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Biomedical subjects

R Horton

Publications and source records attributed to R Horton.

At least 307 records · Page 17Linked to original sources
PubMed1980

Is urinary flow rate a major regulator of prostaglandin E excretion in man?

Urinary PGE2 excretion is enhanced in several polyuric states in man suggesting that PGE2 synthesis could be a mediator of diuresis. To explore the alternate hypothesis that polyuria is the cause of the increased PGE2 excretion, we increased urine flow rate by intravenous administration of dextrose and water with different magnesium, calcium and potassium solutions in four normal males. Urinary PGE excretion rose in parallel with urine volume (r = 0.65 p < 0.01) independently of the electrolyte solution. To determine the effects of chronic alterations in water balance in 5 female subjects, we sequentially regulated oral water intake to induce 1, 2, 4 and 8 liters of urine volume/day. During low (40 mEq) sodium diets, PGE increased from 540 +/- 50 to 4880 +/- 1240 ng/d with increasing urinary volume (r = 0.81, p < 0.01). Similarly, for 200 mEq sodium intake PGE paralleled urinary volume (from 630 +/- 100 to 4740 +/- 800 ng/d, r = 0.61, p < 0.01). In vitro sample dilution studies demonstrated no interference from method blank, and the addition of thin layer chromatography prior to Sephadex chromatography failed to alter assay measurements. We conclude that extreme increases in urinary flow rate may directly enhance PGE excretion in man.

Adult↗
PubMed1980

Alteration in the metabolism of dihydrotestosterone in elderly men with prostate hyperplasia.

In vivo androgen kinetics were determined in six young (21--49 yr) and elderly men (62-77 yr) with prostatge hyperplasia (BPH). Steady-state infusions of [14C]testosterone and [3H]androstanediol (3 alpha diol) were given, which allowed determination of the conversions testosterone leads to dihydrotesterone (DHT) in equilibrium or formed from 3 alpha diol. These infusions also yield metabolic clearance data which, together with meaurement of nonisotopic steroid levels, yield estimations of blood production rates. The production rate for testosterone was 6.04 +/- 1.66 vs. 3.69 +/- 0.62 mg/d, whereas the production rate for 3 alpha diol was 319 +/- 57 and 193 +/- 34 micrograms/d (P < 0.05 both groups). The irreversible conversion rate of testosterone to DHT was 3.1 +/- 0.4 and 3.5 +/- 0.9% (NS). The back conversion of 3 alpha diol to dHT was high (68 +/- 25 vs. 81 +/- 17, NS) indicating that 3 alpha diol might cause BPH as a result of conversion to DHT in vivo. The conversion of DHT to 3 alpha diol is reduced in the elderly group (15.8 +/- 2.6 and 6.3 +/- 1.4, P < 0.001). Since DHT formation in the prostate is a key event in the development of BPH and blood DHT appears to be a measure of extrasplanchnic sexual target tissue activity, our in vivo studies suggest that the tissue increase in DHT may result from reduced metabolism and the activity of 3 alpha-oxidoreduction favors the oxidative pathway in elderly men.

Adult↗
PubMed1980

Deoxycorticosterone and aldosterone clearance and binding in normal and hypertensive man.

Deoxycorticosterone (DOC) may play a role in several hypertensive disorders in man, but the dynamics of DOC metabolism are unclear. To characterize DOC binding to plasma proteins and its MCR, 12 patients with essential hypertension and 10 age-matched controls were studied. In control subjects, the DOC MCR was nearly identical to the stimultaneously measured aldosterone MCR (719 +/- 32 vs. 734 +/- 61 liters/m2 x day, respectively), and the MCRs of both steroids were not significantly different in essential hypertension (682 +/- 49 and 672 +/- 50 liters/m2 x day, respectively). Whole blood MCR was also unaltered by hypertension. The DOC whole blood MCRs were 1056 +/- 85 and 1040 +/- 69 liters/m2 x day for control and hypertensive subjects, respectively. The aldosterone whole blood MCRs were 916 +/- 96 and 941 +/- 67 liters/m2 x min. The similarity of the DOC MCR to the aldosterone MCR suggested minimal binding of DOC to high affinity carrier proteins, and this was confirmed by equilibrium dialysis with [3H]DOC at 37 C. In plasma, 6 +/- 1% of DOC is unbound, 84 +/- 3% is bound to albumin, and only 10 +/- 4% is bound to nonalbumin proteins. We conclude that the dynamics of DOC closely resemble those of aldosterone, with minimal plasma binding to specific binding proteins and high MCR that are unaltered in essential hypertension.

Adult↗
PubMed1980

Noradrenergic influences on sound-induced seizures.

The preferential alpha-2 noradrenergic agonists, clonidine (0.2--0.4 mg/kg), oxymetazoline (2.5--10.0 mg/kg) and UK 14,304 (0.6 mg/kg), when given i.p., reduce the severity of audiogenic seizures in 19- to 26-day-old DBA/2 mice. This protective effect can be diminished or reversed by alpha-2 noradrenergic antagonists such as yohimbine (2.5 mg/kg) or piperoxan (20--50 mg/kg) given i.p. or phentoalamine (100 micrograms) given intracerebroventricularly. It is not reversed by the preferential alpha-1 noradrenergic antagonist phenoxybenzamine (5 mg/kg) given i.p. Yohimbine, (1--2.5 mg/kg), piperoxan (20--50 mg/kg) or phenoxybenzamine (5 mg/kg) given i.p. alone did not change the severity of audiogenic seizure responses. Phentolamine (10--100 micrograms) or prazosin (10--50 micrograms) given intracerebroventricularly induced spontaneous limb myoclonus in some mice. Audiogenic seizure responses were unchanged after phentolamine (10--100 micrograms) but were reduced after prazosin (25--50 micrograms). Activation of a receptor pharmacologically similar to the peripheral alpha-2 noradrenergic receptor protects against seizures in this epilepsy model.

Acoustic Stimulation↗
PubMed1979

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.

Amino Acid Sequence↗
PubMed1979

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.

Adult↗
PubMed1979

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.

Adult↗
PubMed1978

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.

4-Aminobutyrate Transaminase↗
PubMed1978

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.

Aged↗
PubMed1978

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.

Animals↗
PubMed1978

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.

Adult↗