Opiate receptors and β-endorphin levels in brain areas of dogs with portal-systemic encephalopathy

Clinical observation has indicated a supersensitivity to morphine in patients with hepatic encephalopathy. With the aim of clarifying the issue, radioreceptor binding studies of opiate receptors were performed in frontal cortex and hypothalamus of 6 dogs with mild portal-systemic encephalopathy induced by chronic treatment with dimethylnitrosamine followed by porto-caval shunt end-to-side. beta-Endorphin assays were performed in the same areas with radioimmunoassay. Opiate receptors labeled with [3H]naloxone in both areas showed a significant increase in the receptor densities (Bmax) without changes in the dissociation constant (KD). In parallel beta-endorphin levels showed a decline during the development of encephalopathy in both areas. The increased densities of opiate receptors in the mild stage of encephalopathy may explain the supersensitivity to morphine in patients with liver diseases.     

Relationships between squalene and cholesterol in bile: effect of ursodeoxycholic acid administration in patients with radiolucent gallstones

Squalene is an obligate intermediate of cholesterol synthesis and plasma squalene to cholesterol ratio correlates significantly with cholesterol synthesis rate in the liver. Sixteen nonobese patients with radiolucent gallstones were randomly allocated into two treatment groups receiving 15 mg/kg/day ursodeoxycholic acid (group A) or 15 mg/kg/day lactose (group B) administered three times daily for 30 days. In group A, biliary squalene to cholesterol ratio was significantly lowered (from 1.19 to 0.86, P less than 0.02), as was cholesterol saturation (from 1.39 to 0.95, P less than 0.001); levels of plasma very-low-density lipoprotein cholesterol (VLDL-C) (from 30 to 26 mg/dL) and plasma VLDL-triglyceride (VLDL-TG) (from 81 to 68 mg/dL) decreased significantly only in the group taking ursodeoxycholic acid. No variations of squalene concentrations and squalene to cholesterol ratio were observed in the plasma of both groups. Biliary cholesterol saturation during ursodeoxycholic acid administration correlated directly with squalene to cholesterol ratio in bile; reduction of these two parameters is accompanied by decreased VLDL-C levels.     

Effect of acebutolol on left ventricular hemodynamics and anatomy in systemic hypertension

In 18 patients with mild or moderate essential hypertension who responded favorably to acebutolol antihypertensive therapy, echocardiography (echo) was performed in the basal condition and after 6 and 12 months of follow-up. Acebutolol induced a significant decrease in blood pressure (BP), from a basal value of 167 +/- 3/105 +/- 2 mm Hg to 138 +/- 5/90 +/- 2 mm Hg after 6 months (p less than 0.01) and to 134 +/- 3/91 +/- 3 mm Hg after 1 year (p less than 0.01), and in heart rate, from 75 +/- 3 to 63 +/- 2 beats/min after 6 months (p less than 0.01) and to 63 +/- 2 beats/min after 1 year (p less than 0.01). The decrease in BP was achieved through a decrease in cardiac output from 6.3 +/- 0.28 to 5.3 +/- 0.25 liters/min after 6 months (p less than 0.05) and to 5.32 +/- 0.2 liters/min after 1 year (p less than 0.05), which resulted from a reduction in heart rate; stroke volume did not show significant change during the treatment and left ventricular (LV) performance was improved. There was a parallel decrease in LV posterior wall and ventricular septal thicknesses and estimated LV mass. In patients with LV hypertrophy, the change in mass was significantly correlated with the change in heart rate both after 6 and 12 months of therapy (r = 0.6234, p less than 0.05 and r = 0.7121, p less than 0.05 after 6 and 12 months, respectively).     

Effect of isoproterenol on the "early repolarization" syndrome.

A study has been carried out on a group of subjects with RS-T segment elevation, a normal variant of early repolarization. Following isoproterenol administration, the RS-T segment became isoelectric. In most cases this was accompanied by shorter QT and longer QTc intervals. The same effects were observed after physical exertion but not after atropine or amyl-nitrite. Propranolol administration exaggerated RS-T elevation. Considering the mechanism with which isoproterenol acts and some analogies with the electrocardiographic picture experimentally obtained by means of the unilateral stimulation of the stellate ganglions, the hypothesis is advanced that the normal variant of early repolarization is related to an enhanced activity of the right sympathetic nerves.     

Decreased hepatic insulin extraction in subjects with mild glucose intolerance

The fact that hyperinsulinemia occurs in simple obesity and mild glucose intolerance has been well established. Altered hepatic insulin extraction may influence the levels of circulating hormone. The simultaneous measurement of insulin and C-peptide concentrations in peripheral blood enables an in vivo estimation of hepatic insulin removal. To evaluate hepatic insulin extraction, insulin and C-peptide responses to oral glucose were studied in 176 obese and nonobese subjects with normal, impaired, or diabetic glucose tolerance. Insulin levels as well as insulin incremental areas in glucose intolerant subjects were significantly higher than in weight-matched controls. The levels of C-peptide as well as C-peptide incremental areas were only slightly enhanced in subjects with impaired glucose tolerance, whereas they were reduced in subjects with diabetic tolerance. The molar ratios of C-peptide to insulin, both in the fasting state and after ingestion of glucose, as well as the relationship between the incremental areas of the two peptides were used as measures of hepatic insulin extraction. They were significantly reduced in glucose intolerant subjects and, to a lesser extent, in nondiabetic obese subjects. These results indicate that peripheral hyperinsulinemia in subjects with simple obesity or impaired glucose tolerance is a result of both pancreatic hypersecretion and diminished hepatic insulin extraction. In subjects with a more severe degree of glucose intolerance, decreased hepatic insulin removal is the primary cause of hyperinsulinemia.     

The antiketogenic effect of alanine in normal man: evidence for an alanine-ketone body cycle

The effect of alanine on ketone body levels, independent of hormonal changes, in normal man has been investigated. Five normal subjects were given somatostatin infusions (200 micrograms/hour) for 3 hr. After 1 hr alanine or isotonic saline was infused for 2 hr. With saline blood beta-hydroxybutyrate and acetoacetate levels rose steadily to a peak of 0.230 plus or minus 0.053 and 0.112 plus or minus 0.023 mmole/l respectively. With alanine beta-hydroxybutyrate and acetoacetate levels plateaued at 0.099 plus or minus 0.020 and 0.055 plus or minus 0.006 mmole/l respectively. Alanine levels reached nearly 1 mmole/l but a significant effect on ketone body levels was apparent at physiologic levels (less than 0.6 mmole/l). Plasma fatty acid and glycerol levels did not change significantly. Insulin C-peptide and glucagon levels were suppressed to a similar extent in both experiments. These results support the view that alanine suppresses ketogenesis in man by a direct hepatic effect independent of insulin and glucagon. It is suggested that this forms part of a negative feedback substrate cycle between alanine and ketone bodies.     

Effects of acetylsalicylic acid and indomethacin on growth hormone secretion in man

To investigate the possibility that prostaglandins (PG) take part in the control of growth hormone (GH) secretion in humans, we have studied the effects of protracted and acute administration of acetylsalicylic acid (ASA) and indomethacin (ID), two PG synthesis inhibitors, on basal and insulin-stimulated GH secretion in normal volunteers. In eight subjects, oral administration of 3.2 g daily of ASA for 4 days clearly reached GH response to insulin hypoglycemia (p < 0.01, ANOVA). In six additional subjects, GH response to hypoglycemia was not modified by a 4-day oral treatment with 300 mg daily of ID. The pattern of plasma free fatty acids (FFA) and blood glucose during the insulin tolerance test was not significantly affected by ASA treatment. After ID the O time value of the above parameters was somewhat higher than under basal conditions, while the drop of blood glucose, but not of FFA, was slightly more pronounced. Acute oral administration of 1.5 g ASA in 12 subjects did not appreciably modify baseline plasma GH, FFA, and blood glucose levels. By contrast, a single oral dose of 100 mg ID in 12 subjects caused a moderate but significant rise (p < 0.05) of plasma GH levels together with a clear elevation (p < 0.01) of plasma FFA and blood glucose levels with respect to a group of controls treated with a placebo. Collectively these results are compatible with the possibility that PG play a physiologic stimulating role in the control of GH secretion, although an effect of ASA and ID unrelated to PG inhibition cannot be ruled out, In any event, in view of the number of endocrine and metabolic alterations induced by ASA and ID, these drugs seem to merit further study.     

Inhibitory effect of somatostatin on dibutyryl cyclic AMP-induced insulin and growth hormone release in human subjects.

The effect of somatostatin on the responses of blood glucose, plasma immunoreactive insulin (IRI), growth hormone (GH), and free fatty acids (FFA) to the injection of dibutyryl cyclic AMP (DBC) was studied in six normal volunteers. DBC, when injected alone, induced a rapid increase in blood glucose and plasma IRI levels, while GH concentrations showed a less marked and more delayed increase and plasma FFA showed a clear downtrend. Somatostatin infusion suppressed the GH and IRI release induced by DBC, potentiated its hyperglycemic effect and changed the pattern of FFA. These results suggest that somatostatin inhibits hormone secretion distal to the generation of cyclic AMP.     

Dose-response study of the inhibiting effect of somatostatin on growth hormone and insulin secretion in normal subjects and acromegalic patients.

A dose-response study of the effect of somatostatin on plasma growth hormone (GH) and immunoreactive insulin (IRI) levels was performed in normal subjects and acromegalic patients. In normal subjects 150 mug of somatostatin completly suppressed GH and IRI responses to arginine, while with 75 and 37.5 mug only a partial suppression was usually observed. Basal levels of plasma IRI were significantly lowered within 15 min from the start of somatostatin injection at each of the three dose levels. In three acromegalics the doses of 150 and 75 mug of somatostatin were effective in lowering both GH and IRI levels; the dose of 37.5 mug was still effective in lowering plasma IRI levels, while GH levels were not significantly modified. A dose of somatostatin inhibiting GH secretion without affecting insulin secretion has not been found either in acromegalics and in normals. It was concluded that the effects of somatostatin on GH and IRI secretion cannot be easily dissociated.     

Positive feedback sympathetic reflexes and hypertension.

A pressor reflex that can be elicited from the thoracic aorta in conscious dogs is described. Distension of the aorta excites sympathetic afferent fibers and results in an increase in arterial blood pressure because of increased sympathetic outflow to the heart and blood vessels. The reflex center for this positive feedback mechanism is located in the spinal cord and, when the reflex is activated, it can modulate other negative feedback control systems.     

Enzymes related to lipogenesis in the adipose tissue of obese subjects.

In a group of ten adult obese subjects, maintained for 15 days on a normal caloric intake and balanced diet, the activity of hexokinase (EC 2.7.1.1),6-phosphofructokinase (EC 2.7.1.11), and ATP citratelyase (EC 4.1.3.8) in the adipose tissue was significantly increased, both on a protein and on a fat cell number basis, compared to matched normal subjects. The activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49), malate dehydrogenase (EC 1.1.1.37), and malate dehydrogenase (decarboxylating) (NADP) (EC 1.1.1.40), on the other hand, was unchanged. Since both hexokinase and 6-phosphofructokinase are rate-limiting in glycolysis, their enhanced activity would indicate the occurrence of an increased capacity to metabolize glucose and therefore to generate alpha-glycerophosphate. The elevation of ATP citrate-lyase would suggest increased lipogenesis, owing to the regulatory role that this enzyme plays in fatty acid synthesis. The normal activity of glucose-6-phosphate dehydrogenase and malate dehydrogenase (decarboxylating) (NADP), which supply NADPH for the reduction of acetyl-CoA to fatty acids, would suggest that the change in lipogenesis is of moderate degree, thereb) affecting only the most rate-limiting enzyme, ATP citrate-lyase. These data, on the whole, are consistent with the occurrence of enhanced triglyceride formation. Whether the enzyme changes observed are adaptive or genetic in nature remains to be clarified.     

Heterogeneity of the erythrocyte Na-K pump status in human obesity

The number of Na-K pump units, the Na-K-ATPase activity, the K transport turnover rate per pump unit and the intracellular Na and K concentrations were measured in the erythrocytes of 56 obese patients and 20 normal subjects. No differences were found between the two groups. In obese patients, we failed to observe any influence of dietary habits, age of onset, or family history of obesity on the Na pump status. On the other hand, we found that the number of pump units was not a close reflection of the membrane cation transport and in some patients with an abnormally high number of pump units, an inappropriately low Na-K-ATPase activity was observed. We also identified two small groups of obese patients with, respectively, abnormally high or low K transport turnover rate per pump unit. Our study seems to support the hypothesis that abnormalities in the erythrocyte Na-K pump system are not usual in the obese population but are probably present only in a limited number of selected patients.     

Inhibitory effect of calcitonin on growth hormone and insulin secretion in man

The effect of calcitonin administration on basal and arginine-stimulated growth hormone and insulin plasma levels was investigated. The intramuscular injection of synthetic salmon calcitonin (100 U MRC) in five normal subjects produced a significant decrease (p less than 0.05) in insulin concentration. The same amount of calcitonin given 15 min before an arginine infusion test in seven normal subjects significantly reduced the response of growth hormone (p less than 0.025) and insulin (p less than 0.005) to the stimulus.     

Somatostatin inhibition of insulin secretion in insulin-producing tumors.

Synthetic linear somatostatin infused in two patients with insulin producing tumors lowered slightly basal insulin and a little less basal glucose levels; above all it inhibited insulin release induced by glucose, glucagon, and tolbutamide.     

Rapid increase of intraventricular conduction delay in the genesis of ventricular fibrillation after atropine

A 45-year-old man with severe chronic ischemic heart disease, after being given 2 mg total of intravenous atropine for a junctional rhythm of 39–41 beats/min developed heart rate acceleration associated with rapid changes in intraventricular conduction delay to a critical degree so that ventricular fibrillation occurred. This finding supports recent experimental observations that a relationship exists between conduction delay, the rate of change of conduction delay in ischemic myocardium and the initiation of ventricular fibrillation.     

Effect of somatostatin on blood glucose, plasma growth hormone, insulin, and free fatty acids in normal subjects and acromegalic patients

Synthetic growth-hormone-release inhibitory hormone (GRIH, somatostatin) infused in seven acromegalics significantly lowered plasma growth hormone (GH) and immunoreactive insulin (IRI) levels, did not have any effect on blood glucose, and significantly increased plasma free fatty acids (FFA). Somatostatin, when infused in three normal subjects during an arginine test, inhibited plasma GH and IRI responses. Hypoglycemia-induced GH release was also blocked by somatostatin in two normal subjects thus tested.