Lack of prostaglandin effect on sodium balance and hyperreninemia in adrenalectomized rats.

Glucocorticoids are known inhibitors of prostaglandin production. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are promoters of natriuresis and renin release. Excessive prostaglandin production, therefore, might contribute to the altered sodium balance and renin release observed in primary adrenal insufficiency. To test this hypothesis, sodium balance and prostaglandin production were measured in adrenalectomized rats and in animals receiving prostaglandin inhibitors or replacement dexamethasone. Compared to sham-operated controls, adrenalectomized rats had decreased two-day sodium balance and elevated plasma renin concentration (PRC), renal PGE2 production, and renal 6-ketoprostaglandin F1 alpha (6kPGF1 alpha, the nonenzymatic metabolite of PGI2); however, no appreciable change in aortic 6kPGF1 alpha production was observed. Dexamethasone given to adrenalectomized rats normalized PRC but had no effect on sodium balance or prostaglandin production. Likewise, prostaglandin inhibitors did not alter the sodium balance or decrease the PRC post adrenalectomy. These data confirm renal prostaglandin production is increased in adrenalectomized rats, but suggest that the elevation is not due directly to glucocorticoid deficiency. Further, PRC levels in adrenal insufficiency do not appear to be prostaglandin mediated. In conclusion, excessive renal prostaglandin production does not contribute to altered sodium balance or increased PRC in adrenalectomized rats.

Conjugated estrogens reduce endothelial prostacyclin production and fail to reduce postbypass blood loss.

Intravenous conjugated estrogens correct bleeding times and reduce bleeding in uremia, gastrointestinal telangiectasias, and liver disease. One study found a similar benefit in patients undergoing open heart surgery. The mechanism by which conjugated estrogens improve bleeding times is unknown. We report on the effect of estrogens on endothelial prostacyclin production and bleeding in coronary bypass surgery. In a randomized, double-blind trial, 16 male patients undergoing elective coronary artery bypass surgery received four daily infusions of conjugated estrogens (0.6 mg/kg/day) or placebo, preoperatively. Groups were similar with respect to age, preoperative hemostatic profiles, and pump time. Conjugated estrogens significantly reduced greater saphenous vein endothelial prostacyclin production in the estrogen group compared to control subjects. Postoperative blood loss was not reduced, with a trend toward increased blood loss in the treatment group. We have shown that conjugated estrogens reduce endothelial prostacyclin production and fail to reduce blood loss in coronary bypass surgery.

Effect of minoxidil on platelet function and the synthesis of prostaglandins in platelets.

At the 12.5 micrograms level, minoxidil prevents the irreversible aggregation of platelets by 2 x 10(-6) mol/L adenosine diphosphate (ADP). Levels of minoxidil greater than 12.5 micrograms cause a reversal of primary aggregation by 2 x 10(-6) mol/L ADP. Aggregation of platelets in response to 125 micrograms of arachidonic acid is measurably reduced by 12.5 micrograms of minoxidil and totally suppressed by 30 micrograms. Concurrent with the inhibition of platelet aggregation, increasing concentrations of minoxidil cause a gradual reduction in the synthesis of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2). In the presence of 100 micrograms of minoxidil, PGE2 is reduced from a control value of 87.7 +/- 2.2 pg/ml to 23.9 +/- 3.2 pg/ml. At this level of minoxidil, TxB2 drops from 105 +/- 3.3 ng/ml to 10.5 +/- 2.6 ng/ml. The effect of minoxidil on platelet aggregation is not associated with increased cyclic adenosine monophosphate synthesis. All data support the conclusion that minoxidil functions (in platelet metabolism) primarily as a cyclooxygenase inhibitor.

Effects of hypothyroidism and short-term aging on whole blood thromboxane and arterial prostacyclin synthesis.

Hypothyroidism results in decreased platelet aggregation and has unique effects on the development of atherosclerosis and angina pectoris. Because prostacyclin and thromboxane A2 profoundly influence platelet function and vascular tone and are thought to be important in the development of atherosclerosis and angina pectoris, we studied the effects of hypothyroidism in rats on the in vitro elaboration of prostacyclin passively by aortic tissue and of thromboxane A2 by thrombin-stimulated whole blood. Hypothyroidism induced by iodine 131 (given at age 7 weeks) persistently caused a mild decrease in platelet count (P less than 0.01) and 30% decrease in immunoreactive thromboxane B2 (the hydrolysis product of thromboxane A2) generation per platelet (P less than 0.01) compared with age-matched euthyroid rats. Between 20 and 23 weeks of age immunoreactive 6-ketoprostaglandin F1 alpha (the hydrolysis product of prostacyclin) generation decreased by 30% in euthyroid rats. In hypothyroid rats less than 23 weeks of age, 6-ketoprostaglandin F1 alpha production was the same as that of age-matched euthyroid rats. With further aging, 6-ketoprostaglandin F1 alpha production did not decrease as it did in euthyroid rats. Hypothyroid rats more than 20 weeks old had, therefore, significantly greater 6-ketoprostaglandin F1 alpha production than age-matched euthyroid rats (P less than 0.005). L-Thyroxine given daily for 28 days to 23-week-old hypothyroid rats caused a rapid increase in platelet count and a delayed normalization of the thromboxane synthetic abnormality. 6-Ketoprostaglandin F1 alpha production transiently increased in response to L-thyroxine, but decreased to the euthyroid level after 28 days of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemoperfusion of phencyclidine in the dog.

Experiments were conducted to determine whether charcoal hemoperfusion (HP) would be useful in severe phencyclidine (PCP) overdose. Dogs were given a single 5 mg/kg injection of PCP. In 6 experiments HP for 2.5 hours was done; and in 6 control experiments, the extracorporeal circuit contained no HP cartridge. The number of seizures, symptoms, duration of coma, and PCP concentrations in the tissues of HP dogs were not different from control. PCP clearance by HP was 67 +/- 16.5 ml/min. PCP recovery by HP was 2.25 +/- 0.25 mg (2.0% of the administered dose). Urinary excretion of PCP was 1.33 +/- 0.46 mg (1.2% of the dose). Volume of distribution of PCP was 21.8 +/- 1.7 L/kg. Due to the high volume of distribution, high lipid solubility and low plasma levels of PCP, HP was not effective in managing PCP overdose in the dog.

Decreased alpha-adrenergic receptors in newborn platelets: cause of abnormal response to epinephrine.

Platelets of newborn infants fail to aggregate or release adenosine diphosphate in response to epinephrine. Because epinephrine-induced aggregation is an alpha-adrenergic event, we considered the possibility that newborn platelets possess fewer alpha-adrenergic receptors than do those of adults. Therefore we compared the specific binding of the alpha-adrenergic antagonist, [3H]-dihydroergocryptine (DHE), in intact washed platelets prepared from paired samples of maternal and cord platelet-rich plasma. Newborn platelets demonstrated normal kinetics of [3H]-DHE binding and normal affinity for [3H]-DHE. Scatchard analysis of [3H]-DHE binding indicated a single class of binding sites that exhibited a high affinity for the radioligand (Kd = 10 nM). Maternal platelets were found to bind approximately 2-fold more [3H]-DHE than newborn platelets (3.70 +/- 0.28 vs. 1.74 +/- 0.17 fmol/10(7) platelets) at saturation. This corresponds to 223 +/- 17 vs. 105 +/- 11 binding sites per platelet (p less than 0.001). Repeat washing of newborn platelets did not yield increased [3H]-DHE binding suggesting the binding sites had not previously been masked by elevated circulating levels of catecholamines in venous cord blood. When control platelets were incubated with concentrations of [3H]-DHE that half-saturated the alpha-adrenergic receptors, diminution of platelet function comparable to that seen in newborn platelets was observed. Since maternal and newborn platelets are similar size, it appears that a deficiency of alpha-adrenergic receptors may account for the diminished response of newborn platelets to epinephrine.

Neonatal platelet function: a membrane-related phenomenon?

Synthesis of prostaglandin endoperoxides was evaluated in paired maternal and cord blood samples. Platelets from mothers and neonates aggregated normally in response to arachidonic acid (AA). Cyclooxygenase activity was evaluated by monitoring the incorporation of radioactivity into prostaglandin endoperoxide metabolites after incubation with 1-14C-AA. Thin layer radiochromatograms of methylated incubation products revealed three main peaks corresponding to 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid, 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT), and 8-(1-hydroxy-3-oxoproply)-9,12-L-dihydroxy-5,10-heptadecadienoic acid (TXB2). Maternal and neonatal platelets incorporated similar amounts of radioactivity into HHT and TXB2. Radioimmunoassay for TXB2 in thrombin-clotted PRP revealed no significant differences between maternal and neonatal platelets. Since these metabolites are derived from cyclic endoperoxides formed by the action of cyclooxygenase on AA, we conclude that prostaglandin endoperoxide synthesis is fully developed in neonatal platelets. Mutual correction of collagen-induced platelet aggregation and ADP release was observed when equal volumes of neonatal and aspirin-treated adult platelet-rich plasma were mixed. Therefore, since neonatal platelets contain normal amounts of storage pool nucleotides, we also conclude that the defective secondary aggregation and release seen in neonatal platelets is caused by a failure in the release of AA from membrane phospholipids upon stimulation with collagen or epinephrine.

Tissue threshold changes during the first months of immunotherapy.

The cutaneous, ocular and nasal sensitivity to ragweed extract was studied in seven patients during the early months of ragweed immunotherapy. Decreased skin sensitivity (p < 0.01) developed, as well as reduced conjunctival and nasal sensitivity. These changes correlated with the cumulative dose of extract administered and with levels of blocking antibody. However, there was no correlation between changes in tissue threshold and changes in ragweed specific IgE.

Clinical and immunological studies of timothy antigen D immunotherapy.

The response to preseasonal immunotherapy with aqueous grass extract, timothy antigen D, or water-soluble timothy (WST) in alginate was compared in patients sensitive to grass pollen. Injections of antigen D in alginate produced little evidence of clinical or immunologic response. Treatment with aqueous grass extract or WST in alginate, on the other hand, significantly reduced the seasonal rise in grass-specific IgE. Aqueous extract therapy was also associated with a decline in leukocyte sensitivity during the pollen season, while WST treatment produced the greatest rise in hemagglutinating antibodies.

Gluconeogenic response to mannoheptulose in the rat.

Since administration of mannoheptulose induces temporary hyperglycemia, the present study was conducted to elucidate this phenomenon. The results indicate that mannoheptulose stimulates the activity of hepatic fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase, and enhances incorporation of alanine into blood glucose and hepatic glycogen. In addition, mannoheptulose increases plasma levels of glucagon and hepatic cyclic AMP concentration. Gluconeogenic effects of mannoheptulose appear to be mediated by glucagon.

Effect of l-Homoserine on the Growth of Mycobacterium tuberculosis.

l-Homoserine was observed to inhibit the growth of Mycobacterium tuberculosis. In the metabolism of M. tuberculosis, l-homoserine was found to be a precursor of threonine, isoleucine, and methionine. l-Homoserine-inhibited cells contained elevated levels of the enzyme acetohydroxy acid synthetase. In addition, washed cell suspensions of M. tuberculosis formed significant amounts of alpha-amino-n-butyric acid from supplements of l-homoserine. dl-Alpha-amino-n-butyric acid proved to be much more inhibitory for growth than l-homoserine. Growth antagonism by l-homoserine was reversed by l-lysine, l-threonine, and combinations of l-leucine with l-valine. At the cellular level, these amino acids reduced the amount of acetohydroxy acid synthetase in cells grown with l-homoserine and competed with dl-homoserine-4-(14)C for entrance into the extractable cell pool. l-Isoleucine also antagonized the conversion of l-homoserine to alpha-amino-n-butyric acid. Available data indicated that the effect of l-homoserine was related to its conversion to alpha-amino-n-butyric acid which subsequently inhibited growth.