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Biomedical subjects

R Horton

Publications and source records attributed to R Horton.

At least 289 records · Page 16Linked to original sources
PubMed1983

Cigarette smoking inhibits prostacyclin formation.

Urinary prostacyclin (PGI2) was measured in 12 chronic smokers and 12 non-smokers after inhalation of smoke from nicotine-containing and nicotine-free cigarettes. In a separate study a pressor dose of noradrenaline, which increases PGI2, was given to smokers and non-smokers. PGI2 was measured as the stable metabolite, 6-keto-PGF1 alpha in 4 h urine samples by radioimmunoassay after chromatography on LH-20 'Sephadex'. Smoking of nicotine-free cigarettes had no effect on PGI2 release in either smokers or non-smokers. In non-smokers inhalation of nicotine-containing tobacco smoke increased heart-rate, blood-pressure, and urine osmolality, but did not affect urinary 6-keto-PGF1 alpha. In contrast, when chronic smokers used nicotine-containing cigarettes there was a highly significant reduction in excretion of 6-keto-PGF1 alpha (192 +/- 20 to 138 +/- 17 ng/g creatinine). Noradrenaline increased PGI2 in non-smokers (181 +/- 16 to 348 +/- 56) but not in smokers. Smoking of nicotine-containing tobacco abolished the PGI2 response to noradrenaline. These observations suggest that inhalation of nicotine-containing tobacco smoke reduces vascular PGI2 production; this may be a factor in the development of accelerated cardiovascular disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

The effect of adrenergic stimulation on urinary prostaglandin E2 and 6 keto PGF1 alpha in man.

To evaluate the details of the adrenergic stimulation of urinary prostaglandins in man, ten normal volunteers were given various agonists and antagonists. The effect of 4 hour IV infusions of norepinephrine (NE), NE + phentolamine (PHT), NE + phenoxybenzamine (PHB), NE + prazosin (PZ), isoproterenol (ISO), and PHT alone on urinary PGE2 and PGI2 (6 keto PGF1 alpha) were determined. PGE2 and 6 keto PGF1 alpha were measured by radioimmunoassay from 4 hour urine samples. NE stimulated both PGE2 (196 +/- 40 to 370 +/- 84 ng/4 hrs/g creatinine and 6 keto PGF1 alpha (184 +/- 30 to 326 +/- 36), both p less than 0.01. In contrast, ISO had no effect on either PGE2 or 6 keto PGF1 alpha excretion. Alpha blockade with PHT. PHB, or PZ inhibited the NE induced systemic pressor effect. However, the effect of the alpha blockers on the NE induced stimulation of PGE2 and 6 keto PGF1 alpha varied. PHT did not alter the NE stimulated PGE2 or 6 keto PGF1 alpha release (370 +/- 84 vs. 381 +/- 80) PGE2 and (326 +/- 50 vs. 315 +/- 40) 6 keto PGF1 alpha both p greater than 0.2). PHT alone stimulated only 6 keto PGF1 alpha. PHB and the specific alpha 1 antagonist PZ similarly eliminated the NE induced prostaglandin release. These results suggest that adrenergically mediated urinary prostaglandin release in man is via an alpha receptor with alpha 1 characteristics.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Amoxycillin/clavulanic acid: the effect of probenecid.

The effect of probenecid on the combination of amoxycillin/clavulanic acid has been compared with the effect on amoxycillin alone and it has been shown that probenecid, whilst producing its expected effect on amoxycillin, did not affect the clavulanic acid concentration of the combination. A possible minor role for tubular secretion of clavulanic acid is discussed.

Adult↗
PubMed1983

Reciprocal changes in active and inactive renin after converting enzyme inhibition in normal man.

Since one mechanism by which converting enzyme inhibition (CEI) increases renin is removal of angiotensin II negative feedback on the juxtaglomerular cell, we studied the time course of changes in active and inactive renin after CEI. After equilibration on a 25 meq/day sodium diet, captopril was given as a single 50-mg oral dose (acute phase), and then was administered as 50 mg every 6 h for 3 days to seven normal volunteers (chronic phase). In the acute phase, supine blood pressure fell 12 +/- 2 mm Hg (P less than 0.02). Active renin acutely increased 12.5 +/- 0.9 times the baseline value, peaking at 3-4 h. Inactive renin, measured by acid activation of trypsin activation, decreased in all subjects to 10% or less of control from 2 to as long as 6 h post-CEI and then returned to baseline levels by 8 h (P less than 0.01). With chronic CEI, active renin was elevated to 10.8 +/- 2.4 times the baseline level, and after 48 h inactive renin levels rose to 4.0 +/- 0.6 times the baseline (P less than 0.02). To determine whether the acute changes in inactive and active renin occurred because of captopril's effect on renin in the circulation or kidney, a single dose of captopril was administered to three subjects with mild to moderate renal insufficiency and hyporeninemic hypoaldosteronism. In contrast to normal subjects, these patients had no change in active and inactive renin levels when given captopril, suggesting that changes observed in the normals were renal mediated rather than a plasma phenomenon. We conclude that CEI 1) acutely increases active renin while reciprocally reducing the inactive form, and 2) chronically increases both active and inactive renin. These studies support the hypothesis that inactive renin may be a precursor of circulating active renin.

Adult↗
PubMed1983

Stimulation of renal prostaglandins by pressor hormones in man: comparison of prostaglandin E2 and prostacyclin (6 keto prostaglandin F1 alpha).

The effect of vasoconstrictive agonists and their nonpressor analogs on renal prostaglandin production was investigated in normal subjects maintained on constant diets. Arginine vasopressin (AVP), 10 U, desamino-d arginine vasopressin (dDAVP), 4 micrograms, angiotensin II (AII), 5 ng/kg . min, des-Asp angiotensin II (AIII), 5 ng/kg . min, norepinephrine (NE), 0.1 microgram/kg . min, and NE plus phenoxybenzamine (PHB), 0.8 mg/kg, were administered on separate days. Prostaglandin E2 (PGE2) and the stable prostacyclin metabolite, 6 keto prostaglandin F1 alpha were measured in 4-h urine collections by procedures with high resolution chromatography and RIA using highly specific antisera. AVP and dDAVP similarly reduced urine volume and increased urine osmolality. AII, AIII, NE, and NE + PHB did not alter basal urine volume, osmolality, creatinine, or electrolyte excretion. Blood pressure was similarly increased by AII and NE infusions (23 +/- 3 vs. 19 +/- 2 (SE) mm Hg). AVP and AII increased only PGE2 excretion (61 +/- 8 to 151 +/- 34 ng/4 h for AVP, and 38.7 +/- 7 to 75 +/- 19 ng/4 h for AII, P less than 0.05). The nonpressor analogs, dDAVP and AIII, had no effect on urinary prostaglandin excretion. In contrast, NE increased both PGE2 (from 38.7 +/- 7 to 74.5 +/- 12 ng/4 h, P less than 0.02) and 6 keto prostaglandin F1 alpha (from 34.6 +/- 8 to 56.1 +/- 9 ng/4 h, P less than 0.02). alpha-Blockade with PHB totally abolished the NE-induced systemic pressor and prostaglandin stimulatory effect. These data suggest that renal PGE2 and prostacyclin are not altered in parallel by vasoactive stimuli. PGE2 appears to be released in response to agents that induce renal vasoconstriction and reduced renal blood flow whereas renal prostacyclin excretion is stimulated by an adrenergic agonist via alpha-receptor activation and not vasoconstriction per se.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome.

Hirsutism can occur in the presence of normal or near normal levels of serum testosterone, unbound testosterone (uT), dehydroepiandrostene sulfate, androstenedione, and dihydrotestosterone. However, we have found that serum androstanediol glucuronide (3 alpha-diol G) is markedly increased in idiopathic hirsutism and it serves as an excellent marker of peripheral androgen metabolism and action. In the present work, we studied 12 hirsute (H) and 12 nonhirsute (NH) patients with polycystic ovary syndrome (PCO) and 13 age and weight matched controls in order to determine if differences in sex steroid levels or peripheral tissue androgen events were associated with hirsutism. Serum unbound estradiol levels and LH-FSH ratios were similar in both groups of women with PCO, and both were significantly higher than levels in controls (P less than 0.05). Whereas serum testosterone, uT, and androstenedione were elevated in both H-PCO and NH-PCO patients compared to controls, the levels in these two groups were similar. Serum dehydroepiandrostene sulfate was higher in PCO patients compared to controls, but H-PCO patients had slightly higher levels than NH-PCO patients. Serum delta 5-androstenediol was also slightly higher in H-PCO compared to NH-PCO patients. Dihydrotestosterone was normal and unconjugated; 3 alpha-diol was higher than normal in both groups of patients with PCO, although H-PCO patients had higher levels than NH-PCO patients. Compared to these relatively minor changes between the PCO patient groups, serum 3 alpha-diol G was markedly elevated in H-PCO patients (approximately 10-fold), yet normal in NH-PCO patients (P less than 0.01). The ratios of serum 3 alpha-diol G-uT were similar in NH-PCO patients and controls, but were elevated in H-PCO patients (P less than 0.01). These data indicate that: 1) women with PCO have increased circulating androgen levels regardless of the presence or absence of hirsutism; and 2) the presence of hirsutism is not only a function of circulating androgen levels, but may also be determined by events in peripheral tissues.

Adolescent↗
PubMed1982

3 alpha, 17 beta-androstanediol glucuronide in plasma. A marker of androgen action in idiopathic hirsutism.

Biologically active androgens and peripheral androgen metabolites in plasma were measured in 25 women with idiopathic hirsutism (IH). Plasma testosterone was not significantly elevated. Free testosterone however was increased although the elevation was not impressive (10.9 +/- 6.6 SD vs. 3.3 +/- 1.5 ng/dl) and one-fourth of the cases had normal unbound testosterone. Dihydrotestosterone (DHT) values were elevated (23.5 +/- 14 vs. 12.5 +/- 3.59) but again over half of the values were within the normal range. In our series of mild to moderate cases, 3 alpha-diol was not at all discriminatory. However, plasma 3 alpha-diol glucuronide was markedly increased (604 +/- 376 vs. 40 +/- 10 ng/dl), and elevated in all but one mild case. Previous studies document that DHT is the important androgen in skin and formation of DHT and 3 alpha-diol is markedly increased in vitro in IH. Since 3 alpha-diol glucuronide is derived largely from extrasplanchnic events, beta-glucuronidase is present in skin, and androgen stimulates formation of the enzyme in extrasplanchnic tissue, we conclude that 3 alpha-diol glucuronide is a marker of peripheral androgen action and markedly elevated in IH.

Androstane-3,17-diol↗
PubMed1982

Conversion of progesterone from the adrenal or ovary to deoxycorticosterone in plasma.

The in vivo conversion of progesterone to deoxycorticosterone (DOC) by peripheral 21 hydroxylation was studied in normal men and women. The technique used was to infuse labeled progesterone under steady state conditions and isolate the precursor and product from blood by multiple chromatography steps. DOC was chromatographed as both the steroid and its acetylated derivative. The conversion rate was found to be 1.3 +/- 0.1% in men and women despite differences in the concentration of progesterone during the cycle. Since progesterone was very low in men and women in the follicular phase of the cycle, we conclude that DOC is derived from direct secretion. However, progesterone rises to 1073 +/- 101 ng per dl in the luteal phase and the calculations indicate that DOC increases from 8.3 +/- 0.4 (SE) to 15.6 +/- 1.3 ng per dl. 3/4 of luteal phase DOC is from conversion of progesterone. Acute ACTH increases both progesterone and DOC, and almost all of the DOC in plasma is from direct secretion. However, chronic ACTH excess and adrenal 21 hydroxylase deficiency is associated with a fraction (1/4-1/5) of DOC from progesterone indicating that the peripheral conversion rate is unrelated to the adrenal enzyme defect.

Adrenal Glands↗
PubMed1981

Evidence for a dual action of converting enzyme inhibitor on blood pressure in normal man.

We studied the effect of a converting enzyme inhibitor (CEI), Captopril SQ 14,225 50 mg p.o. in eight supine normal subjects under a high sodium (150 mEq/d) and low sodium (25 mEq/d) diet. On high sodium, plasma renin (PRA) and aldosterone were basal and Saralasin did not lower mean blood pressure. However, CEI induced an 11.4 +/- 3.2 mm fall in blood pressure (p less than 0.02) and either indomethacin 50 mg or ibuprofen 800 mg (PI), when given simultaneously on another day abolished the blood pressure response (2.5 +/- 0.9 mm Hg, p greater than 0.5). In contrast, on a low salt diet where renin was increased, CEI induced a drop in blood pressure which was not significantly altered by PI (12.8 +/- 1.1 vs. 10.0 +/- 3.1 mm Hg, p greater than 0.5). CEI increased plasma renin on both diets (1.7 +/- 0.5 to 3.5 +/- 0.8 and 2.8 +/- 0.6 to 12.5 +/- 3.1 ng/ml/hr respectively both p less than 0.05). Aldosterone did not change (high Na+) or fell (low Na+). Inhibition of Prostaglandin synthesis did not significantly block the renin rise from CEI suggesting that the direct angiotensin II negative feedback is relatively independent of acute prostaglandin release. Our studies suggest that CEI has a dual hypotensive action. In a low renin state, the hypotensive action appears to be mediated through vascular prostaglandins.

Adult↗
PubMed1981

Studies of the renal vasoactive systems in hyporeninemic hypoaldosteronism.

Plasma renin activity, total renin, active renin, and aldosterone were measured as well as urinary prostaglandin E2 and kallikrein in a group of patients with hyperkalemia (6.1-7.7 mEq per liter) and hyporeninemic hypoaldosteronism. Plasma renin activity and aldosterone were low and the response was markedly blunted to upright posture, and furosemide. The rise in cortisol but not aldosterone was normal following ACTH stimulation. Active renin was depressed; however, total renin was normal. Urine PGE was variable including some low values, but the mean of the group was normal (p greater than 0.1). Urine kallikrein excretion was markedly diminished and undetectable in most cases. Fludrocortisone normalized potassium but minimally increased kallikrein in the patients. The possibility exists that kallikrein deficiency in these patients may underlie the inability to generate active renin.

Adrenocorticotropic Hormone↗
PubMed1981

Studies on the origin of androstanediol and androstanediol glucuronide in young and elderly men.

The in vivo origin of androstanediol (3 alpha diol) and its glucuronide was studied in six young and five elderly men undergoing cardiac catheterization. Constant infusions of [14C]testosterone and [3H]3 alpha diol were given, and blood was obtained from the aorta and hepatic vein in order to measure metabolic clearance, splanchnic extraction, and the possibility of splanchnic production of both 3 alpha diol and its glucuronide. In young elderly men, the concentrations of labeled and unlabeled testosterone, dihydrotestosterone, and 3 alpha diol were lower in the hepatic vein than in the aorta. The specific activities of dihydrotestosterone and 3 alpha diol were the same in blood entering and leaving the splanchnic compartment. The plasma concentration of 3 alpha diol was 18 +/- 2 in the young men and 15 +/- 4 ng/dl in the elderly group. However, the blood production rate of 3 alpha diol determined from the metabolic clearance and morning plasma concentration was reduced (324 vs. 199 micrograms/day) as a result of lower clearance in the elderly men. Plasma 3 alpha diol glucuronide concentrations were 197 +/- 68 and 96 +/- 35 ng/dl in the two groups. No difference in the concentration of 3 alpha diol glucuronide was observed across the splanchnic tissues by mass, radioactive levels, specific activity, or 14C to 3H ratios. The 14C to 3H ratio for 3 alpha diol glucuronide was 10 times higher than for the free steroid, indicating that more than 90% of the glucuronide originates from a pool separate from blood 3 alpha diol. Both the splanchnic extraction of 3 alpha diol and the metabolic clearance were reduced in elderly men. These studies indicate that both 3 alpha diol and its glucuronide in blood result from extrasplanchnic events. A major reduction in the plasma concentration of 3 alpha diol glucuronide occurs in the aging male, although no difference is seen in the levels of the unconjugated 3 alpha diol. 3 alpha diol and its glucuronide are derived principally by extrahepatic (target) tissue events.

Adult↗
PubMed1981

Hyperreninemic hypoaldosteronism in the critically ill: a new entity.

To define the changes in adrenal gland function during critical illness, we evaluated 28 severely ill patients with persistent hypotension who were hospitalized in a medical intensive care unit. The patients had increased plasma cortisol (mean +/- SE, 40.1 +/- 10.1 micrograms/dl). PRA was increased in all subjects (21.6 +/- 7.2 ng/ml.h); however, the plasma aldosterone concentration was inappropriately low in 18 of the subjects, with values ranging from 1-9 ng/dl, despite normal serum potassium concentrations (4.3 +/- 0.1 meq/liter) and increased concentrations of the aldosterone percursor, 18-hydroxycorticosterone. These 18 patients had hypotension associated with major infections and a high mortality rate (78%). Infusions of ACTH or angiotensin II were associated with a normal aldosterone response in only 2 of the 14 patients tested, also suggesting that the defect was probably at the level of the zone glomerulosa cell. Although infection was a common underlying illness, no other factors, such as dopamine administration, decreased angiotensin-converting enzyme activity, or increased aldosterone clearance, could be implicated as the cause of the phenomena. Thus, selective hypoaldosteronism in the presence of high renin levels exists in a substantial percentage of hypotensive critically ill patients.

Acute Disease↗
PubMed1980

Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy.

THIP, 4,5,6,7-tetra hydroisoxazolo[5,4-C]pyridine-3-ol, has been evaluated as an anticonvulsant in DBA/2 mice showing audiogenic seizures, and in baboons, Papio papio, with photosensitive epilepsy. No protection against seizures was seen after THIP, 1-4 mg/kg, intraperitoneally in mice. THIP, 8 mg/kg, reduced clonic and subsequent seizure responses at 1 h. It also reduced rectal temperature and impaired posture and spontaneous activity. In baboons THIP, 0.25-8 mg/kg, iv, failed to protect against photically induced myoclonic responses. Toxic signs after THIP, 8 mg/kg, included focal or generalised myoclonus. THIP is thus not effective against reflex epilepsy.

Animals↗
PubMed1980

Induction of renin release by exogenous prostaglandins in hyporeninemic hypoaldosteronism.

A deficiency in renal prostaglandin synthesis has been proposed as the cause of the syndrome of hyporeninemic hypoaldosteronism. To determine if renin release could be stimulated by pharmacologic infusions of PGA1, we infused PGA1 0.075 to 0.60 microgram/kg/min to nine patients with the syndrome. Total renal PGE production as measured by urinary PGE excretion was normal (650 +/- 169 vs 400 +/- 55 ng/24hr in normal subjects). Renin (PRA) was markedly depressed in all patients despite stimulation with upright posture and furosemide (1.0 +/- 0.4 vs 9.3 +/- 0.7 ng/ml/hr, p < 0.001). But in two patients PGA1, induced an increase in renin similar to that of normal subjects. PRA increased to a lesser degree in two other patients and plasma aldosterone slightly increased. Five showed no response. Infusions of nitroprusside in doses and duration that mimicked the hypotensive effects of PGA1 failed to increase PRA or aldosterone. The data suggest that total renal PGE production is normal in patients with the syndrome of hyporeninemic hypoaldosteronism. Although orthostasis, furosemide and nitroprusside do not increase renin, prostaglandin A1 infusion appears to be a potent stimulus to renin release in some of the patients.

Aldosterone↗