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K I Williams

Publications and source records attributed to K I Williams.

At least 19 recordsLinked to original sources
PubMed1991

Characterization of Gaddum's substance R.

1. When the isolated small intestine of the rat is perfused via the mesenteric artery, an oxytocic principle (Gaddum's substance R) is released which is detectable in the perfusate after 30 min and is present in samples collected 8 h later. 2. The oxytocic activity of substance R is lost after boiling but is unaffected by treatment with thioglycolate. Furthermore, atropine, methysergide and indomethacin failed to antagonize uterine contractions to substance R. 3. Neither substance R nor urinary kallikrein alone induce a contraction of the guinea-pig isolated ileum. However, in the presence of kininogen both substance R and urinary kallikrein produce a slow and prolonged contraction of the guinea-pig ileum. 4. The oxytocic and kininogenase properties of both substance R and urinary kallikrein are inhibited by Trasylol. 5. Soy bean trypsin inhibitor (SBTI) selectively inhibited both the oxytocic and the kininogenase activities of substance R but not those of urinary kallikrein. 6. Gel filtration of substance R resolved a single peak of oxytocic activity with an estimated molecular weight of 40 kDa. 7. We conclude that substance R is a kininogenase enzyme which may be distinguished from plasma kallikrein by its molecular weight and from urinary kallikrein by its susceptibility to SBTI. The exact nature of this enzyme remains to be elucidated.

Animals↗
PubMed1989

Metabolism of estrogens by rabbit blastocysts: formation of estrogen glucosides and preferential conversion of estrone to estradiol-17 beta.

When day 6 rabbit blastocysts were cultured (3 embryos/mL) in medium 199 containing 3.68 microM estradiol-17 beta (E2), 40% of E2 was metabolized in 24 h, at a rate of 18 pmol/embryo(b)/h, yielding 4 major metabolite fractions. Two of them were identified to be estrogen glucosides: 17 beta-hydroxyestra-1,3,5(10)-trien-3-yl beta-D-glucopyranoside (E(2)3G) (12 pmol/b/h) and 17-oxoestra-1,3,5(10)-trien-3-yl beta-D-glucopyranoside (E(1)3G) (0.5 pmol/b/h). If the blastocysts were cultured in 3.68 microM E1 medium, 75% of E1 was metabolized in 24 h (34.1 pmol/b/h); most of it appears as E2 (8 pmol/b/h), E(1)3G (16 pmol/b/h), and E(2)3G (6 pmol/b/h). Thus, the 17 beta-hydroxysteroid dehydrogenase activity in the rabbit blastocysts catalyzes mainly in the direction of the E1----E2 conversion, with little or no E2----E1. This may be responsible in part for the faster metabolism of E1 than E2 by the rabbit blastocyst. In comparison with the rat, mouse, and hamster blastocyst, the rabbit embryo shows an additional capability to conjugate large amounts of estrogens into glucosides by steroid glucosyltransferase.

17-Hydroxysteroid Dehydrogenases↗
PubMed1984

Endothelial-dependent relaxant effects of vaso-active intestinal polypeptide and arachidonic acid in rat aortic strips.

The relaxant actions of vaso-active intestinal polypeptide (VIP), acetylcholine (ACh), histamine and papaverine have been compared using circular muscle strips of rat aorta contracted with noradrenaline (NA). Arachidonic acid (AA) in a low dose (6.7 X 10(-7M) also relaxed the aorta. The relaxant actions of all these substances except papaverine were abolished by removal of the endothelial cells. Higher doses of AA (6.7-13.4 X 10(-6M) contracted aortic strips in the absence of NA but the con tractile effect "faded" while AA was still present in the bathing fluid. De-endothelialisation abolished this "fade" portion of the response leaving a sustained contracture. Indomethacin inhibited the contractile effect of AA revealing a weak inhibitory effect. However, it did not affect the relaxations induced by VIP, ACh, histamine or papaverine. ETYA abolished the relaxant actions of all these substances except papaverine. The results are consistent with the hypothesis that VIP, ACh and histamine relax the rat aorta via an endothelial-dependent mechanism which may involve the synthesis of a lipoxygenase product.

Acetylcholine↗
PubMed1983

Differences in the stability of prostacyclin in human, rabbit and rat plasma.

Prostacyclin (PGI2) is a potent vasodilator and inhibitor of platelet aggregation, however, its half-life in aqueous solutions at neutral or acid pH is very short. In this study we have investigated the stability of PGI2 in plasma from different species and have demonstrated that the half-life of the anti-aggregatory and the hypotensive activity of PGI2 is considerably prolonged in human plasma. Interestingly the activity of PGI2 was not maintained on incubation in rat or rabbit plasma indicating that the stabilising factor may be confined to human plasma. Whether such stabilisation prolongs the half-life of PGI2 in the human circulation merits investigation.

Adult↗
PubMed1983

Metabolism of 2-methoxyestrone in normal men.

We studied, in four normal men, the metabolism of 2-methoxyestrone (2-MeOE1) using pulse injections of either [3H]2MeOE1 (two men) or [14C]methoxy-2-MeOE1 plus [3H]2-MeOE1 (two men) by analysis of blood samples drawn at increasing time intervals after the pulse and of urine collected for 5 days. The disappearance from the blood of radioactivity as 2-MeOE1 could be characterized as a function that was the sum of three exponentials. The mean +/- SE value for the initial volume of distribution was 32 +/- 9 liters, and the mean MCR was 2470 +/- 770 liters/day. The disappearance of total 3H radioactivity from the blood was considerably slower, with a mean MCR of 290 +/- 30 liters/day, indicating the presence of a slowly turning over pool of 2-MeOE1 metabolites, probably including the 2-MeOE1 3-sulfate conjugate. The disappearance of total 14C radioactivity was slower than that of total 3H, indicating considerable demethylation of 2-MeOE1 with a very slow excretion of 14C from the released methyl group. In none of the subjects could we find in the blood radioactivity as unconjugated [3H]2-hydroxyestrone ( [3H]2-OHE1). However, examination of the urine indicated that considerable demethylation of [3H]2-MeOE1 had occurred. At least 64% of the urinary 3H-containing metabolites from the mixed dose had lost the 14C-bearing methoxylcarbon atom. The fractionated metabolites were qualitatively and quantitatively similar to those found earlier for [3H]2-OHE1. We conclude that 2-MeOE1, which of itself has little biological activity, can act as a pool of potentially active 2-OHE1 in the tissues.

Adult↗
PubMed1982

Synthesis of deuterium- and tritium-labelled 4-hydroxyandrostene-3,17-dione, an aromatase inhibitor, and its metabolism in vitro and in vivo in the rat.

The metabolism of the aromatase inhibitor-4-hydroxyandrostenedione (4-OHA) was studied in vitro and in vivo in the rat. To accomplish this, deuterium- and tritium-labeled 4-OHA were prepared from 4-hydroxyandrosta-4, 6-dione-3,17-dione. The latter was synthesized from 4-androstene-3,17-dione. Using deuterated 4-OHA in in vitro incubations of rat ovarian microsomes, 4-hydroxytesterone (4-OHT) was identified by gas chromatography/mass spectroscopy as the major metabolite. 4-OHT constituted approximately 20% of the total radioactivity from [6,7-3H]-4-OHA in the ovarian microsomal incubations. Conversion of [6,7-3H]-4-OHA to 4-hydroxyesterone was approximately 0.1%. The major metabolite of [6, 7-3H]-4-OHA in vivo identified in the free, neutral fraction of rat blood was 3 beta-hydroxyandrostane-4,17-dione. The metabolite accounted for approximately 5% of the total radio-activity in the blood, Whereas 4-OHT accounted for only 0.1%, 4-OHT inhibited in vitro ovarian aromatization by 59%, but 3 beta-hydroxyandrostane-4-17-dione had little effect. It was concluded that the in vivo effects of 4-OHA previously reported are largely due to its own activity although additional effects of its metabolic products cannot be excluded.

Androstenedione↗
PubMed1982

Relaxin inhibits prostacyclin release by the rat pregnant myometrium.

Porcine relaxin (30 microgram/ml) when incubated with separated myometrial tissue from 20 day pregnant rats inhibited basal prostacyclin output by 50%. However, relaxin did not inhibit the increased prostacyclin output observed when myometrial tissue was incubated with the prostaglandin precursor, arachidonic acid (10 microgram/ml). When prostacyclin release was stimulated by incubation with oxytocin (10 mU/ml), however, relaxin completely inhibited the increased output. The results suggest that relaxin interferes with basal and oxytocin-stimulated prostacyclin formation in pregnant myometrial tissue by inhibiting the action of the enzyme phospholipase A2 which is responsible for liberating the precursor arachidonic acid endogenously.

Adenosine Diphosphate↗
PubMed1982

Platelets from diabetic subjects show diminished sensitivity to prostacyclin.

Prostacyclin, an unstable metabolite of arachidonic acid metabolism, has been shown to have potent platelet antiaggregatory and vasodilator activity. Available evidence suggests that arterial prostacyclin production is diminished in the diabetic state. In this study we have examined the sensitivity of platelets from diabetic subjects to the antiaggregatory effects of prostacyclin in vitro and report that platelets from some diabetic patients show diminished sensitivity to the antiaggregatory effects of prostacyclin. Thus diabetic subjects may not only have diminished prostacyclin production but also their platelets may be less sensitive to its effects. These findings may help to explain the increase in vascular disease observed in diabetic patients.

Adenosine Diphosphate↗
PubMed1982

The effect of experimental diabetes on prostacyclin production by tissues from pregnant rats.

Prostacyclin (PGI2) the major product of arachidonic acid metabolism in blood vessels has potent platelet anti-aggregatory and vasodilator activities. Recently it has been shown that PGI2 production is depressed in arterial tissue from diabetic patients. We have studied the effect of experimental diabetes on PGI2 production in both arterial and myometrial tissue from pregnant rats to determine whether myometrial PI2 production is affected in a similar way to vascular synthesis. We confirm that vascular production of PGI2 is diminished in pregnant diabetic rats but this reduction appears to be related to the duration of diabetes. However no difference was seen in myometrial PGI2 production between diabetic and control pregnant rats. It therefore appears that the effect of the diabetic state on PGI2 synthesis in this study shows a degree of selectivity.

Animals↗
PubMed1981

Trapped blood elements within the decidua of the rat pregnant uterus generate a lipoxygenase product(s) which inhibits myometrial prostacyclin synthesis.

1 Prostacyclin (PGI(2)) production by chopped segments of rat pregnant uterus was low compared with synthesis by separated myometrial tissue. Incubation of separated myometrium with decidua (2:1 by weight) led to an inhibition of myometrial PGI(2) output.2 Boiling decidual tissue abolished the inhibitory influence on myometrial PGI(2) output. Preincubation of decidua with 5,8,11,14-eicosatetraynoic acid (ETA) (30 mug/ml) also suppressed decidual inhibitory activity but indomethacin (30 mug/ml) was ineffective.3 Incubation of decidual and myometrial tissue with arachidonic acid (AA) 10 mug/ml did not increase the inhibition of myometrial PGI(2) synthesis, even if the decidua were pre-incubated with indomethacin.4 Myometrial PGI(2) production was reduced if the chopped tissue was pre-incubated with soya bean lipoxidase for 10 min at 4 degrees C. This reduction was reversed if the lipoxidase was incubated with ETA (30 mug/ml) for 30 min at 37 degrees C before addition to the myometrial tissue.5 Perfusion of the uterus to remove blood elements removed the inhibitory action that the decidua exerted upon myometrial PGI(2) production. PGI(2) synthesis by separated decidual and whole uterine tissue was markedly elevated.6 The addition of rat blood platelets (0.75 x 10(9)/ml) to incubations of perfused decidual tissue reduced PGI(2) output and restored the inhibitory action that the decidua exerted on myometrial PGI(2) synthesis.7 It is concluded that a lipoxygenase enzyme contained in blood platelets trapped within the decidual vasculature produces a hydroperoxy acid which inhibits decidual PGI(2) production or myometrial PGI(2) synthesis when the tissues are incubated together. It is suggested that perfusion is a pre-requisite before study of PGI(2) synthesis in highly vascularised tissues.8 The pathophysiological importance of such platelet lipoxygenase products is discussed.

Animals↗
PubMed1981

Catechol estrogen formation by brain tissue: characterization of a direct product isolation assay for estrogen-2- and 4-hydroxylase activity and its application to studies of 2- and 4-hydroxyestradiol formation by rabbit hypothalamus.

A direct product isolation assay for quantifying the formation of 2- and 4-hydroxyestradiol (2-OHE2 and 4-OHE2) from [6,7-3H]estradiol by rabbit hypothalami in vitro was developed, and the assay was used to characterize some properties of estrogen-2- and 4-hydroxylase activity in this tissue. The reaction was carried out under conditions that minimized further metabolism of enzymatically formed catechol estrogens. A simple two-step separation procedure, involving the use of a neutral alumina column, followed by thin layer chromatography, was developed to isolate the enzymatically formed catechol estrogens in a radiochemically homogeneous form. The detergent, Tween-80, was found to activate the enzyme and was used routinely at a concentration of 0.1% in the assay. The formation of 2-OHE2 was linear up to 10 min and with increasing protein concentrations up to 150 micrograms/incubation. Similar values were obtained for 4-OHE2. Maximum velocities (Vmax) for the formation of 2- and 4-OHE2 were 190 and 270 pmol/mg protein . 10 min, respectively. The apparent Km values with respect to estradiol for 2-OHE2 and 4-OHE2 were 125 and 150 microM, respectively. The highest specific activity for the enzyme was present in the 100,000 X g supernatant (S3), while the activity in the microsomal fraction (P3) was less than that in the original homogenate. Enzyme activity depended on the presence of NADPH and oxygen and was inhibited by CO as well as by high concentrations of SKF-525A. Estrogen-2- and 4-hydroxylase activity in rabbit hypothalamus differed from that in rat liver in two respects. In the liver, enzyme activity was localized in the microsomal fraction and was virtually abolished by Tween-80. In contrast, enzyme activity in rabbit hypothalamus was maximal in the soluble fraction (100,000 X g supernatant)and was stimulated by the detergent.

Animals↗
PubMed1980

Effects of uterine stimulant drugs on prostacyclin production by the pregnant rat myometrium. I. Oxytocin, bradykinin and PGF2 alpha.

The release of prostacyclin from chopped myometrial fractions of 18-20 day pregnant rats was assayed by inhibition of ADP-induced aggregation of citrated rabbit platelet-rich plasma. Preincubation of myometrial tissue with oxytocin 10 mU/ml increased prostacyclin generation from 2.25 +/- 0.48 (control) to 3.75 +/- 0.73 ng/mg over 15 minutes. Bradykinin 20 microgram/ml also caused a significant increase in myometrial prostacyclin output from 2.26 +/- 0.19 to 4.26 +/- 0.64 ng/mg. PGF2 alpha 1 microgram/ml did not increase prostacyclin release significantly. Pretreatment of myometrial tissue with the phospholipase inhibitor mepacrine significantly reduced the peptide-stimulated release of prostacyclin. The results suggest that prostacyclin production may play an important role in modulating the actions of oxytocin and bradykinin in the pregnant rat myometrium.

Adenosine Diphosphate↗
PubMed1980

Prostacyclin formation by the pregnant human myometrium.

Human myometrium taken between 15 and 42 weeks of pregnancy released a material in vitro which possessed anti-aggregatory activity. This material parallelled authentic prostacyclin in this action; it possessed a similar stability at alkaline pH and generation of activity was inhibited by indomethacin. Production of the prostacyclin-like material by the myometrium was similar at weeks 15 and 38 of pregnancy but a 4-fold increase in synthesis had occurred by 40 weeks. It is suggested this increase may be important for parturition.

Adenosine Diphosphate↗
PubMed1980

Factors affecting prostacyclin formation by the rat pregnant myometrium.

1 The scraped myometrium of the pregnant uterus of the rat, when chopped and incubated, released an antiaggregatory material closely resembling prostacyclin (PGI2). The material was conclusively identified as PGI2 by identification of its hydrolysis product 6-oxo-prostaglandin F12 (6-oxo-PGF1 alpha) by gas chromatography-mass spectrometry (GC-MS). 2 Peak concentrations of PGI2 were detected after 15 min incubation of 20 degrees C. These concentrations were significantly higher than those detected at 37 degrees C, when largest amounts of prostacyclin were formed after 3 min incubation. The concentrations of 6-oxo-PGF1 alpha detected were similar at the different temperatures. 3 When samples were incubated at pH 8 and 20 degrees C, peak concentrations of prostacyclin were maintained between 15 and 35 min of incubation. When pH 7.4 was employed, prostacyclin concentration in the incubate fell to undetectable limits within this time. 4 Incubation of the chopped myometrium with arachidonic acid or phospholipase A2 stimulated prostacyclin production. 5 Preincubation of myometrial tissue for 10 min at 37 degrees C with inhibitory drugs before chopping reduced prostacyclin output. The doses needed to reduce PGI2 output by 50% (ID50) were: mepacrine (280 micrometer/ml), indomethacin (20 microgram/ml), 5,8,11,14 eicosatetraynoic acid (23 microgram/ml), 15-hydroperoxy arachidonic acid (23 microgram/ml) and tranylcypromine (225 microgram/ml). 6 It is suggested that due to the large amounts of material available, the rat pregnant myometrium is a useful model for the study of factors affecting prostacyclin synthesis.

Animals↗