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Biomedical subjects

R Horton

Publications and source records attributed to R Horton.

At least 253 records · Page 14Linked to original sources
PubMed1987

Antihypertensive effect of enalapril in essential hypertension: role of prostacyclin.

The effects of enalapril alone and in combination with the cyclooxygenase inhibitors sulindac and indomethacin on blood pressure (BP), plasma aldosterone, renin activity and converting enzyme activity were evaluated in 29 patients with mild to moderate essential hypertension, 26 of whom had low plasma renin activity. Patients were randomly assigned to one of three treatment groups. All patients underwent a 4-week placebo phase (phase I), then received enalapril (20 mg BID) for 4 weeks (phase II). In phase III, group I (n = 10) continued on enalapril alone; group II (n = 9) received sulindac 200 mg BID plus enalapril, and group III (n = 10) received indomethacin 50 mg BID plus enalapril, all for 4 weeks. Enalapril lowered BP significantly (mean supine BP 149/100 in phase I vs. 134/90 in phase II, p less than 0.05) without inhibiting aldosterone production. The BP effect was not blunted by concomitant administration of sulindac or indomethacin. Enalapril lowered converting enzyme activity to 25% to 30% of baseline and tended to increase renin activity. In the 10 patients who received indomethacin (group III), the effects of enalapril alone and enalapril plus indomethacin on urinary excretion of 6-keto prostaglandin F1 alpha (PGF1 alpha), a stable metabolite of prostacyclin (PGI2), were examined. Enalapril increased urinary 6-keto PGF1 alpha in group III from 118 +/- 23 to 194 +/- 38 ng/g creatinine (p less than 0.05), while addition of indomethacin reduced 6-keto PGF1 alpha to basal levels (138 +/- 26 ng/g creatinine).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1987

The inhibitory role of 12- and 15-lipoxygenase products on renin release.

Release of arachidonic acid from membrane phospholipids is a limiting step in the synthesis of both cyclooxygenase products and lipoxygenase products. The direct effects of prostacyclin and some lipoxygenase products on renin release were studied using rat renal cortical slices. Prostacyclin, at concentrations of 10(-5) M, stimulated renin secretion, but this effect was short-lived. Leukotrienes or their precursor, 5-hydroperoxyeicosatetraenoic acid, did not affect basal renin release. In contrast, 10(-9) M 12-hydroperoxyeicosatetraenoic acid and 10(-8) M 12-hydroxyeicosatetraenoic acid were potent inhibitors of renin secretion. Similarly, 15-hydroperoxyeicosatetraenoic acid and its hydroxy derivative, 15-hydroxyeicosatetraenoic acid, at somewhat higher molar concentrations (10(-6) M) also reduced basal renin. These studies confirm prostacyclin as a potential renin secretagogue; however, its action in vitro is transient, probably because of its rapid degradation. Our studies provide new evidence that products of the 12-lipoxygenase and 15-lipoxygenase pathways, reported to be present in renal vascular tissue, are potent inhibitors of renin secretion and much more active on a molar basis on renin secretion than is prostacyclin. These studies suggest the potential presence of a dual system of stimulation and suppression that may regulate renin secretion in normal and clinical states.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1987

Circulating dihydrotestosterone may not reflect peripheral formation.

We compared the blood (PBDHT) and urine (PUDHT) production rate of dihydrotestosterone (DHT) in normal men and women to determine whether peripheral formation was totally reflected in blood. PBDHT was similar when measured at both sites in men (674 +/- 79 vs. 788 +/- 207 SE micrograms/d); however, PUDHT was greater than PBDHT in women (174 +/- 55 vs. 55 +/- 8 micrograms/d, P less than 0.02). Excretion rates of DHT and 3 alpha-androstanediol (3 alpha diol) were similar in both sexes despite major differences in blood levels. However, between sexes large differences were present in 3 alpha diol glucuronide (3 alpha diolG) in both plasma and urine. These observations indicate that peripheral (renal) formation of DHT and probably 3 alpha diol were not accurately determined by measurement of these steroids in blood. The large difference between blood and urine production rates in women suggests an important role of non-testosterone precursors of 5 alpha-reduced steroids. Measurements of 3 alpha diolG may provide more insight into these peripheral events.

Androstane-3,17-diol↗
PubMed1987

Production of 3 alpha-androstanediol glucuronide in human genital skin.

3 alpha-Androstanediol glucuronide (3 alpha diol-G) is produced extrasplanchnically and is a good clinical marker of androgen action in peripheral tissues. However, the direct formation of androgen glucuronides in peripheral sites such as skin has not been determined in man. Genital skin from 21 premenopausal women and 8 men and foreskin from 6 neonates were incubated with either [14C]testosterone [14C]dihydrotestosterone (DHT) to determine the production of DHT glucuronide and 3 alpha diol-G in skin. After hydrolysis of incubation medium with glucuronidase, followed by extraction and sequential chromatography, constant 3H to 14C ratios of 3 alpha diol confirmed the production of DHT glucuronide and 3 alpha diol-g. The conversion of DHT to 3 alpha diol-G was higher than the conversion from testosterone (P less than 0.05), and conversion was higher in men than in women. These data provide evidence for the direct formation of C19 steroid glucuronides by human skin.

Adult↗
PubMed1987

Baroreflex control of renin release in spontaneously hypertensive rats after administration of felodipine.

The baroreflex control of heart rate will be rapidly reset to operate at a lower pressure level after blood pressure reduction by felodipine. The present study investigates whether the baroreflex control of renin release in spontaneously hypertensive rats (SHR) will also be reset after prolonged felodipine administration. Conscious SHR, fitted with catheters in the tail artery and vein, were given felodipine intravenously for 5 hours. The initial reflexogenic elevation in plasma renin activity and heart rate caused by felodipine-induced blood pressure reduction were successively normalised with time. Heart rate returned to pre-drug values after 3 hours and plasma renin activity after 5 hours of stable blood pressure reduction. This indicates rapid resetting of baroreflex control of both cardiac and renal function after blood pressure reduction by felodipine.

Animals↗
PubMed1987

Baroreflex control of heart rate and renin release in SHR following administration of felodipine, an antihypertensive Ca2+ antagonist.

Baroreflex control of renin release following acute and prolonged blood pressure reduction by felodipine administration was investigated in conscious spontaneously hypertensive rats (SHR) fitted with arterial and venous catheters. Basal values of mean arterial pressure (MAP), heart rate (HR), and plasma renin activity (PRA) were obtained in SHR and in SHR given felodipine for 2 weeks (SHRF). In SHRFMAP was reduced by 12% (p less than 0.01) versus SHR, but PRA and HR were similar. Acute i.v. infusion of felodipine, during 5 h, maintained MAP reduction by 40%. Initially, HR increased 29 +/- 3% but returned to predrug levels after 3 h. PRA increased from 1.4 +/- 0.5 to 6.5 +/- 1.0 ng/ml/h. After 5 h PRA had reached low levels equal to those in SHR given placebo instead of felodipine. In SHR pretreated with metoprolol neither HR nor PRA increased following felodipine, an indication that the observed changes were neurogenically determined. This suggests that baroreflex control of cardiac and renal function resets within 3-5 h following blood pressure reduction by felodipine.

Animals↗
PubMed1987

Safety in numbers.

Explore the source record for details and available documents.

Electric Wiring↗
PubMed1986

Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism.

Hyporeninemic hypoaldosteronism is an important cause of hyperkalemia and is characterized by low renin secretion. We found that prostacyclin, a potent vasodilator and renin secretagogue, was markedly reduced--as reflected by its stable urinary metabolite 6-keto-prostaglandin F1 alpha--in seven patients with hyporeninemic hypoaldosteronism as compared with seven matched controls with renal insufficiency and as compared with 12 normal volunteers (mean +/- SE, 42 +/- 7 vs. 185 +/- 37 and 164 +/- 20 ng per gram of creatinine, respectively; P less than 0.001). In contrast, renal prostaglandin E2 excretion was similar in all three groups. A low-dose infusion of calcium or norepinephrine (known stimulants of prostacyclin) increased renal prostacyclin release in normal subjects and controls with renal insufficiency. Neither agonist, however, increased the low basal prostacyclin excretion in the patients (49.6 +/- 11 [basal] vs. 62 +/- 20 [norepinephrine] and 47.5 +/- 16 [calcium]; P greater than 0.8). To evaluate the functional importance of the altered prostacyclin production, we studied the responses of renal blood flow and blood pressure to the calcium infusion. The calcium infusion did not alter blood pressure or renal blood flow in the normal subjects or the controls with renal insufficiency. In contrast, the same dose of calcium in the patients with hyporeninemic hypoaldosteronism produced a rise in mean blood pressure (from 91 +/- 6 to 104 +/- 8 mm Hg, P less than 0.05) and a fall in renal blood flow (from 673 +/- 58 to 560 +/- 42 ml per minute per 1.73 m2, P less than 0.05). These results indicate that a deficiency of prostacyclin could explain the low active-renin concentration and altered vasomotor tone seen in hyporeninemic hypoaldosteronism.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Evidence that prostacyclin modulates the vascular actions of calcium in man.

Increases in extracellular calcium (Ca++) can alter vascular tone, and thus may result in increased blood pressure (Bp) and reduced renal blood flow (RBF). Ca++ can stimulate prostaglandin E2 (PGE2) and/or prostacyclin (PGI2) release in vitro, which may modulate Ca++ vascular effects. However, in man, the effect of Ca++ on PG release is not known. To study this, 14 volunteers received low-dose (2 mg/kg Ca++ gluconate) or high-dose (8 mg/kg) Ca++ infusions. The low-dose Ca++ infusion did not alter systemic or renal hemodynamics, but selectively stimulated PGI2, as reflected by the stable metabolite 6-keto-PGF1 alpha in urine (159 +/- 21-244 +/- 30 ng/g creatinine, P less than 0.02). The same Ca++ infusion given during cyclooxygenase blockade with indomethacin or ibuprofen was not associated with a rise in PGI2 and produced a rise in Bp and fall in RBF. However, sulindac, reported to be a weaker renal PG inhibitor, did not prevent the Ca++ -induced PGI2 stimulation (129 +/- 33-283 +/- 90, P less than 0.02), and RBF was maintained despite similar increases in Bp. The high-dose Ca++ infusion produced an increase in mean Bp without a change in cardiac output, and stimulated urinary 6-keto-PGF1 alpha to values greater than that produced by the 2-mg/kg Ca++ dose (330 +/- 45 vs. 244 +/- 30, P less than 0.05). In contrast, urinary PGE2 levels did not change. A Ca++ blocker, nifedipine, alone had no effect on Bp or urinary 6-keto-PGF1 alpha levels, but completely prevented the Ca++ -induced rise in Bp and 6-keto-PGF1 alpha excretion (158 +/- 30 vs. 182 +/- 38, P greater than 0.2). However, the rise in 6-keto-PGF1 alpha was not altered by the alpha 1 antagonist prazosin (159 +/- 21-258 +/- 23, P less than 0.02), suggesting that calcium entry and not alpha 1 receptor activation mediates Ca++ pressor and PGI2 stimulatory effects. These data indicate a new vascular regulatory system in which PGI2 modulates the systemic and renal vascular actions of calcium in man.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Role of atrial natriuretic factor in renin release.

Atrial natriuretic factor (ANF) was studied for its effect on renin release by rat renal cortical slices. ANF (rat) alone (10(-9)-10(-6) M) had no effect on basal renin release, but significantly (P less than 0.001) potentiated angiotensin II (AII) inhibition of renin secretion in doses as low as 10(-9) M. ANF also potentiated the inhibitory effect of AII on 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (which alters intracellular calcium) and calmidazolium (a calmodulin blocker) effects on renin release. ANF did not inhibit the action of isoproterenol, which probably acts through cAMP, at doses below micromolar concentrations. Large, probably pharmacological amounts (greater than 10(-6) M) produce some inhibition. Since AII action on renin is associated with increases in intracellular calcium, our studies suggest that ANF acts by altering the intracellular calcium-calmodulin-mediated steps of AII action on this tissue and not via cAMP.

Angiotensin II↗
PubMed1986

Androstanediol glucuronide plasma clearance and production rates in normal and hirsute women.

We studied the kinetics and metabolism of tritiated 5 alpha-androstane-3 alpha-17 beta-diol glucuronide (3 alpha diolG) in normal and hirsute women. We found no difference in the MCR of 3 alpha diolG between normal and hirsute women [130 +/- 39 (+/- SD) vs. 157 +/- 81; P = NS]. The blood production rate was markedly increased in hirsute women (187 +/- 50 vs. 604 +/- 355 micrograms/day; P less than 0.001) and correlated well with the plasma 3 alpha diolG level (r = 0.96). In women, the conversion ratio of 3 alpha diolG to unconjugated 3 alpha diol or dihydrotestosterone was less than 1%, while the conversion ratio to dihydrotestosterone glucuronide was about 6%. We conclude that the elevated plasma levels of 3 alpha diolG characteristic of hirsutism reflect increased production of this androgen metabolite.

Adult↗
PubMed1986

Pharmacokinetics of parenteral ticarcillin formulated with clavulanic acid: Timentin.

The pharmacokinetics of a formulation of clavulanate potentiated ticarcillin (Timentin) have been investigated following a bolus intravenous injection of 1.2 g, infusions of 3.2 g over periods ranging from 30 minutes to three hours, and a bolus dose of 1.2 g followed by an infusion of 3.2 g. The effect of probenecid has also been investigated. The serum levels of clavulanic acid are discussed in relation to the microbiology and therapeutic implications.

Bacteria↗
PubMed1985

The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women.

Spironolactone (S) has been used successfully for the treatment of hirsutism. We evaluated whether the effects of S on serum androgens and hair growth are dose-related and whether S affects secreted androgens to the same degree as peripherally derived androgens. Two groups of 15 hirsute patients, similarly matched, received either 100 or 200 mg S daily for 3 months. Serum total testosterone (T) decreased significantly (P less than 0.05) and to a similar degree with both dosages, whereas unbound T was unaltered. Dehydroepiandrosterone sulfate was unaltered, whereas androstenedione decreased with 200 mg S (P less than 0.05). Peripherally derived serum dihydrotestosterone decreased to a similar degree with 100 and 200 mg S (P less than 0.05), whereas 5 alpha-androstane-3 alpha-17 beta-diol (3 alpha-diol) increased (P less than 0.05) similarly with both dosages. Serum 3 alpha-diol glucuronide (3 alpha-diol-G) increased with both dosages, but not significantly. Anagen hair shaft diameters decreased significantly in both groups by 19% +/- 8% and 30% +/- 4% (P less than 0.05). No correlation was found between hair growth and serum androgens. Because serum unbound T was largely unaltered by S, it is suggested that the antiandrogenic effects of S are primarily related to its peripheral effect. However, there is no good clinical marker for this effect as levels of 3 alpha-diol and 3 alpha-diol-G increase.

Adult↗