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Biomedical subjects

C J Kenyon

Publications and source records attributed to C J Kenyon.

At least 109 records · Page 6Linked to original sources
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

Inhibition by etomidate of steroidogenesis in isolated bovine adrenal cells.

Adverse side effects of the anaesthetic etomidate have been indirectly linked with inhibition of adrenocorticoid synthesis. The present in vitro study has shown that this is a direct effect and indicated which biosynthetic reactions are affected by etomidate. Isolated bovine adrenocortical cells were incubated with and without 10(-8)M ACTH and with increasing doses of etomidate (0-625 ng/ml). ACTH-stimulated cortisol synthesis was significantly inhibited by a concentration of etomidate (25 ng/ml), which is much less than therapeutic plasma levels (100-500 ng/ml). Both basal and ACTH stimulated synthesis of cortisol, progesterone, 17 alpha hydroxyprogesterone and corticosterone were inhibited by 625 ng etomidate/ml whereas deoxycorticosterone output was more than doubled with this dose of anaesthetic. These observations suggest that etomidate inhibits mitochondrial cytochrome P450-dependent hydroxylation reactions in the adrenal steroidogenic pathway.

Adrenal Cortex↗
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

Antinatriuretic and kaliuretic activities of the reduced derivatives of aldosterone.

The mineralocorticoid activities of the two dihydro- and the four tetrahydroisomers of the ring A-reduced derivatives of aldosterone were tested in adrenalectomized male rats. Potency was assessed by three criteria. Overall mineralocorticoid activity is expressed as the ability to reduce the urinary Na+/K+ ratio; antinatriuretic activity is represented by decreases in urinary Na+/creatinine; kaliuretic activity is shown by increases in K+/creatinine. All measurements were made on urine collected in the period 1-3 h postinjection. Measurements of overall activity indicate that the potency of aldosterone is greater than 5 alpha-dihydroaldosterone (DHA) greater than 3 alpha, 5 alpha-tetrahydroaldosterone (THA) greater than 3 alpha, 5 beta-THA greater than 3 beta, 5 alpha-THA greater than 5 beta-DHA greater than 3 beta, 5 beta-THA. Measurements of individual cation effects indicated that reduced derivatives generally, and the 5 alpha-reduced derivatives in particular, have greater antinatriuretic than kaliuretic activity. For example 5 alpha-DHA possesses between 7% and 17% of the antinatriuretic activity of aldosterone but only 0.7-2.7% of the kaliuretic activity. 5 alpha-DHA and 3 alpha, 5 beta-THA at concentrations of 10(-7)M were also shown to have mineralocorticoid activity in the isolated toad bladder; both caused an increase in the short circuit current across this epithelium although not to the level shown by a similar concentration of aldosterone. 5 beta-DHA appeared to be inactive at this dose.

Adrenalectomy↗
PubMed1982

Aldosterone and its metabolism in spontaneously hypertensive rats (SHR).

The development of hypertension in spontaneously hypertensive rats (SHR) was blocked by adrenalectomy and restored with aldosterone treatment. The blood pressures of normotensive strains of rat were not affected by aldosterone. Infusions of 10 micrograms aldosterone/day into adrenalectomized (ADX)--SHR, Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats completely suppressed plasma renin activity in all strains and lowered plasma potassium levels to below normal in WKY and SD rats; aldosterone treated SHR were normokalemic. In acute studies, SHR responded normally to the antinatriuretic actions of aldosterone but gave a shallower kaliuretic response compared with WKY and SD rats. The urine of ADX-SHR injected with 3H-aldosterone contained a larger proportion of polar neutral metabolites of aldosterone than WKY urine but smaller amounts of acidic and sulfate metabolites. HPLC of the neutral metabolites showed that several polar compounds were present in larger amounts in SHR urine but that unmetabolized aldosterone was less than in WKY urine.

Adrenalectomy↗
PubMed1982

Mutagenesis and cellular responses to DNA damage.

Treatment of Escherichia coli with DNA-damaging agents results in the increased expression of a set of din (damage-inducible) genes. We have studied the regulation and function of these genes by using the Mud(Ap, lac) bacteriophage to obtain fusions of the beta-galactosidase structural gene to the promoters of various din genes. By this technique, we have shown that the uvrA, uvrB, and umuC genes are induced by UV and other DNA damaging agents. The products of the uvrA and uvrB genes are required for the excision repair of pyrimidine dimers and other bulky lesions; the umuC gene product is required for most chemical mutagenesis in E. coli. Genetic analyses of all of the din-lac fusions isolated to date indicate that lexA is the direct repressor of each of the din genes and that proteolytic cleavage of the lexA protein is required for their induction. We have also been studying the mechanism by which the clinically isolated plasmid pKM101 increases the susceptibility of cells to chemical mutagenesis. Inasmuch as the effects of pKM101 on mutagenesis are recA+ lexA+ -dependent and the plasmid can suppress the nonmutability of a umuC mutant, it seems likely that pKM101 may carry an analog of the chromosomal umuC gene. By insertion mutagenesis using Tn5, we identified an approximately 2,000-base pair region of pKM101 which is necessary for its effects on mutagenesis.

Bacterial Proteins↗
PubMed1981

Expression of the E. coli uvrA gene is inducible.

UvrA+-dependent excision repair is one of the most important systems in Escherichia coli for repairing UV-induced pyrimidine dimers and a variety of other forms of DNA damage. The uvrA protein acts in conjunction with the uvrB and uvrC gene products to introduce a nick at the of a DNA lesion and thus initiate the repair process. We have recently used the Mud(Ap, lac) operon fusion vector to identify a set of genes whose expression is induced by DNA damage. One Mud(Ap, lac) insertion mapped at the uvrA locus and made the cells sensitive to UV light. In this fusion strain, beta-galactosidase expression was induced by DNA-damaging agents in a recA+lexA+-dependent fashion. We were surprised by this result because uvrA+-dependent excision repair is observed both in cells in which protein synthesis has been inhibited and in recA- and lexA- cells, findings which have led to the conclusion that the uvrA gene product is constitutively expressed and not under the control of the complex recA+lexA+ regulatory circuitry (see below). We have investigated this possibility further and describe here the generation and characterization of a set of fusions of the lac genes to the promoter of the uvrA gene. We confirm that the uvrA gene product is induced by DNA damage in a recA+lexA+-dependent fashion.

DNA Repair↗
PubMed1981

Inducibility of a gene product required for UV and chemical mutagenesis in Escherichia coli.

The product of the umuC gene is required for UV and chemical mutagenesis in Escherichia coli. By the use of the Mud(Ap, lac) bacteriophage, we have obtained an operon fusion of the lac structural genes to the promoter/regulatory region of the umuC gene. The strain containing the umuC::Mud(Ap, lac) fusion was identified on the basis of its UV nonmutability. Strains containing this putative null allele of umuC were (i) nonmutable by UV and other agents, (ii) slightly UV sensitive, and (iii) deficient in their ability to carry out Weigle reactivation of UV-irradiation bacteriophage lambda. The UV nonmutability of the strain could be suppressed by a derivative of the mutagenesis-enhancing plasmid pKM101. beta-Galactosidase synthesis in umuC::Mud(Ap, lac) fusion strains was inducible by UV and other DNA-damaging agents. Genetic analysis of the regulation of beta-galactosidase in umuC::Mud(Ap, lac) strains suggests that the lexA protein is the direct repressor of the umuC gene and that a function of the recA protein, probably its protease activity, is required for the removal of the lexA repressor at the time of umuC induction.

Bacterial Proteins↗
PubMed1981

Effect of adrenalectomy on the transmission of IgG in young rats.

Antibody transmission in rats aged 17 days was unaffected by adrenalectomy performed at 13 days. The normal 'closure' of the jejunum to antibody is delayed by about 2 days in adrenalectomised rats. Adrenalectomy at 13 days has no apparent effect on plasma volume or haematocrit. Plasma corticosterone levels increase fivefold between 14 and 20 days, but in early weaned animals with 'closed' guts, corticosterone levels were not raised.

Adrenalectomy↗
PubMed1981

The role of aldosterone in the development of hypertension in spontaneously hypertensive rats.

A continuous sc infusion of aldosterone for 2 weeks (10 micrograms/day) markedly increased the blood pressure of male, adrenalectomized (ADX), spontaneously hypertensive rats (SHR) from 142 to 178 mm Hg, which was similar to the increase seen in a group of sham-operated SHR. The blood pressure in a group of ADX SHR maintained without aldosterone declined from 141 to 119 mm Hg during the 2 weeks after surgery. Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats treated in an identical fashion remained normotensive throughout. Adrenalectomy caused hyperkalemia in all strains of rat. Plasma potassium levels in aldosterone-treated WKY and SD rats were lower than those in sham-operated controls, but were similar to those in corresponding groups of SHR. Acute renal responses of ADX male rats showed that SHR reabsorbed more water and sodium of an injected isotonic saline load than WKY rats and excreted less potassium than either WKY or SD rats. Sensitivity to aldosterone in the three strains of rats was compared using the urinary sodium to creatinine and potassium to creatinine ratios 1-3 h postinjection of aldosterone. Decreases in the urinary ratio of sodium to creatinine in response to various doses of aldosterone (0-1.25 micrograms aldosterone) were similar for the three strains of rat. ADX SHR appeared to be less responsive to the kaliuretic actions of aldosterone than WKY and SD rats. The present studies show that aldosterone is essential to the development of hypertension in SHR. The hypertensinogenic actions of aldosterone in these rats may be related to a blunted kaliuretic response to mineralocorticoids.

Adrenalectomy↗
PubMed1980

DNA-damaging agents stimulate gene expression at specific loci in Escherichia coli.

Operon fusions in Escherichia coli were obtained that showed increased beta-galactosidase expression in response to treatment with the DNA-damaging agent mitomycin C. These fusions were generated by using the Mud(ApR, lac) vector [Casadaban, M.J. & Cohen, S.N. (1979) Proc. Natl. Acad. Sci. USA 76, 4530-4533] to insert the lactose structural genes randomly into the bacterial chromosome. Induction of beta-galactosidase in these strains, which carried fusions of lac to these din (damage-inducible) loci, was (i) triggered by UV light as well as by mitomycin C and (ii) abolished by either a recA- or a lexA- mutation. Similar characteristics of induction were observed when the lactose genes were fused to a prophage lambda promoter by using Mud(ApR, lac). These results indicate that E. coli contains a set of genes that, like prophage lambda genes, are expressed in response to DNA-damaging agents and regulated by the recA and lexA gene products. These din genes map at five bacterial loci. One din::Mud(ApR, lac) insertion results in a UV-sensitive phenotype and may be within the uvrA transcriptional unit.

DNA Repair↗
PubMed1979

Captopril (SQ 14225) depresses drinking and aldosterone in rats lacking vasopressin.

Angiotensin II is dipsogenic, and vasopressin (ADH) regulates renal water excretion. Together, these hormones govern overall mammalian water balance. The Brattleboro rat with inherited diabetes insipidus (DI) lacks ADH and is therefore a convenient model with which to elucidate mechanisms regulating water metabolism. In the present studies, angiotensin II has also been removed from DI rats by the administration of an inhibitor (captopril, SQ 14225; D-2-methyl-3-mercaptopropanoyl-L-proline) of the enzyme which converts angiotensin I, the relatively inert component of the renin-angiotensin system, to angiotensin II, the biologically active substance. SQ 14225 reduced the drinking rates, and after 6 days lowered peripheral plasma aldosterone concentrations were associated with hyperkalaemia. We conclude that the polydipsia of diabetes insipidus partly results from elevated plasma renin activities and angiotensin II concentrations seen in this syndrome. Further, the apparent hypoaldosteronism of DI Brattleboro rats reflects differences in both tissue usage of the steroid and adrenocortical sensitivities associated with polyuria, hyperosmolarity and possibly potassium wasting.

Adrenal Cortex Hormones↗
PubMed1978

High affinity calcium binding peptides from the gills, gut and kidneys of the freshwater eel (Anguilla anguilla).

We report the isolation of high affinity calcium-binding peptides from homogenates of gills, gut and kidneys of the freshwater eel Anguilla anguilla. These peptides show identical gel-filtration profiles on Biogel P-6, from which a molecular weight of 3500 was estimated. The average binding constant (Kf) for calcium is 7 . 10(7)M-1, and MgCl2 up to 5 mM does not displace calcium.

Animals↗