Effect of amlodipine on hemodynamic and endocrine responses to mental stress.

Little is known about the effects of antihypertensive drugs on hemodynamic responses to mental stress. We studied 24 patients with mild-to-moderate hypertension in a double-blind random-sequence crossover study comparing placebo with amlodipine titrated up from 5 to 10 mg daily. After 1 month of treatment, the subjects performed 20 min of a frustrating cognitive task. At baseline before task, amlodipine significantly reduced systolic pressure (128.9+/-8.2 mm Hg v 140.3+/-10.7 mm Hg, P < .001), diastolic pressure (81.7+/-7.7 mm Hg v 90+/-7.5 mm Hg, P < .001), and total peripheral resistance (37.5+/-15 v 45.6+/-23.7 mm Hg/L/min, P < .05), while elevating baseline norepinephrine levels (2286+/-731 pmol/L v 1788+/-546 pmol/L, P < .001). Blood pressure during the stress task was significantly less with amlodipine than with placebo (systolic 142.3+/-12.3 mm Hg v 150.9+/-14.6 mm Hg, P < .001; diastolic 87.9+/-8.4 mm Hg v 97.7+/-9.3 mm Hg, P < .001), whereas norepinephrine was significantly higher (2754+/-1007 pmol/L v 1970+/-740 pmol/L, P < .001). There were no significant differences in cardiac output, plasma lipids or lipoproteins, or markers of platelet activation. Heart rate increased significantly during stress, but there was no significant difference between amlodipine and placebo either at baseline or during stress. Our conclusion is that amlodipine reduces blood pressure at baseline and during mental stress, but raises basal and stress-related plasma catecholamines. This finding may have implications for the recent controversy over the safety of calcium channel antagonists, and suggests the potential relevance of combining amlodipine with adrenergic blockers.

Dietary orotic acid accentuates the hepatic response to phenobarbital in rats.

In rats treated with phenobarbital for 3 days and simultaneously fed a semisynthetic diet containing 1.0% orotic acid, the extent of the increases in liver microsomal phosphatidylcholine, phosphatidylethanolamine, total RNA, total protein, and cytochrome P-450 were significantly greater than they were in rats treated identically with phenobarbital but without dietary orotic acid. This is attributed primarily to the stimulation of hepatic phosphatidylcholine synthesis by dietary orotic acid. In the absence of phenobarbital, orotic acid was shown to cause some increase in liver smooth endoplasmic reticulum components, but not cytochrome P-450. Orotic acid also decreased the activity of microsomal phosphatidylethanolamine N-methyltransferase, which may have contributed to the increase in the microsomal content of phosphatidylethanolamine. The hypothesis is advanced that phospholipid availability is a limiting factor in the hepatic response to phenobarbital. When more phospholipid is available to provide the structural framework for biogenesis of endoplasmic reticulum, all of the hepatic actions of phenobarbital, including induction of cytochrome P-450, are amplified.

Clinical evaluation of serum thyroglobulin measurement using a commercial kit in the diagnosis of recurrent thyroid cancer.

The value of serum thyroglobulin assay employing a kit manufactured by Diagnostic Products Corporation in the detection of recurrence of thyroid carcinoma in patients treated by thyroidectomy and ablative therapy was assessed by clinical follow-up and radioiodine scanning of 122 patients over a 2-year period. A total of 204 specimens were analysed. The assay was found to be sensitive and highly specific for the detection of recurrent thyroid carcinoma provided that lipemic sera are clarified by ultracentrifugation prior to measurement and that results from those patients who demonstrate positive serum antithyroglobulin antibodies are excluded. The predictive value of a serum thyroglobulin level above 20 pmol/L was 96% for recurrence of thyroid carcinoma. The predictive value for non-recurrence was 98% for serum thyroglobulin levels below 10 pmol/L. The specificity and sensitivity of the assay were poor for serum thyroglobulin levels between 10 and 20 pmol/L. In recurrence-free patients, the serum thyroglobulin levels were not changed by withdrawal of thyroid replacement therapy 4-7 weeks prior to sampling.

Increased catabolism of phosphatidylcholine to betaine regulates the liver phosphatidylcholine content in rats fed orotic acid.

Feeding a semi-synthetic diet containing 1% orotic acid to rats for one day stimulates the CDPcholine pathway of liver phosphatidylcholine synthesis 4.5-fold without significantly increasing the liver phosphatidylcholine level. The liver betaine level increases 1.6-fold. The present experiments were performed to investigate the source of the increased liver betaine. Orotic acid feeding did not alter the rate of oxidation of 1,2[14C] choline to betaine. After liver phosphatidylcholine was labelled in vivo with 2[14-C]-ethanolamine, over 90% of the choline-derived radioactivity was recovered in liver betaine and this was consistently increased in rats fed orotic acid. It is concluded that the increased synthesis of liver phosphatidylcholine caused by dietary orotic acid is accompanied by an increased rate of liver phosphatidylcholine catabolism, with betaine as the major end-product of the choline moiety.

Actions of dietary orotic acid on liver synthesis of phosphatidylcholine and phosphatidylethanolamine in rats.

The in vivo rates of the reactions of the cytidine pathways of liver phosphatidylcholine and phosphatidylethanolamine synthesis were measured in rats after 1 day of feeding on a semisynthetic diet containing 1% orotic acid. The calculations were made from the specific and total radioactivity versus time curves of the precursors and products following intraportal injection of [1,2-14C]choline, [2-14C]ethanolamine, and [2-3H]glycerol. The liver CTP level was increased twofold and the rates of CDP-choline and phosphatidylcholine synthesis were stimulated 4.5-fold in the rats fed orotic acid. The rate of CDP-ethanolamine synthesis was increased but could not be accurately quantified because of its extreme rapidity. No change occurred in the rate of the ethanolaminephosphotransferase reaction and the overall rate of phosphatidylethanolamine synthesis was unchanged by orotic acid feeding. The catalytic activities of the enzymes of the cytidine pathways of phosphatidylcholine and phosphatidylethanolamine synthesis were not affected by feeding orotic acid for 1 day. Similar findings were obtained 3 h following intragastric administration of 100 mg of orotic acid. The results suggest the possibility that changes in the levels of liver CTP may play a role in regulation of the cytidine pathway of liver phosphatidylcholine synthesis but not of phosphatidylethanolamine synthesis, because the latter pathway appears to be tightly controlled at the ethanolaminephosphotransferase step.

Early effects of dietary orotic acid upon liver lipid synthesis and bile cholesterol secretion in rats.

Dietary orotic acid is known to cause impaired fatty acid synthesis and increased cholesterol synthesis in rats. We found that the impaired fatty acid synthesis occurs during the first day of orotic acid feeding and, in studies with albumin-bound [1-14C]palmitic acid, an associated decrease in the rate of esterification of this fatty acid into triacylglycerol, phospholipid, and cholesteryl ester was observed. These changes may result from the known decreases in liver levels of adenine nucleotides or, as reported here, from decreased liver CoASH levels in orotic acid-fed rats. The increase in hepatic cholesterol synthesis occurred during the second day of orotic acid feeding. It was detected by increased incorporation of [1,2-14C]acetate into cholesterol by liver slices and by a 7-fold increase in HMG-CoA reductase activity. At the same time the biliary output of cholesterol was increased 2-fold and studies using 3H2O revealed that the output of newly synthesized cholesterol in bile was increased 5-fold. The content of cholesteryl ester in hepatic microsomes decreased during orotic acid feeding but free cholesterol was unchanged. The findings are interpreted to suggest that the increased bile cholesterol secretion caused by orotic acid is a result of impaired hepatic cholesterol esterification and that the increase in HMG-CoA reductase activity is a result of diminished negative feedback due to the depleted content of cholesteryl ester in the hepatic microsomes.

Pool sizes of the precursors for phosphatidylcholine synthesis in developing rat lung.

1. Pulmonary maturation in the rat is accompanied by a 30% postnatal increase in the pool size of choline, a 4-fold overall prenatal and postnatal decrease in the level of cholinephosphate, a 3-fold decrease in CDPcholine levels and a 2-fold increase in the content of phosphatidylcholine. 2. The level of 1,2-diacyl-sn-glycerol in rat lung increases 5-fold during the fetal and neonatal periods. Only minor alterations were noted in the fatty acid composition. 3. These results are consistent with an increase in the relative rates of the cholinephosphate cytidylyl-transferase and cholinephosphotransferase steps of phosphatidylcholine production during pulmonary maturation. The relative rate of the step catalyzed by phosphatidate phosphohydrolase may also be increased.

Hormonal induction of pulmonary maturation in the rabbit fetus: effects of maternal treatment with estradiol-17 beta on th endogenous levels of cholinephosphate, CDP-choline and phosphatidylcholine.

1. Administration of estradiol-17 beta to pregnant rabbits at 25 days gestation (term, 31 days) resulted n a significant increase in the incorporation of [14C]-choline, but not [14C]ethanolamine, into the lipids of fetal lung slices. The incorporation of [35S]methionine was not affected. 2. Enzymatic assays conducted in vitro revealed no significant effect on either the activities of several enzyme markers for subcellular organelles, the activities of the enzymes responsible for the production of phosphatidylglycerol and phosphatidylinositol, membrane-bound or aqueously dispersed phosphatidate-dependent phosphatidic acid phosphohydrolase activities or the activities of the auxiliary enzymes responsible for the synthesis of dipalmitoylphosphatidylcholine. 3. The activity of the enzymes involved in the choline pathway for the de novo biosynthesis of phosphatidylcholine were not significantly altered except for a 66% increase in the CTP:cholinephosphate cytidylyltransferase activity assayed in the cytosol. The addition of phosphatidylglycerol stimulated cholinephosphate cytidylyltransferase activity approx. 3-fold. However, in the presence of this lipid, the activities in cytosol from control and treated fetuses were similar, indicating that the increased activity noted in the absence of phosphatidylglycerol was due to an activation of existing cytidylyltransferase activity rather than an increase in total enzyme units. 4. Estrogen treatment of the does was also associated with a marked decrease in the levels of cholinephosphate in fetal lung and significant increases in the levels of CDPcholine and phosphatidylcholine. These alterations in pool size are consistent with an increase in the activity of cholinephosphate cytidyltransferase in vivo. The results suggest that cholinephosphate cytidylyltransferase may catalyse an important rate-determining reaction in the synthesis of phosphatidylcholine in fetal lung. The data also support the view that the reaction catalysed by CDPcholine:diacylglycerol cholinephosphotransferase also has a regulatory role during development.

Pulmonary phosphatidylcholine biosynthesis. Alterations in the pool sizes of choline and choline derivatives in rabbit fetal lung during development.

1. Progressive changes were noted in the pool sizes of choline in fetal rabbit lung between 25 and 30 days gestation (term, 31 days) and between 30 days gestation and adult lung. The level of choline in adult lung was double the level in the fetal lung at 25 days gestation. The pool size of choline phosphate decreased 10-fold during this period while the level of CDPcholine decreased by 30%. The phosphatidylcholine content increased 3-fold during development. The major change in the relative pool sizes was a marked decrease in the ratio of choline phosphate to CDPcholine from 26:1 at 25 days gestation to 3.4:1 in adult lung. 2. No differences were detected between the uptake of [14C]choline into slices from fetal lungs at 25 days gestation or slices from adult lung. However, the ability of the adult slices to convert [14C]choline into its derivatives was 30% lower than slices from fetal lung. In addition, whereas fetal slices contained significantly more radioactivity in choline phosphate and CDPcholine, adult slices incorporated significantly more [14C]choline into phosphatidylcholine. Experiments with [3H]choline and 32Pi revealed that the 3H/32P ratio of choline phosphate in fetal or adult slices was identical to the isotopic ratio in phosphatidylcholine, indicating that under the experimental conditions, negligible radioactivity was incorporated by base-exchange. Because of the marked decrease in the pool size of choline phosphate during development, it cannot be concluded that the increase in the incorporation of radioactive choline into phosphatidylcholine is indicative of increased production of phosphatidylcholine by the de novo pathway. The results suggest that if the de novo pathway is responsible for the increase in phosphatidylcholine content, this increase is due to a change in the parameter controlling the flux through the choline phosphate cytidylyltransferase step. The results also indicate that the metabolic flux through choline phosphotransferase is also enhanced during pulmonary development.