Intravenous prostaglandin E1 reduces soluble vascular cell adhesion molecule-1 in peripheral arterial obstructive disease.

OBJECTIVES: Elevated levels of soluble (s) vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1, pointing to activation of cells involved in vascular inflammation, have been previously reported in peripheral arterial obstructive disease (PAOD). We tested the hypothesis that intravenous prostaglandin E(1) (PGE(1)) treatment, which produces clinical benefits in this condition, might decrease such levels. METHODS: Ten subjects (age range 58 +/- 10 years, 6 male, 4 female) with characterized Fontaine stage IIa to IV PAOD (ankle/arm pressure index <0.96) were entered into a treatment protocol with twice daily intravenous infusions of PGE(1) (alprostadil) at 120 microg per day, repeated for 10 consecutive days. Preinfusion and postinfusion plasma samples were stored for blind enzyme immunoassays of soluble adhesion molecules and the fibrinolytic marker tissue plasminogen activator, type-1 plasminogen-activator inhibitor, and D -dimer. RESULTS: Estimates of severity of pain at rest, consumption of analgesics, magnitude of trophic lesions, remission to lower Fontaine stages, and favorable changes in the venoarteriolar reflex documented significant beneficial effects of the treatment. Significant (P <.01) pretreatment and posttreatment reductions of in all soluble markers explored were found. Particularly, sVCAM-1 exhibited a significant decrease after each infusion, which was sustained at the last day of treatment (from 854 +/- 214 ng/mL to 775 +/- 215 ng/mL across the first infusion, from 773 +/- 146 ng/mL to 680 +/- 110 ng/mL across the last infusion). CONCLUSION: Thus a global decrease of vascular cell activation appears to occur as a result of PGE(1) administration and may contribute to the observed clinical benefits in PAOD.

Exercise increases soluble adhesion molecules ICAM-1 and VCAM-1 in patients with intermittent claudication.

Adhesion molecules play a relevant role in the pathogenesis of vascular diseases. In 21 patients with intermittent claudication and 18 sex- and age-matched control subjects, we measured plasma levels of the circulating form of the adhesion molecules E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) alongside von Willebrand factor (vWF), at rest, at maximally tolerated exercise and 5, 15 and 30 min after exercise. In controls, plasma sICAM-1 levels did not change with exercise, while in claudicants they increased from 285+/-15 to 317+/-16 ng/ml (p<0.01). Also for sVCAM-1 exercise did not modify plasma levels of sVCAM-1 in controls but increased it in claudicants from 671+/-45 to 751+/-47 ng/ml (p<0.05). Similarly, vWF did not change with exercise in controls, but increased in claudicants from 100+/-9% to 111+/-8% of value for pooled normal plasma (p<0.05). Exercise-induced changes in sICAM-1 negatively correlated with the maximal tolerated walking time, which is an index of disease severity. These findings indicate that, in claudicants, exercise is associated with increase in plasma levels of sICAM-1 and sVCAM-1.

Role of inhibition of atrial natriuretic factor release in the down-regulation of salt excretion.

UNLABELLED: We investigated the role of atrial natriuretic factor (ANF) in the down-regulation of sodium excretion (UNaV). Seven subjects were sequentially studied while ingesting a normal-salt diet (220 mmol NaCl/day, NSD), a very low-salt diet (20 mmol NaCl/day, VLSD) for six days, and again at NSD for nine days. After one day of VLSD, a negative salt balance of 85 mmol was achieved and plasma ANF decreased from 19.1 (SE 2.5) to 7.2 (SE 2.1) pg/ml, whereas plasma renin activity (PRA) and plasma aldosterone (ALD) increased after the third and second day, respectively. During restoration of volemia (NSD), ANF increased after the third day; in contrast, PRA and ALD decreased earlier. Seven other subjects kept at low-salt diet (50 mmol NaCl/day) were studied during ANF infusion (at 2, 4, 8 ng/min/kg body wt). Increases of ANF from 10.3 (SE 0.9) pg/ml (basal condition) to levels of 24.0 (SE 1.9) pg/ml (infusion study), occurring physiologically in the same subjects after NSD, evoked increases in UNa V that accounted for 62% of UNa V rise necessary to balance the NSD, whereas PRA or ALD did not change. Plasma ANF, unlike PRA or ALD, was directly correlated with UNa V. IN CONCLUSION: (a) ANF changes earlier than PRA and plasma aldosterone during VLSD; (b) PRA and ALD respond more promptly than ANF in the recovery from hypovolemia; (c) during ingestion of a low-salt diet, changes in plasma ANF by infusion account for more than half the increase in UNa V following the shift from low- to normal-salt diet independently of alterations in PRA and ALD.

Impact of preoperative CA 15-3 levels in operable breast cancer. Comparison with tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA).

CA 15-3, TPA and CEA were assayed before surgery in 60 patients with breast cancer. A significant association was found between preoperative CA 15-3 levels and some of the most important prognostic factors in breast cancer, such as lymph node status and tumor size. No similar association was discovered for CEA and TPA. Preoperative CA 15-3 levels were also significantly associated with early recurrences of the disease, thus adding useful information to prognosis especially in N+ patients.

Effects of a two-month treatment with low oral doses of cyclosporin on renal function.

To test the effects of short-term therapy with low doses (LD) of cyclosporin A (CsA) in subjects with normal renal function, seven patients receiving CsA to treat psoriasis were studied. Clearances in maximal H2O diuresis were performed to evaluate changes in GFR (CIn), RPF (CPAH) and tubular function before starting CsA (BAS), after 2 days (S1) and 1 month (S2) of oral therapy with 5 mg/kg per day CsA. The study was repeated at the withdrawal of CsA after tapering (S3) and 2 months after the withdrawal (S4). The studies were performed 12 h after the evening dose of CsA. RPF was significantly less than in BAS throughout the therapy and returned almost to basal values in S4. GFR was significantly less than in BAS both in S2 and in S3. In S4, in spite of an increase, GFR was still significantly less than in BAS. Both in S2 and in S3 proximal tubular fractional sodium reabsorption was significantly less than in BAS and, consequently, both sodium delivery to diluting segments and sodium reabsorption in diluting segments increased. Moreover, both in S2 and in S3 fractional sodium reabsorption in diluting segments and free-water generation were greater than in BAS. In S4 tubular function returned almost to basal values. Our data suggest that short-term therapy with low dose CsA impairs renal function; this impairment is not completely reversed after drug withdrawal.

CA 15-3 in human breast cancer. Comparison with tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA).

CEA, TPA, CA 15-3 were assayed in 238 patients in follow-up for breast cancer after surgery. CA 15-3 showed the best sensitivity and specificity; the predictive value of a positive CA 15-3 test was three times higher than CEA and TPA. No association was found between marker positivity and the number of organs involved by metastases. CA 15-3 positivity was significantly associated with visceral rather than soft tissue recurrences; no significant similar association was observed for CEA and TPA. CA 15-3 serum levels were early predictors of relapse in four out of nine patients within a 6-12 month follow-up period.

Angiotensin II inhibition with captopril on plasma ADH, PG synthesis, and renal function in humans.

Using captopril (C), an angiotensin (ANG) I converting-enzyme inhibitor, to increase endogenous prostaglandins (PGs) and to decrease endogenous ANG II synthesis, we studied the relationship between endogenous ANG II, PG, and antidiuretic hormone (ADH) release in seven normal volunteers before (control study) and after inhibition of PG synthesis by a single dose of aspirin (ASA study). In the control study, following the administration of 100 mg of C, there was a significant increase of plasma PGE2, plasma-renin activity (PRA), and urinary PGE2 and 6-keto-PGF1 alpha and a decrease of plasma ADH. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were unaffected by C; urine output, fractional sodium excretion (FENa), and osmolal clearance (Cosmol) increased; and urinary osmolality (Uosmol) decreased significantly after C. In the ASA study PG were undetectable in plasma and significantly reduced in urine 1 h after aspirin and did not increase when C was added. Plasma ADH decreased and PRA increased, as in the control study, after C, whereas GFR, RPF, urine output, FENa, Cosmol, and Uosmol were unchanged. These results suggest that the effect of C on ADH release may be mediated, to a large extent, by a fall in endogenous circulating ANG II, since ADH decreased in the presence of both high or undetectable levels of PGE2. The results also suggest that the increase in PGE2 induced by C may precipitate the diuretic and natriuretic effects of acute C administration.

Effects of angiotensin II on plasma ADH, prostaglandin synthesis, and water excretion in normal humans.

To verify whether angiotensin II (ANG II) stimulates ADH release in humans and to evaluate whether endogenous prostaglandins influence the resulting renal effect of ADH, nonpressor and low pressor doses of ANG II were infused in nine normal volunteers under normal conditions (control study) and after prostaglandin synthesis inhibition with aspirin (ASA study). During ANG II infusion plasma ADH increased in both conditions. Plasma PGE2, urinary PGE2, and urinary 6-keto-PGF1 alpha increased only in the control study, whereas they were undetectable in the plasma and significantly reduced in the urine in the ASA study. ANG II caused a significant fall of glomerular filtration rate, renal plasma flow (with an increase in filtration fraction), fractional sodium excretion, and urine output in both studies. Despite the reduced urine output, urine osmolality decreased significantly in the control study, whereas it increased after aspirin administration. These results suggest that intravenous ANG II stimulates ADH release in humans but that the renal effects of the resulting increase in plasma ADH are different depending on the presence or absence of endogenous prostaglandins.

Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome.

To verify whether or not an increased secretion of ADH may cause the water retention commonly observed in nephrotic syndrome, 16 nephrotic patients and 13 normal control subjects were studied in basal conditions and following a water load or an iso-osmotic blood volume expansion by 20% albumin infusion. In the basal condition there were no differences in plasma ADH, urine output, urinary osmolality (UOsm), and plasma renin activity between nephrotic patients and control subjects; POsm, PNa+, UNaV, and blood volume (BV) instead, were significantly lower in nephrotic patients than in control subjects. Following the water load control subjects reached a minimal UOsm of 82 +/- 12 mOsm/kg at 60 min and excreted completely the ingested water in 150 min; nephrotic patients reached a minimal UOsm of 160 +/- 111 mOsm/kg at 120 min, and the water was eliminated completely in 240 min. Plasma ADH decreased significantly in the first hour following water load only in control subjects. A significant direct correlation was observed between plasma ADH and POsm in control subjects (ADH = -85 + 0.30 POsm, P less than 0.001) but not in nephrotic patients. Plasma ADH was inversely correlated with BV in nephrotic patients (ADH = 15.47 -0.17 BV, P less than 0.001) but not in normal control subjects. In nephrotic patients with reduced BV the expansion of BV with 20% albumin was effective in reducing the plasma levels of ADH and promoting a water diuresis. Our results demonstrate a sustained volume mediated secretion of ADH in the nephrotic syndrome, which is responsible for the impairment in water excretion.

Intropic effects of several antiarrhythmic drugs.

The effects of intravenous administration of several quinidine-like antiarrhythmic drugs (bunaftine, monochloroacetyl ajmaline, lidocaine, mexiletine, disopyramide, aprindine, diphenylhydantoin, procainamide) on left ventricular performance, evaluated by systolic time intervals (STI), were studied in 100 patients with atherosclerotic heart disease. The STI were measured: the pre-ejection period (PEP), the isometric contraction time (ICT), the left ventricular ejection time (LVET), corrected LVET (LVETc), and the PEP/LVET ratio. The degree of impairment of left ventricular performance was maximal after aprindine and disopyramide administration. This was demonstrated by significant increases in the PEP, ICT, and PEP/LVET and by significant decreases in LVET and LVETc, in patients in both III-IV and I-II NYHA classes. Bunaftine, monochloroacetyl ajmaline, and lidocaine induced a less marked impairment of myocardial performance, since the PEP, ICT, and PEP/LVET increases were not significant compared to controls in patients in NYHA class I-II, and since no variation of LVET and LVETc were observed. Mexiletine effects on myocardial performance appear to be intermediate between these groups of drugs. Diphenylhydantoin and procainamide, considered separately because of their effects on heart rate and blood pressure which are not possessed by the other drugs, induced significant increases of PEP in NYHA class III-IV patients. However, the effects of these 2 drugs on myocardial performance may have been underestimated, due to the concomitant hemodynamic effect of these drugs.

Influence of acetylsalicylic acid on glucose turnover in normal man.

This study was designed to evaluate the influence of intravenous infusion (72 mg min-1) of lysine acetylsalicylate (LAS), an inhibitor of endogenous prostaglandin synthesis, on glucose homeostasis in normal man. LAS infusion produced a transient decrease of both hepatic glucose production (Ra, p less than 0.01) and peripheral glucose uptake (Rd, p less than 0.01). Since Ra fell more than Rd, a slight but significant decrease of plasma glucose concentration occurred. Glucose metabolic clearance rate also showed a rapid, although transient, decrease after the start of LAS infusion. Plasma insulin rose twofold in response to LAS, while plasma glucagon remained unchanged. The failure of the glucose clearance to increase as a consequence of the augmented insulin levels suggests that salicylate compounds may cause a state of insulin resistance.

Effects of oral salt loading on beta-adrenergic receptor responsiveness in normal and hypertensive subjects.

The effect of oral salt loading (400 mmol per day of NaCl for 7 days) on cardiac and pancreatic beta-receptor responsiveness has been evaluated in 12 patients with established essential hypertension and in seven age-matched control subjects. Cardiac beta-receptor responsiveness was evaluated by assessing the dose of isoprenaline which increased a stable heart rate by 25% (chronotropic dose 25%, CD 25%). Pancreatic beta-receptor responsiveness was measured by the incremental areas of insulin secretion induced by iv infusion of increasing amounts of isoprenaline. Before salt load, CD 25% was significantly higher in hypertensives compared with controls (7.84 +/- 1.34 micrograms vs 3.9 +/- 0.48 micrograms, P less than 0.05) while there was no difference in the isoprenaline-induced insulin secretion between the two groups of subjects. After salt loading, CD 25% was significantly reduced in hypertensive patients but was not modified in normal subjects. Therefore, the difference in CD 25% was no longer detectable between the two groups (5.5 +/- 1.42 micrograms vs 3.2 +/- 0.48 micrograms in normal subjects and in hypertensives, respectively, NS). Furthermore, salt loading failed to induce any change in isoprenaline-induced insulin secretion in either groups. These results support the existence of a relationship between sodium intake and adrenergic beta-receptor responsiveness in human hypertension.

Differential effects of insulin on splanchnic and peripheral glucose disposal after an intravenous glucose load in man.

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg(-1) min(-1)) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg(-1) min(-1); (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg(-1) min(-1)); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg(-1) min(-1)). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls ( approximately 170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 muU/ml at 90 min. NSGB switched from a net output of 1.71+/-0.13 to a net uptake of 1.5-1.6 mg kg(-1) min(-1) due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78+/-0.13 to 1.6-1.8 mg kg(-1) min(-1); P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 muU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 muU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 muU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg(-1) min(-1)). Peripheral glucose uptake rose to the same extent as in controls. IT IS CONCLUDED THAT: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.

Mechanisms of epinephrine-induced glucose intolerance in normal humans.

To evaluate the role of the splanchnic bed in epinephrine-induced glucose intolerance, we selectively assessed the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose production, and peripheral glucose uptake by combining infusion of [3-(3)H]glucose with hepatic vein catheterization. Normal humans received a 90-min infusion of either glucose alone (6.5 mg/kg(-1) per min(-1)) or epinephrine plus glucose at two dose levels: (a) in amounts that simulated the hyperglycemia seen with glucose alone (3.0 mg/kg(-1) per min(-1)); and (b) in amounts identical to the control study. During infusion of glucose alone, blood glucose rose twofold, insulin levels and net posthepatic insulin release increased three- to fourfold, and net splanchnic glucose output switched from a net output (1.65+/-0.12 mg/kg(-1) per min(-1)) to a net uptake (1.56+/-0.18). This was due to a 90-95% fall (P < 0.001) in hepatic glucose production and a 100% rise (P < 0.001) in splanchnic glucose uptake (from 0.86+/-0.14 to 1.71+/-0.12 mg/kg(-1) per min(-1)), which in the basal state amounted to 30-35% of total glucose uptake. Peripheral glucose uptake rose by 170-185% (P < 0.001). When epinephrine was combined with the lower glucose dose, blood glucose, insulin release, and hepatic blood flow were no different from values observed with glucose alone. However, hepatic glucose production fell only 40-45% (P < 0.05 vs. glucose alone) and, most importantly, the rise in splanchnic glucose uptake was totally blocked. As a result, splanchnic glucose clearance fell by 50% (P < 0.05), and net splanchnic glucose uptake did not occur. The rise in peripheral glucose uptake was also reduced by 50-60% (P < 0.001). When epinephrine was added to the same dose of glucose used in the control study, blood glucose rose twofold higher (P < 0.001). The initial rise in splanchnic glucose uptake was totally prevented; however, beyond 30 min, splanchnic glucose uptake increased, reaching levels seen in the control study when severe hyperglycemia occurred. Splanchnic glucose clearance, nevertheless, remained suppressed throughout the entire study (40%-50%, P < 0.01). It is concluded that (a) the splanchnic bed accounts for one-third of total body glucose uptake in the basal state in normal humans; (b) epinephrine markedly inhibits the rise in splanchnic glucose uptake induced by infusion of glucose; and (c) this effect does not require a fall in insulin and is modulated by the level of hyperglycemia. Our data indicate that the splanchnic bed is an important site of glucose uptake in post-absorptive humans and that epinephrine impairs glucose tolerance by suppressing glucose uptake by both splanchnic and peripheral tissues, as well as by its well known stimulatory effect on endogenous glucose production.

Renal function in borderline hypertensive first-degree relatives of essential hypertensives. Effects of sodium load.

Renal function in the basal state and after sodium load has been investigated in 21 borderline, hypertensive, first-degree relatives of established hypertensives and in 21 age- and sex-matched, normal subjects with no family history of hypertension. During intravenous infusion of inulin and p-aminohippurate in saline, both groups showed a decrease in plasma aldosterone levels (p less than 0.05) but renal plasma flow (595 +/- 48 vs. 750 +/- 59 ml/min, p less than 0.05), diuresis (1.4 +/- 0.2 vs. 2.2 +/- 0.5 ml/min, p less than 0.05), natriuresis (0.21 +/- 0.02 vs. 0.3 +/- 0.02 mEq/min, p less than 0.05) and sodium clearance (1.05 +/- 0.1 vs. 2.4 +/- 0.4 ml/min, p less than 0.05) in borderline hypertensives were higher than in the control group. After the salt load (NaCl, 1.35% i.v., 5 ml/min for 2 h) there was an increase in blood pressure and a decrease in plasma aldosterone and potassium levels in both groups. However, borderline hypertensives showed higher diuresis, natriuresis, sodium clearance and also kaliuresis compared to normotensives. These results suggest that borderline hypertensives already present the changes in renal function which are characteristics of established hypertensives.

Inverted response of arginine vasopressin to postural change in patients with essential hypertension.

1. This study was designed to compare the response of plasma arginine vasopressin (AVP) to head-up tilt in hypertensive patients and in normals. 2. As expected, plasma AVP showed a consistent increase (P less than 0.005) in normal subjects after tilt while plasma volume decreased significantly (P less than 0.02). On the contrary, in hypertensive patients, after tilt both plasma AVP (P less than 0.025) and plasma volume (P less than 0.05) decreased. 3. These findings, thus, indicate that essential hypertension is characterized by an inverted response of arginine vasopressin to postural change.

The glucoregulatory response to intravenous glucose infusion in normal man: roles of insulin and glucose.

In order to differentiate the roles of hyperinsulinemia and hyperglycemia per se in the homeostatic response to i.v. glucose administration, two groups of normal subjects were given either glucose alone (3.5 mg kg-1 min-1) or glucose (3 mg kg-1 min-1) in conjunction with somatostatin (500 microgram hr-1), insulin (0.15 mU kg-1 min-1) and glucagon (1 ng kg-1 min-1). Glucose kinetics were measured by the primed-constant infusion of 3-3H-glucose. During the infusion of glucose alone, plasma glucose stabilized at levels 45--50 mg/dl above the fasting values. Endogenous glucose output was markedly suppressed by 85%--90% while glucose uptake rose to values very close to the infusion rate of exogenous glucose. Glucose clearance remained unchanged. Plasma insulin rose to three-fourfold while plasma glucagon fell by 25%--30%. When glucose was infused with somatostatin, insulin, and glucagon, plasma insulin was maintained at levels 50% above baseline while glucagon remained at preinfusion levels. Under these conditions, the infusion of exogenous glucose resulted in a progressive increase of plasma glucose which did not stabilize until the end of the study period (190 mg/dl at 120 min). Endogenous glucose production was consistently suppressed (52%) but significantly less than observed with the infusion of glucose alone (p less than 0.01). Glucose uptake increased to the same extent as with glucose alone, despite the more pronounced hyperglycemia. Thus, glucose clearance fell significantly below baseline (25%--30%; p less than 0.01). These data demonstrate that hyperglycemia per se (fixed, near basal levels of insulin and glucagon) certainly contributes to the glucoregulatory response to i.v. glucose administration by both inhibiting endogenous glucose output and increasing tissue glucose uptake. However, the extra-insulin evoked by hyperglycemia is necessary for the glucoregulatory system to respond to the glucose load with maximal effectiveness.

Effect of counterregulatory hormones on kinetic response to ingested glucose in dogs.

The disposal of ingested glucose was quantitated in dogs during individual and combined infusion of glucagon, epinephrine, and cortisol. Initial splanchnic extraction of ingested glucose, endogenous glucose production, and glucose uptake were quantitated using a double-tracer technique. Glucagon or cortisol individually had no effect on the kinetic response to glucose ingestion, whereas epinephrine increased glucose levels by 50-100 mg/dl. Epinephrine caused a reduced suppression of glucose production and a marked inhibition of the initial rise in glucose uptake. Initial splanchnic glucose extraction, plasma insulin, and glucagon were not significantly altered. The addition of glucagon and cortisol to epinephrine did not accentuate hyperglycemia, except after 150 min when glucose production increased. We conclude that a) epinephrine produces glucose intolerance when infused individually, b) this effect is primarily dependent on inhibition of glucose uptake and, to a lesser extent, on a reduction in suppression of endogenous glucose output, and c) addition of glucagon and cortisol has only a minor effect on epinephrine-induced changes in glucose disposal. Our data suggest an important role of epinephrine in stress-induced glucose intolerance.

Glucoregulatory response to intravenous fructose administration in the dog.

This study was designed to evaluate the influence of fructose administration on glucose kinetics and the role of fructose conversion to glucose in the maintenance of glucose homeostasis. Intravenous fructose infusion (4.5 mg/kg min-1) produced a stable plasma fructose concentration of about 20 mg/dl and a small but sustained decrease (10 mg/dl) of plasma glucose levels. The latter effect was entirely attributable to a rapid 30-35% fall in hepatic glucose output which later returned slowly to pre-infusion levels. No significant change in the rate of glucose utilization was observed. The rate of fructose conversion to glucose rose progressively during fructose infusion reaching a plateau of 1.4 mg/kg min-1 which corresponded to about 40% of total glucose production. Furthermore, as much as one third of the infused fructose was converted to circulating glucose. No appreciable changes in plasma insulin and glucagon levels occurred during fructose infusion while plasma alanine concentration increased remarkably. These data indicate that 1) fructose administration induces a transient fall in endogenous glucose production not accompanied by significant changes in glucose utilization; 2) the rapid conversion of the infused fructose to circulating glucose provides for the restoration of normal rates of glucose production; and 3) the glucoregulatory response to the administration of fructose occurs in the absence of detectable changes in plasma pancreatic hormone concentration.