoxin provoked an increase in systolic blood pressure and splanchnic vascular resistance. Estimated splanchnic blood flow, mean pulmonary artery pressure, and total electromechanical systole decreased. Verapamil did not change basal hemodynamic parameters. Tiapamil decreased diastolic blood pressure and systemic and splanchnic vascular resistance. Both drugs attenuated the vasoconstricting effect of digoxin on the splanchnic vascular bed. Results indicate that calcium antagonists might be beneficial in treatment of digitalis‐induced splanchnic vasospasm.