PubMed Health⌕ Search

Biomedical subjects

D Kimball

Publications and source records attributed to D Kimball.

8 recordsLinked to original sources
PubMed1997

Calcium channel block by (-)devapamil is affected by the sequence environment and composition of the phenylalkylamine receptor site.

The pore-forming alpha 1 subunit of L-type calcium (Ca2+) channels is the molecular target of Ca2+ channel blockers such as phenylalkylamines (PAAs). Association and dissociation rates of (-)devapamil were compared for a highly PAA-sensitive L-type Ca2+ channel chimera (Lh) and various class A Ca2+ channel mutants. These mutants carry the high-affinity determinants of the PAA receptor site in a class A sequence environment. Apparent drug association and dissociation rate constants were significantly affected by the sequence environment (class A or L-type) of the PAA receptor site. Single point mutations affecting the high-affinity determinants in segments IVS6 of the PAA receptor site, introduced into a class A environment, reduced the apparent drug association rates. Mutation I1811M in transmembrane segment IVS6 (mutant AL25/-I) had the highest impact and decreased the apparent association rate for (-)devapamil by approximately 30-fold, suggesting that this pore-lining isoleucine in transmembrane segment IVS6 plays a key role in the formation of the PAA receptor site. In contrast, apparent drug dissociation rates of Ca2+ channels in the resting state were almost unaffected by point mutations of the PAA receptor site.

Animals↗
PubMed1993

The benzazepine/benzothiazepine binding domain of the cardiac L-type Ca2+ channel is accessible only from the extracellular side.

The whole-cell tight seal recording technique was used to investigate location of benzothiazepine binding site of the cardiac L-type Ca2+ channel. For this we utilized a permanently charged compound, SQ 32.428, out of a series of benzazepine drugs which have been characterized as competitive inhibitors of diltiazem binding. The non-permanently charged derivative SQ 32.910 was initially tested to electrophysiologically establish Ca2+ antagonistic properties of benzazepines. Upon extracellular application, either compound was able to completely block Ca2+ currents. At a stimulating frequency of 0.2 Hz IC50 concentrations of SQ 32.910 and SQ 32.428 were determined as 35 nM and 15 microM, respectively. Intracellular application of SQ 32.428 was then compared to control experiments in the absence of drug. Initially, adequate drug dialysis was confirmed with 100 microM D890, which produced a progressive inhibition of Ca2+ currents within 10 min after whole-cell access. In contrast, internal application of 100 microM SQ 32.428 did not change time-course of Ca2+ currents compared to control run-down. These results show that the benzazepine/benzothiazepine binding domain of the cardiac L-type Ca2+ channel is accessible only from the extracellular side and therefore suggest an extracellular location on the alpha 1-subunit of the Ca2+ channel protein.

Animals↗
PubMed1987

New evidence for a direct effect of prolactin on rat adrenal steroidogenesis.

The direct effect of prolactin on rat adrenal steroidogenic enzyme activity was evaluated by measuring plasma and adrenal cytosol steroid levels and adrenal microsomal 3B-hydroxysteroid dehydrogenase/isomerase (3B-HSD), 21 hydroxylase (21-OHase) and mitochondrial 11-hydroxylase (11-OHase) after in vivo administration of purified rat prolactin (rPRL) to adult, female Sprague-Dawley rats. Animals were ovariectomized, hypophysectomized and replaced with ACTH. Two days after surgery rPRL was administered i.p. at doses of 1.0, 10.0 and 100.0 micrograms (micrograms) every 4 hours for 5 days to experimental animals. Control rats received vehicle injections. All rats were sacrificed by decapitation and blood and adrenal glands collected. The adrenals were pooled into each rPRL dose group and mitochondria, microsomes and cytosol prepared from each pool. The activities of 3B-HSD, 21-OHase and 11-OHase were measured using as substrates 14C-dehydroepiandrosterone, 14C-progesterone and 14C-deoxycorticosterone, respectively. Plasma prolactin levels rose from 9.9 +/- 2.5 ng/ml in the control animals to 166.0 +/- 37.7 ng/ml (p less than 0.001) in the 100 micrograms rPRL dose group. Plasma corticosterone levels were not statistically different in the experimental groups when compared to controls. However, adrenal weight was increased in the high dose rPRL group (34.9 +/- 0.9 mg vs 41.9 +/- 1.2 mg, p less than 0.025). Hyperprolactinemia did not influence microsomal 3B-HSD or mitochondrial 11-OHase activities but was associated with a dose dependent decrease in microsomal 21-OHase activity when compared to controls (p less than 0.001). Adrenal cytosol progesterone levels increased with increasing rPRL dose consistent with a 21-OHase block during hyperprolactinemia. These data suggest that prolactin has a direct effect on rat adrenal 21-OHase in vivo.

Adrenal Cortex↗
PubMed1986

New mitomycin analogs produced by directed biosynthesis.

When the normal fermentation medium for the production of mitomycin C with Streptomyces caespitosus is supplemented with a number of primary amines, two new types of mitomycin analogs described as Type I and Type II are produced. Type I analogs are related to mitomycin C with the amine substitution at position C7 on the mitosane ring. Type II analogs also contain the same substitutions at C7 but the conformation of the mitosane ring is related to mitomycin B having an OH at positions C9a and a methyl substituted aziridine. The products obtained from the supplementation of the medium with methylamine, ethylamine, propylamine, propargylamine and 2-methylallylamine were isolated and characterized. In all cases the Type I analogs are more active in a prophage induction test and against L1210 lymphatic leukemia in mice. A number of other amines have been tested and shown to yield new products that have not yet been isolated. No secondary amines are incorporated.

Animals↗
PubMed1979

Propylene glycol as a cause of an elevated serum osmolality.

Two severely burned patients experienced the onset of marked hyperosmolality during topical treatment with a cream containing silver sulfadiazine as an antimicrobial agent. Serum samples from both patients were studied for the presence of substances absorbed from the vehicle of the cream. Prophylene glycol, in concentrations which were high enough to account for the difference between calculated and measured osmolality, was demonstrated in the sera of these patients by gas chromatography.

Administration, Topical↗