Biomedical subjects
R Horton
Publications and source records attributed to R Horton.
v-Src enhances phosphorylation at Ser-282 of the Rous sarcoma virus integrase.
The Rous sarcoma virus (RSV) integrase (IN) and the beta polypeptide (beta) of the reverse transcriptase are posttranslationally modified by phosphorylation on Ser at amino acid position 282 of IN. When IN was immunoprecipitated from RSV (Prague A strain) virions, approximately 30 to 40% of the IN molecules were phosphorylated. When IN was immunoprecipitated from a v-src deletion mutant (delta Mst-A) of RSV or from avian myeloblastosis virus (AMV), the percentage of IN molecules that were phosphorylated was significantly reduced. This reduction in phosphorylation of IN between virions was verified by [35S]Met-[35S]Cys or 32P labeling of IN, followed by immunoprecipitation analysis using antisera directed to the amino or carboxyl terminus of IN. In delta Mst-A or AMV, a nonphosphorylated, slightly truncated (at the carboxyl terminus) polypeptide was the major species of IN. The enhanced phosphorylation of IN does not appear to be a general function of transformed cells, since enhanced phosphorylation was not detected in AMV derived from viremic chickens or from a v-src deletion mutant of RSV propagated in a chemically transformed quail cell line, QT6. From these data, we conclude that v-Src is necessary for efficient phosphorylation of IN and beta.
Convulsant drug action on GABA and taurine synthesis.
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Structure of 2-hydroxy-5-nitrobenzylated carboxypeptidase A.
Bovine pancreatic carboxypeptidase A (EC 3.4.12.2) was treated with dimethyl (2-hydroxy-5-nitrobenzyl)sulfonium chloride at pH 7.5, resulting in a preparation which consisted primarily of a monohydroxynitrobenzylated derivative of the enzyme. Samples of the hydroxynitrobenzylated enzyme were subjected to tryptic digestion and to cyanogen bromide cleavage, and resulting peptides were isolated chromatographically. One tryptic hydroxynitrobenzyl-containing peptide was isolated; its amino acid composition was that of the N-terminal tryptic segment of carboxypeptidase Agamma (residues 8--35). Likewise, CNBr cleavage of the hydroxynitrobenzylated enzyme revealed that the hydroxynitrobenzyl group resided in the N-terminal fragment, FN (residues 8--22). Neither of these hydroxynitrobenzylated peptides contains Trp, the amino acid residue which is characteristically the site of hydroxynitrobenzylation in proteins, and each was found to contain approximately one less Asx than the corresponding native peptide. Both dansylation and automated Edman degradation procedures revealed that the N-terminal Asn of carboxypeptidase Agamma had been modified by hydroxynitrobenzylation of the enzyme. Thus the sulfonium salt reacts with carboxypeptidase A in the same manner as that established earlier for 2-hydroxy-5-nitrobenzyl bromide (Radhakrishnan, T.M., Bradshaw, R.A., Deranleau, D.A. and Neurath, H. (1970) FEBS Lett. 7, 72--76). Such reactivity of the alpha-amino group presumably reflects its unique location with respect to Trp residues in the tertiary structure of the enzyme.
Renal prostaglandins and sodium balance in normal man.
We investigated the relationship between urinary prostaglandin E (PGE) excretion and sodium and water balance. PGE excretion was measured in thirteen healthy male volunteers on the metabolic ward during conditions of high sodium (200 mmols/day) and low sodium diets (40 mmols/day) and during intravenous administration of saline and of dextrose and water, using each subject as his own control. PGE excretion was higher on the high sodium than on the low sodium diet (191 +/- 37 SE versus 98 +/- 41 ng/6h, p less than 0.01). Saline and dextrose and water infusions significantly increased PGE excretion while subjects were on low sodium diets (to 314 +/- 74 and 443 +/- 152 ng/6h, respectively, p less than 0.01). While on high sodium diets the increase in PGE excretion during infusions was not significant. To further evaluate the role of prostaglandin in sodium excretion the study was repeated with simultaneous administration of indomethacin or ibuprofen to inhibit prostaglandin synthesis. Sodium excretion from saline and dextrose and water infusions were unaltered. The data suggest that dietary content of sodium may alter PGE excretion, but that acute changes in PGE excretion during saline administration reflect water balance rather than sodium load.
The anticonvulsant action of the (-)- and (+)-enantiomers of propranolol.
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Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease.
Prostaglandins may modulate renal function and play a role in the hyperreninism and angiotensin pressor resistance of chronic liver disease. To study this possibility, we evaluated 12 patients with alcoholic cirrhosis and ascites. Urine immunoassayable prostaglandin E in 5 female patients was 3.3 +/- 0.5 micrograms/day [normal, 0.3 +/- 0.1 (SE)], renin was 14.6 +/- 3.7 ng/ml.h, and aldosterone was 76 +/- 19 ng/dl. After either indomethacin (200 mg) or ibuprofen (2000 mg) for 1 day, urine immunoassayable prostaglandin E fell to 0.8 +/- 0.4 micrograms/day, renin to 8.0 +/- 2.4 ng/mol.h, and aldosterone to 54 +/- 14 ng/dl (all P less than 0.01). Pressor sensitivity increased dramatically, and creatinine clearance transiently fell from 73 +/- 10 to 32 +/- 7 cc/min (P less than 0.01). Because a primary effect on renin might explain the renal impairment, an additional study used propranolol to lower renin activity. Renal function was unaltered by propranolol. We conclude that prostaglandins play a supportive role in maintaining renal function and are involved in the hyperreninism and pressor resistance of patients with liver disease.
Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA (4-amino-hex-5-ynoic acid) and gamma-vinyl GABA (4-amino-hex-5-enoic acid).
The anticonvulsant potency and neurological toxicity of two new catalytic inhibitors of GABA-transaminase have been assessed in acute experiments in baboons with a natural syndrome of photic epilepsy. gamma-Acetylenic GABA, 160--200 mg/kg, or gamma-vinyl GABA, 450--950 mg/kg, intravenously, gave complete protection against generalised myoclonus or seizure responses induced by photic stimulation (in baboons without or with priming with subconvulsant doses of allylglycine). The protection became maximal 1--3 h after injection, and continued for 7--24 h. Signs characteristic of the acute toxicity of anticonvulsant drugs (nystagmus and ataxia) were not seen. The potential use of these compounds in human epilepsy deserves investigation.
Transmitter synthesis and convulsant drugs: effects of pyridoxal phosphate antagonists and allylglycine.
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Regional changes in the concentrations of cerebral monoamines and their metabolites after ethanolamine-O-sulphate induced elevation of brain gamma-aminobutyric acid concentrations.
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The extrasplanchnic origin of blood dihydrotestosterone in elderly men.
The splanchnic extraction and interconversion of testosterone (T) and dihydrotestosterone (DHT) were studied in 5 elderly men undergoing cardiac catheterization using a constant infusion of [1,2-3H] testosterone and [4-14C] DHT. Metabolic clearance rate (MCR), splanchnic extraction (SE), splanchnic clearance (SC), extrasplanchnic clearance (ESC), transfer constant in blood ([p] T-DHT BB) and transfer constant across the liver ([p] T-DHT SB) were calculated. The MCRT was 675 +/- 108 (mean +/- SC) L/day and MCRDHT was 409 +/- 68 L/day. SET was 45.9 +/- 7.0% and SEDHT was 18.5 +/- 5.4%. When these values are compared with those recently reported by us for normal men, there is a 1/3 reduction in SET and 1/2 reduction for SEDHT in elderly men. The calculated SCT and ESCT were 355 +/- 72 L/day and 320 +/- 86 L/day, respectively. SCDHT and ESCDHT were 145 +/- 48 L/day and 263 +/- 77 L/day respectively, suggesting that a major fraction of DHT is metabolized in extrasplanchnic organs. No evidence for a net appearance of DHT by either mass or specific activity analysis in hepatic vein blood was observed indicating that the splanchnic compartment does not contribute DHT into the circulation either by de novo synthesis or via conversion from testosterone. This work indicates that conversion of testosterone to DHT in elderly men occurs entirely in extrasplanchnic tissue.
Coping behavior of elderly flood victims.
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Prostaglandins: renin release and renal function.
Renal prostaglandins have several potential functions in renal physiology. Perhaps their best documented role is the maintenance of renal blood flow during renal ischemia, although they are apparently not essential to blood flow autoregulation in the absence of ischemia. Alterations in sodium excretion parallel the hemodynamic changes induced by prostaglandin infusions and prostaglandin inhibition with indomethacin. A direct action on sodium balance is unproven. Numerous studies, in vivo and in vitro, have convincingly demonstrated that prostaglandins or their precursors stimulate renin release and prostaglandin inhibition blunts renin release independent of hemodynamic and electrolyte balance. These functions of prostaglandins have implicated them in the manifestations of Bartter's syndrome, the nephropathy of liver cirrhosis, renovascular hypertension, and other nephropathies.
Splanchnic extraction and conversion of testosterone and dihydrotestosterone in man.
The splanchnic extraction and interconversion of testosterone and dihydrotestosterone (DHT) were studied in 7 healthy men (ages 29-46 years) undergoing cardiac catheterization. During a constant infusion of [1,2-3H]testosterone and [4-14C]DHT, the arterial and hepatic vein blood samples were taken and radioactive and non-radioactive testosterone and DHT were determined. Metabolic clearance rate (MCR), splanchnic extraction (SE), splanchnic clearance (SC), extrasplanchnic clearance (ESC), transfer constant in blood (T-DHT rhoBB) and transfer constant across the liver (T-DHT rhoSB) were calculated. The MCRT was 952 +- 172 (mean +- SD) 1/day and MCRDHT was 764 +/- 67 1/day in agreement with data from non-catheterized subjects. SET was 68.8 +/- 7.1% (mean +/- SD) and SEDHT was 37.6 +/- 5.9%. SET was significantly greater than SEDHT (P less than 0.001). The calculated SCT and ESCT were 638 +/- 112 (mean +/- SD) 1/day and 314 +/- 190 1/day, respectively. SCDHT and ESCDHT were 343 +/- 95 (mean +/-SD) 1/day and 421 +/-105 1/day, suggesting that a major fraction of testosterone is metabolized in the splanchnic organs and a higher fraction of DHT is metabolized in extrasplanchnic organs. In the interconversion study, overall conversion of testosterone to DHT in blood (T-DHT rhoBB) was 4.0 +/- 0.6% (mean +/- SD). No evidence for a net appearance of DHT by either mass or specific activity analysis in hepatic vein blood was observed in any infusion leading to the conclusion that the overall contribution of testosterone to circulating DHT from the liver (T-DHTrhoSB) was undetectable. This work indicates that conversion of testosterone to DHT occurs entirely in extrasplanchnic tissue in man.
Release of immunoassayable prostaglandin E by the human ischemic kidney.
Immunoassayable prostaglandin E concentration in renal venous plasma was measured in eight patients with renovascular hypertension. Two subjects with bilateral renal artery stenosis had similar concentrations from both renal veins. The six subjects with unilateral artery stenosis had greater concentration on the stenotic side in each case, suggesting that the human ischemic kidney produces increased amounts of prostaglandins.
The prostaglandin and kallikrein-kinin systems in mineralocorticoid escape.
To evaluate the interactions of the renal prostaglandin and kallikrein-kinin systems during mineralocorticoid escape, we administered desoxycorticosterone acetate (DOCA; 20 mg im daily for 10 days) to five normal men and then repeated the study 2-16 weeks later with simultaneous indomethacin (200 mg/day) or ibuprofen (1600 mg/day) for prostaglandin inhibition (PI). Plasma aldosterone, PRA, and urinary prostaglandin E (PGE) were measured by immunoassay; urinary kallikrein activity was measured by esterase activity. With DOCA, subjects gained 2.0 +/- 0.1 (SE) kg and retained 485 +/- 125 milliequivalents (meg) sodium; serum potassium fell from 4.6 +/- 0.2 to 3.2 +/- 0.1 meq/liter, aldosterone fell from 3.8 to 2.2 ng/dl, and PRA fell from 0.9 to 0.1 ng/ml . h (all P less than 0.05). Kallikrein increased from 6.4 +/- 1.6 to 65.3 +/- 18.8 esterase U (P less than 0.01), but PGE (820 +/- 110 vs. 780 +/- 80 ng/day) did not change. With DOCA and PI, PGE fell by 80%. Subjects again gained 2.0 kg and retained 530 +/- 106 meq sodium; aldosterone fell to 1.1, PRA fell to 0.2, and potassium fell to 3.3 (all P less than 0.05 from basal, but P less than 0.4 from DOCA alone). Kallikrein again rose to 56.0 +/- 19.2 (P less than 0.01). However, the rate of sodium retention was enhanced slightly but significantly. These studies demonstrate that with DOCA, urinary kallikrein activity increases but PGE is unaltered. The minimal effects of prostaglandin inhibition and the lack of change in PGE excretion suggest that prostaglandins do not play an important role in mineralocorticoid escape. There is no apparent interaction of prostaglandins with the kallikrein system in this model; however, the kallikrein-kinin system may still play a direct role in the escape phenomena.
Direct conversion of testosterone to dihydrotestosterone glucuronide in man.
Tritiated testosterone and [14C]dihydrotestosterone (DHT) were administered by constant iv infusion into five young and five elderly men undergoing diagnostic cardiac catheterization. The radioactivity concentrations of free and conjugated DHT in arterial and hepatic vein blood samples were then determined. The analysis of the 3H:14C ratio of free DHT in arterial and hepatic vein blood showed that in both groups, the 3H:14C ratio of free DHT was the same in arterial and hepatic vein blood, indicating that splanchnic tissue is not the source of blood DHT from testosterone. This is in agreement with data that the transfer constant across the liver ([rho]T-DHT SD) was undetectable. In both young and elderly men, a significant increase of the 3H concentration of DHT glucuronide in hepatic vein blood was observed, indicating that the splanchnic compartment could be the site of production of DHT glucuronide. The 3H:14C ratio of DHT glucuronide was much higher than that of free DHT in both groups, suggesting that DHT glucuronide is derived from the blood testosterone pool, and most of the DHT from testosterone seems to be conjugated before mixing with blood DHT. This study indicates that a large fraction of DHT produced in the liver from testosterone is efficiently conjugated or further metabolized, and this results in the lack of splanchnic production of free DHT in men.
Prevalence of sickle cell trait and HbC-trait in Blacks from low socioeconomic conditions.
In the present investigation we did not observe age or sex differentials in the prevalence of sickle cell or HbC-traits in Black males or females of low socioeconomic status. When our data were compared to those of others, we found no evidence for a socioeconomic differential in the prevalence of these traits.