Biomedical subjects

D J Morris

Publications and source records attributed to D J Morris.

At least 181 records · Page 10Linked to original sources

PubMed1987

Metabolic derivatives of aldosterone.

Metabolism of aldosterone during the latent period prior to the action of the hormone may be of physiological importance. In the rat, liver metabolizes aldosterone in a sex-dependent manner; larger quantities of neutral polar and reduced aldosterone derivatives are found in male rat kidney; correlating with the larger physiological responses of male rats to aldosterone. The target tissues, mammalian kidney and toad urinary bladder, are also capable of metabolizing aldosterone in situ to neutral polar, 5 alpha- and 5 beta-reduced, and monosulfate derivatives. The 5 alpha-reduced metabolites possess significant antinatriuretic activity and are preferentially synthesized by rat kidney nuclei. The metabolic pathways leading to the synthesis of 5 alpha-reduced metabolites and their subsequent neutral polar derivatives appear to be regulated by dietary sodium and can be inhibited by antimineralocorticoids. At concentrations somewhat higher than aldosterone, these 5 alpha-reduced metabolites also can recreate the development of hypertension and suppress plasma renin activity in young adrenalectomized spontaneously hypertensive rats. Thus, several of the metabolically transformed aldosterone derivatives can be correlated with physiological regulation and/or expression of the actions of the hormone.

Aldosterone↗

PubMed1986

A case of uridine diphosphate galactose-4-epimerase deficiency detected by neonatal screening for galactosaemia.

An infant with a deficiency of the enzyme uridine diphosphate galactose-4-epimerase was detected during galactosaemia screening of the Queensland newborn population. No case of epimerase deficiency has been reported previously in Australia and the incidence in our population is unknown. A deficiency of this enzyme is usually quite benign although two cases with a galactosaemia-like syndrome have been reported. This infant is developing normally, both intellectually and physically, in spite of extremely high levels of red blood cell galactose-1-phosphate. The introduction of newer methods of galactosaemia screening in Australia will probably result in the detection of other cases of this enzyme deficiency.

Australia↗

PubMed1986

The effects of antimineralocorticoids on synthesis of aldosterone metabolites in target tissues.

[3H]Aldosterone is transformed into several metabolites by subcellular fractions of rat kidney. 80-90% of the metabolites synthesized by nuclei and plasma membranes are 5 alpha-DHAldo and 3 alpha,5 alpha-THAldo in ratios of 1:2 and 1:1 respectively; small quantities of 3 beta,5 alpha-THAldo are also synthesized. In contrast, kidney cytosol metabolizes Aldo principally to 5 beta-reduced products with co-chromatograph with 5 beta-DHAldo and 3 alpha,5 beta-THAldo. Several polar neutral metabolites, as well as sulfate and acidic metabolites are also synthesized by the cytosol fraction. Similar 5 alpha-reduced metabolites, 5 alpha-DHAldo, 3 alpha,5 alpha-THAldo and 3 beta,5 alpha-THAldo are also synthesized when [3H]aldosterone is incubated in vitro with toad urinary bladder for 1 and 5 h. Significant quantities of 5 beta- and 20 beta-reduced products and sulfate and acidic metabolites are also synthesized. The metabolism of [3H]aldosterone in both target tissues is significantly inhibited by aldosterone antagonists. Several of the reduced metabolites of aldosterone synthesized in kidney and toad bladder possess significant mineralocorticoid activity. 5 alpha-DHAldo and 3 alpha,5 alpha-THAldo possess 1/10 and 1/30 and 3 alpha,5 beta possesses 1/80-1/100 of the antinatriuretic activity of Aldo. It is suggested that the metabolism of Aldo in its target tissues may be linked to regulation or expression of the hormone's actions.

Aldosterone↗

PubMed1986

Synthesis of 19-noraldosterone, a potent mineralocorticoid.

19-Noraldosterone has been prepared for biological re-evaluation through an extension of a recent synthesis of 19-hydroxyaldosterone: 21-hydroxy-6 beta,19-epoxy-4-pregnene-3,20-dion-20-ethylene ketal-18,11 beta-lactone (1a) was acetylated and then reduced with zinc-acetic acid-isopropanol to the 19-ol 2b. Treatment with sodium acetate transposed the double bond into conjugation, and 2a thus obtained was oxidized with pyridinium chlorochromate to the 19-oxo compound 3. Decarbonylation to the 19-nor lactone 4 was effected by heating with alkali. Protection of the C-3 carbonyl was achieved by ketalization and the resulting mixture of the 5-ene and 5(10)-ene ketals 5 was reduced with DIBAH to the corresponding mixture of the hemiacetals 6. Acid hydrolysis of the latter afforded 19-noraldosterone (7), accompanied by the 18,21-anhydro ketal 8. 19-Noraldosterone in the solid state exists in the cyclic form 7b, which appears to be also the predominant isomer present under conditions of mass spectrometry. [1H]NMR indicates that in chloroform 19-noraldosterone exists mostly as an equilibrium mixture of structures 7a and 7b. Sodium periodate oxidation furnished the gamma-etiolactone 9, confirming the 17 beta configuration in 7.

Aldosterone↗

PubMed1986

Mineralocorticoid activity of 19-hydroxyaldosterone, 19-nor-aldosterone, and 3 beta-hydroxy-delta 5-aldosterone: relative potencies measured in two bioassay systems.

The mineralocorticoid (MC) activities of 19-hydroxyaldosterone (19-OH-Aldo) and 19-nor-aldosterone (19-nor-Aldo) were tested in adrenalectomized male rats. Potency was assessed by three criteria. Overall MC activity is expressed as the ability to decrease the urinary Na+ to K+ ratio; antinatriuretic activity is represented by decreases in the urinary Na+ to creatinine ratio, and kaliuretic activity by increases in the K+ to creatinine ratio. All measurements were made on urine collected 1-3 h postinjection. In this assay, 19-OH-Aldo was 1/100th to 1/140th as active as Aldo, and 19-nor-Aldo possessed MC activity similar to that of Aldo; both steroids possessed antinatriuretic and kaliuretic activities. In contrast, when assayed in vitro in the isolated toad urinary bladder, the natriferic responses of both 19-OH-Aldo and 19-nor-Aldo (10(-8), 10(-7), and 10(-6) M) were not significantly different from those caused by equivalent concentrations of Aldo. 3 beta-Hydroxy-delta 5-Aldo is active as a MC in the adrenalectomized male rat, being 1/20th to 1/35th as active as Aldo, but, in contrast to 19-OH-Aldo, was less active in the isolated toad bladder system. 19-OH-Aldo, 19-nor-Aldo, and 3 beta-hydroxy-delta 5-Aldo could represent important new classes of Aldo analogs.

Adrenalectomy↗

PubMed1986

The rapid decline in erythrocyte transketolase on cessation of high-dose thiamine administration in Korsakoff patients.

This paper reports two studies carried out on patients with the Wernicke-Korsakoff (W-K) syndrome and control subjects. All had been mental hospital inpatients for at least 12 months. In the first study the changes in the thiamine-dependent enzyme erythrocyte transketolase (TK) which followed the administration of oral thiamine are described. Essentially the two patient samples responded similarly. In the second study patients who had been maintained on high-dose thiamine for several months stopped this treatment abruptly. The subsequent decline in TK is described. In W-K patients this decline was rapid and virtually complete at four weeks. In control subjects the decline was much more gradual. These findings offer support to other evidence suggesting a difference between TK in W-K and control subjects.

Alcohol Amnestic Disorder↗

PubMed1985

Sexual behavior of the female porcupine Hystrix africaeaustralis.

Porcupines are sexually active throughout the estrous cycle, and sexual behavior is not affected by the reproductive status and hormonal milieu of females. Increased female-male interactions during estrus are the only indications of behavioral changes during estrus. The lack of aggression shown by females to known males as opposed to aggression shown to strange males, the greater interest shown by males toward certain females, and the superior breeding success of these females suggest a pair-bonding mating system. Limited changes in female receptivity throughout the cycle might be of importance in maintaining the pair-bond.

Animals↗

PubMed1985

The synthesis of reduced metabolites of aldosterone by subcellular fractions of rat kidney: effects of antimineralocorticoids.

Subcellular fractionation of male rat kidney revealed that the nuclear and plasma membrane fractions isolated from the 1,000 g pellet retained a significant proportion of the aldosterone ring-A reducing activity. Improved HPLC solvent systems separated all six possible ring-A reduced metabolites of aldosterone and revealed that 80-90% of the reduced metabolites synthesized by purified nuclei and plasma membranes were 5 alpha-reduced compounds consisting of 5 alpha-DHA and 3 alpha,5 alpha-THA in ratios of 1:2 (nuclei) and 1:1 (membranes). The 105,000 g cytosol also synthesized significant quantities of reduced, hydroxylated, and conjugated metabolites of aldosterone. In contrast, the majority of the reduced metabolites of aldosterone synthesized by kidney cytosol were 5 beta-products, consisting principally of 5 beta-DHA and smaller quantities of 3 alpha,5 beta-THA and 3 beta,5 beta-THA. The synthesis of reduced aldosterone metabolites in the cytosol, nuclear, and plasma membrane fraction was inhibited by both 5 and 50 microM concentrations of the antimineralocorticoids, progesterone, K+-canrenoate, and corticosterone. Progesterone was the strongest inhibitor of the synthesis of 5 alpha-DHA and 3 alpha,5 alpha-THA in both nuclei and plasma membranes. The overall order of inhibition of the synthesis of ring-A reduced metabolites in the kidney subcellular fractions was progesterone greater than K+-canrenoate greater than corticosterone; both progesterone and K+-canrenoate inhibited 5 alpha-reduction more than 5 beta-reduction.

Aldosterone↗

PubMed1985

The hypertensinogenic activity of 19-nor-deoxycorticosterone in the adrenalectomized spontaneously hypertensive rat.

Infusions of 10 or 25 micrograms/day 19-nor-DOC for 2 weeks in adrenalectomized spontaneously hypertensive rats led to significant increases in blood pressure, 55 and 70 mmHg respectively. This study provides further evidence that 19-nor-DOC is a potent hypertensinogenic steroid and that the ADX SHR model is a useful, sensitive bioassay system to test for hypertensinogenic activity.

Adrenalectomy↗

PubMed1985

Synthesis of 19-hydroxyaldosterone and the 3 beta-hydroxy-5-ene analog of aldosterone, active mineralocorticoids.

19-Hydroxyaldosterone (20) and the 3 beta-hydroxy-5-ene analog of aldosterone (HAA) (8) were synthesized from 21-acetoxy-4-pregnene-3,20-dion-20-ethylene ketal-18, 11 beta-lactone (2) as follows: the double bond was transposed from the 4,5 to the 5,6-position by enol acetylation to 3, followed by sodium borohydride reduction. Further reduction of the resulting lactone 4a with diisobutylaluminum hydride (DIBAH) furnished the 20-ketal of HAA 6, from which free HAA (8) and the 18,21-anhydro compound 7 were obtained by acid treatment. The [1H]NMR spectrum of 8 in CDCl3 showed it to be a mixture of two isomeric forms. Correlation with the known aldosterone-gamma-etiolactone (10) was established by periodate oxidation of HAA to the corresponding etiolactone 9 followed by chromic acid oxidation. The preparation of 20 was next effected in the following manner: the diacetate 4b was converted into the 6 beta, 19-oxido compound 13b by addition of hypobromous acid followed by the hypoiodite reaction of the bromohydrin 11. Mild saponification of 13b lead to the corresponding diol 13a, and was followed by selective oxidation to the 3-one 14, readily dehydrobrominated to 15a. Reductive ring opening furnished a mixture of the 19,21-diol 16a and its 5-ene isomer 16b, which was directly converted to the diketal 17. Reduction with DIBAH gave the hemiacetal 18, and hydrolysis of the latter 19-hydroxyaldosterone (20) as a water-soluble solid, accompanied by the 18,21-anhydro compound 19. 19-Hydroxyaldosterone exists in CHCl3 and water as a mixture of mainly two isomers. Periodate oxidation furnished the etiolactone 21. Preliminary results indicate that HAA and 19-hydroxyaldosterone are active mineralocorticoids in the Kagawa bioassay and short-circuit current measurements.

Aldosterone↗

PubMed1985

The effects of 19-nor-aldosterone on blood pressure of adrenalectomized spontaneously hypertensive rats.

The relative hypertensinogenic potencies of recently synthesized 19-nor-aldosterone and its precursor 19-OH-aldosterone were assessed in comparison to that of aldosterone (Aldo) in young (6-week-old) adrenalectomized (ADX) spontaneously hypertensive rats (SHR). Infusion of 19-nor-aldosterone for 2 weeks by Alza mini-osmotic pumps caused significant, dose-dependent increases in the systolic blood pressure (BP) of young ADX SHR; dosages of 0.1 and 0.5 microgram/day raised the BP from 127 +/- 2 mmHg to 164 +/- 9 and 180 +/- 11 mmHg, respectively. During this period, control ADX SHR receiving vehicle only remained normotensive. Similar increases in BP were seen only with infusion of slightly higher dosages of Aldo (0.5 and 1.0 micrograms/day). In contrast, 19-OH-aldosterone infused at higher dosages (10 or 25 micrograms/day) caused little change in BP of ADX SHR. Full suppression of plasma renin activity (PRA) was observed with 0.1 and 0.5 microgram/day 19-nor-aldosterone, whereas Aldo caused similar decreases in PRA only at dosages of 0.5 microgram/day and higher. Interestingly, although infusions of 19-OH-aldosterone did not cause a significant change in BP, these dosages (10 and 25 micrograms/day) significantly suppressed PRA. These studies which show that 19-nor-aldosterone is equipotent to Aldo, and perhaps slightly more active in ADX SHR, indicate that 19-nor-aldosterone is a potentially important hypertensinogenic steroid.

Adrenalectomy↗

PubMed1985

Induction of flavokinase (EC 2.7.1.26) by aldosterone in the rat kidney.

The effect of aldosterone on rat renal flavokinase (EC 2.7.1.26) enzymic activity and concentration was investigated in bilaterally adrenalectomized male Sprague-Dawley rats. Flavokinase enzymic activity was measured in the 100,000 X g supernatant of renal cortex and red medulla and was increased after 3 h by 19% and 42%, respectively, as a result of aldosterone (1.5 micrograms/100 g BW) administration. Dual isotope labeling studies revealed increases of 20-30% and 20-35% in the incorporation of [3H]- and [35S]methionine into rat renal cortical and red medullary flavokinase, respectively, as a result of aldosterone administration. The aldosterone-dependent increases in methionine incorporation were blocked when the mineralocorticoid receptor antagonist spirolactone (SC 26304; 150 micrograms/100 BW) was administered 30 min before aldosterone. The relative concentrations of renal flavokinase also increased by 40% in both the cortex and red medulla 3 h after aldosterone treatment, as determined by an enzyme-linked immunosorbent assay (ELISA). These increases were abolished by actinomycin D (100 micrograms/100 g BW) and cycloheximide (200 micrograms/100 g BW), given 1 h before aldosterone administration. The mineralocorticoid receptor antagonists SC 26304 (225 micrograms/100 g BW) and progesterone (500 micrograms/100 g BW) were also able to inhibit the aldosterone-dependent increase in renal flavokinase concentration. The effect of aldosterone on renal flavokinase concentration was studied from 30 min to 8 h after aldosterone administration. There appeared to be maximum increases of 23-30% and 25-32% after 2.5-3.5 h in the renal cortex and red medulla, respectively. 5 alpha-Dihydroaldosterone, a metabolite of aldosterone with mineralocorticoid activity, was also able to increase renal flavokinase concentrations by approximately 40%. However, dexamethasone, a potent glucocorticoid with little or no mineralocorticoid activity, appeared to have no effect on renal flavokinase, as observed by ELISA. These data suggest that the increase in the relative concentration of renal flavokinase may be due to increased biosynthesis of flavokinase, and ultimately, that renal flavokinase may be an aldosterone-induced protein whose synthesis is mediated through the mineralocorticoid receptor and RNA synthesis.

Adrenalectomy↗

PubMed1984

Synthesis of 3 alpha, 5 alpha-tetrahydroaldosterone.

3 alpha, 5 alpha-Tetrahydroaldosterone (12a), a metabolite of aldosterone, has been synthesized from the lactone 2a or, preferably 11 beta, 21-dihydroxy-5-pregnene-3,20-dione-18-oic acid 3,20-di-(ethylene glycol)-ketal (18----11) lactone 21-acetate (6b), via 11 beta, 21-dihydroxy-5 alpha-pregnane-3,20-dione-18-oic acid 3,20-di-(ethylene glycol) ketal (18----11) lactone 21-acetate (4b). Selective hydrolysis of the latter at C-3 furnished the monoketal 5 which, on reduction with potassium tri-sec-butylborohydride, yielded predominantly 3 alpha, 11 beta, 21-trihydroxy-5 alpha-pregnan-20-one-18-oic acid 20-(ethylene glycol)-ketal (18----11) lactone (8a) and its acetate 8b. Further reduction with diisobutylaluminum hydride afforded 3 alpha, 5 alpha-tetrahydroaldosterone-20-ketal (10a), which was directly hydrolyzed to 12a with dilute acid in tetrahydrofuran-dioxan. Periodate oxidation led to the gamma-etiolactone 14a, which was then further converted into 5 alpha-dihydroaldosterone-gamma-etiolactone (14c).

Aldosterone↗

PubMed1984

Glucocorticoid inhibition of mineralocorticoid action in the rat.

The mineralocorticoid activity of corticosterone based on acute changes in urinary Na+/K+ ratios in adrenalectomized rats was 1000 times less than that of aldosterone. However, corticosterone had only kaliuretic actions whereas aldosterone had both antinatriuretic and kaliuretic properties. Corticosterone inhibited the antinatriuretic actions of aldosterone. Adrenalectomized rats infused continuously with a physiological dose of corticosterone (1 mg/day) were 5 time less sensitive to the antinatriuretic and 25 times less sensitive to the kaliuretic actions of aldosterone when administered acutely than were control adrenalectomized rats. The long term effects of infusions of physiological doses of aldosterone and corticosterone were assessed in adrenalectomized rats maintained in metabolic cages. Aldosterone lowered plasma renin activity and reduced fluid (0.3% NaCl) intake; these effects were diminished when aldosterone and corticosterone were infused simultaneously. Plasma renin activity and fluid intake were correlated in long term infusion experiments. Both hormones had hypokalaemic effects but these were not additive. Corticosterone, but not aldosterone, increased systolic blood pressure and plasma sodium levels. We conclude that glucocorticoid effects on water and electrolyte metabolism are different from those of mineralocorticoids, that glucocorticoids may antagonize mineralocorticoid effects and that interactions between mineralocorticoids and glucocorticoids may be important in long term blood pressure regulation.

Adrenalectomy↗

PubMed1984

Further studies of the mineralocorticoid activity of 19-oxo-deoxycorticosterone.

Antinatriuretic and kaliuretic activities of 19-oxo-deoxycorticosterone (19-oxo-DOC) were measured in male adrenalectomized rats and compared with those of aldosterone. No significant effects of 19-oxo-DOC or aldosterone were observed in the lag period (i.e. the first hour post injection). In the subsequent 2 h, rats injected with 25 micrograms 19-oxo-DOC excreted less than half the sodium and more than twice the potassium compared to rats injected with vehicle alone. Overall mineralocorticoid activity (based on changes in urinary Na+/K+), antinatriuretic activity (based on changes in urinary Na+/creatinine) and kaliuretic activity (based on changes in urinary K+/creatinine) of 19-oxo-DOC were all in the range of 1:100th-1:200th that of aldosterone. These results are not in agreement with a recent report suggesting that 19-oxo-DOC possesses antinatriuretic activity but no kaliuretic activity.

Aldosterone↗

PubMed1984

Aldosterone effects on water and electrolyte metabolism.

The effects of constant infusions of small doses of adrenal steroid hormones on sodium, potassium and water metabolism were studied in male adrenalectomized rats. An infusion of 1 microgram aldosterone/day was sufficient to restore normal sodium and potassium balance in a group of rats fed an unsupplemented diet. Log doses of aldosterone (0.1-10 micrograms/day for 4 days) administered some days after adrenalectomy caused linear increases in the body weight of rats fed a sodium-supplemented diet (0.05 M-NaCl as drinking fluid) during 4 days of treatment. Increases in body weight correlated with renal sodium and water balance. When steroid treatment was started at the time of adrenalectomy, sodium balance was not significantly affected although rats treated with 1 microgram aldosterone/day ate more, drank less saline, produced a smaller volume of urine of greater osmolarity and gained more weight than controls. A dose of 100 micrograms 18-hydroxy-deoxycorticosterone/day had no significant effects. Fluid intake and urine volume were not significantly affected by 1 mg corticosterone/day but food intake, water balance and weight gain were greater than controls. Rats treated with both aldosterone and corticosterone showed a decrease in free water clearance. Aldosterone and corticosterone, both singly and in combination, reduced plasma potassium levels. Plasma sodium levels were only increased when aldosterone was administered on its own. Long-term steroid infusions have revealed more about the physiology of aldosterone action than could acute measurements of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

18-Hydroxydesoxycorticosterone↗

PubMed1983

The metabolism of aldosterone in kidney.

Slices of kidney cortex and medulla from adrenalectomized male rats metabolized aldosterone to at least 4 peaks of polar metabolites as well as reduced metabolites. The majority of the products were ring A-reduced and shown chromatographically to consist of 5 alpha-reduced metabolites; significant quantities of 5 beta-reduced metabolites were also synthesized. Approximately half of the 5 alpha-reduced products cochromatographed with 3 beta,5 alpha-THA and the remainder with 5 alpha-DHA and/or 3 alpha,5 alpha-THA. The anti-mineralocorticoids, spironolactone and progesterone, inhibited renal synthesis of 5 alpha-reduced products of aldosterone by 80%. 5 beta-Reduction was also slightly inhibited. Corticosterone slightly inhibited synthesis of the 5 alpha- and 5 beta-reduced products. Corticosterone and progesterone significantly inhibited the renal synthesis of the polar metabolites of aldosterone, but the inhibition was not significant at this dosage of spironolactone. Interestingly, the nuclei and plasma membranes were shown to be the most active fractions for these aldosterone transformations. Importantly significant quantities of 5 alpha-DHA and/or 3 alpha,5 alpha-THA, which possess 1/10 and 1/30, respectively, of the antinatriuretic activity of aldosterone, were synthesized at these subcellular locations.

Adrenalectomy↗

PubMed1983

The effects of adrenal and gonadal steroids and K+-canrenoate on the metabolism of aldosterone by rat liver microsomes.

The synthesis of polar aldosterone metabolites by rat liver microsomes at physiological concentrations of aldosterone (21.5 nM), was markedly inhibited by progesterone, testosterone, corticosterone, K+-canrenoate and estradiol-17 beta. In contrast, corticosterone and estradiol-17 beta significantly increased the synthesis of reduced aldosterone metabolites by 8- and 15-fold respectively, the majority of which were 5 alpha-reduced products of aldosterone. In experiments at higher substrate (aldosterone) concentrations (20-200 microM) the synthesis of ring A-reduced aldosterone metabolites by liver microsomes followed Michaelis-Menten kinetics with a Km[app] for aldosterone of 160 microM and Vmax[app] of 12.2 nmoles/mg protein/5 min. In these experiments progesterone, testosterone and K+-canrenoate all competitively inhibited the synthesis of reduced metabolites with inhibition constants (Ki [app]) of 70, 85 and 55 microM respectively; however, corticosterone did not. In contrast, estradiol-17 beta increased the rate of synthesis of reduced products by 40%, lowering the Km[app] to 83 microM.

Aldosterone↗