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Biomedical subjects

Y Ko

Publications and source records attributed to Y Ko.

At least 19 recordsLinked to original sources
PubMed1996

CV-11974, the active metabolite of TCV-116 (Candesarten), inhibits the synergistic or additive effect of different growth factors on angiotensin II-induced proliferation of vascular smooth muscle cells.

Many previous studies have demonstrated that angiotensin II (AII) type I (ATI) receptor antagonists remarkably reduced intimal lesions in rats following balloon injury. Using vascular smooth muscle cells (VSMC) in culture, we tested the hypothesis that other classical growth factors may enhance AII effects on VSMC growth, and ATI receptor antagonists may inhibit these effects. AII, platelet-derived growth factor-BB (PDGF-BB), and epidermal growth factor (EGF) caused a 3426 +/- 262%, 277 +/- 69%, and 1568 +/- 62% increase in [3H]thymidine incorporation in VSMC (mean +/- SD, n = 3), respectively. The exposure of the cells to AII in combination with PDGF-BB or EGF resulted in an approximately 2-fold or 1.5-fold elevation of the AII-dependent effect, respectively. 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole-7- carboxylic acid (CV-11974), the active metabolite of the specific nonpeptide AT1 receptor antagonist (+/-)-1-cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimi dazole- 7-carboxylate (TCV-116, Candesartan), suppressed the effect of AII down to basal values, as well as reducing the synergistic effect of PDGF or the additive effect of EGF on AII-induced [3H]thymidine incorporation. AII and PDGF-BB per se induced 57 +/- 19 and 70 +/- 14% increase in VSMC number. Combination of both agonists resulted in a 2-fold increase of the AII effect on cell number. Again, CV-11974 blocked the effect of AII, as well as the additive effect of PDGF-BB on cell number. From these findings, it may be concluded that AT1 receptor antagonists may reduce or prevent the development of intimal lesions following vascular injury through inhibition of direct and indirect growth-promoting effects of AII in VSMC.

Angiotensin II↗
PubMed1996

[Swelling of the ears, chest pain, cough].

A 62-year-old male had tender swelling of both ears with loss of hearing due to edematous swelling of the external auditory canal. The patient complained further about dry cough, pain at the costo-sternal junctions, adynamia and weight loss. Inflammatory parameters were markedly elevated, and histologic work-up of an auricular biopsy revealed lymphocytic infiltration. These findings led to the diagnosis of chronic recurrent polychondritis actually under control after a pulse of glucocorticoids followed by maintenance therapy with 5 mg prednisone.

Chest Pain↗
PubMed1996

Regulation of angiotensin AT1 receptor gene expression during cell growth of vascular smooth muscle cells.

Cell proliferation influences the expression of numerous tissue-specific genes. The angiotensin AT1 receptor is highly expressed on vascular smooth muscle cells where it mediates cell contraction upon activation with angiotensin II. Since vascular smooth muscle cell de-differentiation leads to differential expression of several genes, we investigated the effects of cell growth on angiotensin AT1 receptor gene expression in vascular smooth muscle cells in culture. Northern hybridization analysis revealed a decrease of angiotensin AT1 receptor mRNA levels to approximately 20% in proliferating cells in comparison to growth-arrested cells. There is a correlative loss of membrane-associated angiotensin AT1 receptor protein in growing cells versus non-growing cells, as assessed by saturation radioligand binding assays. In addition, the BB-isoform of platelet-derived growth factor (PDGF-BB), which induces proliferation of quiescent vascular smooth muscle cells, causes a marked down-regulation of angiotensin AT1 receptor mRNA. These data suggest that proliferation of vascular smooth muscle cells leads to reduced angiotensin AT1 receptor gene expression. The mechanisms underlying this process and its physiological implications remain to be defined.

Animals↗
PubMed1995

Development of surrogate substrates for neuropathy target esterase.

Seventeen substrates were synthesized and their activities as surrogate substrates for Neuropathy Target Esterase were tested. Substrates investigated are carbon analogs of phenylvalerate (1) with oxygen and sulfur substituted at the alpha, beta and gamma positions. Phenol and thiophenol esters of these analogs constitute two series of compounds tested. The ratio of catalytic hydrolysis to background hydrolysis increased at lower pH values with all substrates tested including phenylvalerate (1). There was more than a 2.5-fold increase in specific activity with phenylthiopropylethanoate (6) at pH of 6.75 compared to phenylvalerate (1). Furthermore, a 19-fold decrease in Km is reported with compound 6. This and related compounds can be used as the basis of more sensitive assays for neuropathy target esterase. Thiophenyl esters in this series are sufficiently good substrates to hold promise in continuous assays.

Carboxylic Ester Hydrolases↗
PubMed1995

Effects of TCV-116 and CV-11974 on angiotensin II-induced responses in vascular smooth muscle cells.

(+/-)-1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116, Candesartan) and its active metabolite 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (CV-11974) are specific nonpeptide angiotensin AT1 receptor antagonists. In the present study, the inhibitory potency of these two antagonists on the angiotensin II-induced responses in aortic vascular smooth muscle cells from Wystar Kyoto rats was investigated. The specific binding of 125I-angiotensin II to cells was inhibited by CV-11974 and TCV-116 with a half-maximal inhibitory concentration (IC50) of 3 x 10(-11) M and 1 x 10(-9) M, respectively. CV-11974 and TCV-116 inhibited the angiotensin II-induced increase in [3H]thymidine incorporation with an IC50 of 3 x 10(-10) and 5 x 10(-9) M, respectively. Both CV-11974 and TCV-116 (10(-7) M) completely blocked the angiotensin II-induced increase in c-fos mRNA. The inhibitory potency of the metabolite CV-11974 was about 30-100-fold higher than that of the prodrug TCV-116.

Angiotensin II↗
PubMed1995

[Orthostatic hypotension].

We report about a 67-year-old woman presenting with progressive orthostatic vertigo, urinary incontinence and clinical signs of Parkinson's disease. The Schellong test revealed deficient sympathetic orthostatic pressure response without an increase of plasma norepinephrine; therefore, a Shy-Drager syndrome was diagnosed. Because of inefficiency of the general measures (compressive pantyhose), the sympathomimetic agonists, and the centrally active alpha-2-antagonists, norepinephrine was administered via a miniature dosing pump. By this therapeutic regimen a marked improvement of orthostatic hypotension was achieved.

Aged↗
PubMed1995

Effects of somatotropin on the conceptus, uterus, and ovary during maternal recognition of pregnancy in cattle.

Effects of recombinant bovine somatotropin (rbST) on ovarian and uterine function and the production of components of the insulin-like growth factor (IGF) system were examined during the period of maternal recognition of pregnancy in cattle. Lactating dairy cows were treated with 25 mg/d rbST (n = 8) or saline (n = 8) for 16 d after estrus. Ovaries, uteri, and conceptuses were collected on Day 17 after estrus. The length (millimeters) of the conceptus was recorded. The concentration of IGF-I and the content of IGF-binding proteins (BP) in uterine flushings were determined. Corpora lutea (CL) were weighed, and the number of follicles (> or = 2 mm in diameter) were counted. Follicular fluid from the largest and second-largest follicles was assayed for the concentration of IGF-I, IGFBP, progesterone, and estradiol. The length of the conceptus and the total amount of IGF-I in uterine fluid were similar for rbST and control. Recombinant bST increased 1) the weight of the CL, 2) the number of largest follicles (10 to 15 mm in diameter), 3) the concentration of IGF-I in the follicular fluid, 4) the follicular fluid content of IGFBP of the largest estrogenic follicle, and 5) the quantity of IGFBP in uterine flushings. The concentration of progesterone in the follicular fluid tended to be increased in rbST-treated cows, whereas the concentration of estradiol was similar to that of control cows. The concentration of progesterone in plasma was similar for rbST compared with control. In conclusion, the administration of rbST in lactating dairy cows for 16 d after estrus did not alter the growth of the conceptus collected on Day 17. The greatest responses to rbST were found within the ovary, where rbST increased the weight of the CL and altered the amount of IGF-I and IGFBP in the follicular fluid.

Animals↗
PubMed1995

Reverse transcriptase-polymerase chain reaction (RT-PCR): a sensitive method to examine basic fibroblast growth factor-induced expression of the early growth response gene-1 (egr-1) in human umbilical arterial endothelial cells.

Immediate-early genes are expressed upon growth and differentiation in a large variety of cells and species. In the present study we investigated the effect of basic fibroblast growth factor (bFGF) on early growth response gene-1 (egr-1)-mRNA expression in human umbilical arterial endothelial cells (HUAEC). The detection of this gene in HUAEC was performed by Northern blotting and by reverse transcriptase-polymerase chain reaction (RT-PCR). For RT-PCR specific primers for egr-1 and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) were constructed and PCR conditions were optimized. bFGF induced a time- and concentration-dependent increase of egr-1 expression. Maximal expression occurred within 30 min of stimulation with bFGF at a concentration of 50-100 ng ml-1. RT-PCR gave highly reproducible and specific results. The comparison of both methods showed comparable results but a higher sensitivity for RT-PCR in detecting the egr-1 mRNA. RT-PCR is an excellent method for detecting the expression of egr-1 mRNA in HUAEC.

Base Sequence↗
PubMed1995

Kinetics of Na+/H+ exchange in vascular smooth muscle cells from WKY and SHR: effects of phorbol ester.

The kinetic properties of Na+/H+ exchange were investigated in vascular smooth muscle cells (VSMC) in culture from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Antiport activity was measured in 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein-loaded cells after nigericin-induced cytosolic acidification. Studies were performed without (control) and with pretreatment of the cells with phorbol 12-myristate 13-acetate (PMA; 200 nM). Na+/H+ exchange markedly differed between the two strains with lower Hill coefficients [1.56 +/- 0.17 (SE) vs. 2.62 +/- 0.36] and higher maximal activity (Vmax) values (55.85 +/- 5.24 vs. 31.11 +/- 2.38 mmol H+.l-1.min-1) in SHR compared with WKY cell lines. PMA markedly altered the antiport kinetics in WKY VSMC with a decrease in the Hill coefficient (1.75 +/- 0.14) without affecting Vmax (31.88 +/- 1.55 mmol H+.l-1.min-1). In VSMC from SHR, PMA had no effect on the kinetic variables investigated. Thus two kinetic abnormalities are present with respect to Na+/H+ antiport activity in VSMC from SHR compared with WKY, i.e., increased Vmax and decreased Hill coefficient. The observation that PMA does not affect the kinetics of the Na+/H+ antiport in VSMC from SHR suggests a marked degree of antiporter prestimulation in this animal model of genetic hypertension.

Animals↗
PubMed1995

Thromboxane A2 and vascular smooth muscle cell proliferation.

In the present study we describe the intracellular pathways for the transmission of growth signals by the potent vasoconstricting eicosanoids prostaglandin H2 and thromboxane A2 in smooth muscle cells from rat aorta. Carbocyclic thromboxane A2 and U46619 are stable thromboxane A2 mimetics acting at the common thromboxane A2/prostaglandin H2 receptor. Carbocyclic thromboxane A2 (10(-6) mol/L) induced an approximately 2.5-fold increase in [Ca2+]i above the basal value at 25 seconds. Maximal stimulation of the 42-kD mitogen-activated protein kinase isoform by both thromboxane A2 mimetics occurred at 5 minutes. Both thromboxane A2 mimetics at a concentration of 10(-6) mol/L induced the expression of c-fos and early growth response gene-1 (egr-1) mRNA, with a maximum at 30 minutes. Carbocyclic thromboxane A2 (10(-6) mol/L) induced a 3.3-fold increase in [3H]thymidine incorporation into cell DNA above the basal value and produced a 3.5-fold elevation of platelet-derived growth factor-BB-dependent [3H]thymidine incorporation into cell DNA. Similar effects of U46619 (10(-6) to 10(-5) mol/L) alone did in combination with platelet-derived growth factor-BB on cell DNA synthesis were obtained. The thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 (10(-6) mol/L) completely suppressed the mitogenic effect of both thromboxane A2 mimetics (10(-6) mol/L). Pertussis toxin (10 to 100 ng/mL) did not influence the mitogenic effects of the thromboxane A2 mimetics. Carbocyclic thromboxane A2 (10(-6) mol/L) and platelet-derived growth factor-BB (20 ng/mL) per ser caused a 44% and 100% increase in cell number, respectively. In the presence of carbocyclic thromboxane A2 (10(-6) mol/L), platelet-derived growth factor-BB induced a 152% increase in cell number. Similar results were obtained with U46619 alone or in combination with platelet-derived growth factor-BB.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Native low-density lipoprotein (LDL) induces the expression of the early growth response gene-1 in human umbilical arterial endothelial cells.

Low-density lipoprotein (LDL) is thought to be involved in the growth of various cell types including human endothelial cells. Nevertheless, little is known about the signal transduction mechanisms underlying the growth-promoting effects of LDL in endothelial cells. Furthermore, the question whether native LDL participates in the described effects remains unanswered. Here, we show that native LDL induces a dose-dependent elevation in free intracellular Ca(2+)-concentration ([Ca2+]i) as well as a rapid and prolonged increase in intracellular pH (pHi) in human umbilical arterial endothelial cells (HUAEC). Native LDL induces a dose-dependent increase of early growth response gene-1 (egr-1) mRNA expression. The effect is maximal 30 min after addition of LDL to the culture medium. Moreover, native LDL causes an increase in DNA-synthesis and cell proliferation. In addition, the effect of acidic fibroblast growth factor (aFGF) on HUAEC proliferation was enhanced by native LDL.

Calcium↗
PubMed1994

[Headache].

This 46 year old man complained for the first time five years ago about stinging bilateral occipital headache while in prone or horizontal position and disappearing completely in the supine position after a few minutes. Two years ago hypertension with values up to 240/140 mmHg was discovered on a routine examination. For the past six months the patient complained about sudden attacks with headache, hammering pulse, nausea, pallor, sweating and blood pressure values of 200/100 mmHg. A pheochromocytoma measuring 7 x 8 cm was diagnosed on the left side and removed subsequently.

Adrenal Gland Neoplasms↗
PubMed1994

Transient expression of the cytochrome P450 aromatase gene in elongating porcine blastocysts is correlated with uterine insulin-like growth factor levels during peri-implantation development.

The insulin-like growth factors (IGFs-I and -II) are mediators of cellular growth and differentiation. The expression of these growth factor genes is temporally and hormonally regulated in the uterus during pregnancy, suggesting potentially important roles in embryonic development, implantation, and successful progression of pregnancy. A known regulator of uterine IGF-I secretion is estrogen, which is produced by pre-implantation mammalian embryos of several species and whose amounts may be influenced by growth factors via their effects on the transcriptional activities of steroidogenic enzyme genes. We have previously proposed that within the uterine microenvironment, a positive feedback loop may link uterine secretion of IGFs with embryonic production of estrogens to maintain and coordinate the timing of biological signals essential for embryo development. The present study examined the temporal relationships between the levels of conceptus cytochrome P450 aromatase mRNA and protein and concentrations of IGF-I and -II in uterine luminal fluids of pigs. A DNA fragment encoding a highly conserved region among mammalian aromatase P450 proteins was isolated by hybridization screening of a porcine genomic DNA library with a human aromatase P450 cDNA fragment as probe. A synthetic oligopeptide DDVIDGYPVKKGTNI within this highly conserved region was used to generate an antiserum in sheep that recognized a protein of M(r) 49,000 in Western blot analysis of porcine ovarian, placental, endometrial, and conceptus extracts. A radioimmunoassay (RIA) for aromatase P450 was established and validated using this antiserum. RIA demonstrated highest levels of aromatase P450 protein in extracts of days 10, 11, and 12 porcine conceptuses with significantly diminished levels in elongated conceptuses at days 15 and 18. In the conceptus, aromatase P450 was localized to the inner cell layer (hypoblast) of the trophectoderm. A major mRNA transcript of approximately 3 kb in length was demonstrated by Northern blot analysis of conceptus RNA with a porcine aromatase P450 antisense RNA probe. The relative levels of aromatase P450 mRNA were higher in conceptuses at day 12 than at days 15 and 18, in parallel with the levels of aromatase P450 protein. RIA of uterine luminal fluids demonstrated maximal concentrations of IGF-I at day 12, which were significantly decreased by day 15, and increased concentrations of IGF-II by day 12, which were maintained until day 18 of pregnancy. These results demonstrate that the transient expression of conceptus aromatase P450 mRNA and protein in elongating pig blastocysts is coincident with their capacity to secrete estrogens and with the rapidly changing concentrations of IGFs within the uterine microenvironment.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

Evidence for cardiovascular remodeling in a patient with Bartter's syndrome.

In a 56-year-old normotensive white male subject with a 12-year history of hypokalemic alkalosis, hyperreninemia, and aldosteronism, the diagnosis of Bartter's syndrome was established on the basis of an impaired maximal renal diluting capacity and decreased distal fractional chloride absorption [CH2O/(CH2O+CCl)]. Negative urine analysis for diuretics suggested that this renal tubular defect was not secondary to diuretic (ab)use. In this normotensive patient with hyperreninemia and secondary aldosteronism, significant cardiovascular remodeling could be observed. Thus, in spite of normal arterial blood pressure and normal left ventricular systolic function (ejection fraction > 70%), impaired left ventricular diastolic function was observed using pulsed-wave Doppler echocardiography. Moreover, duplex analysis of the common carotid artery revealed significant intima-media hypertrophy with an average intima-media diameter of 0.9 mm (normal < or = 0.6 mm). Also, forearm venous occlusion plethysmography revealed an abnormally high minimal forearm vascular resistance following a 10-min period of forearm ischemia handgrip exercise suggesting remodeling within the peripheral arterioles. Thus, in a patient with Bartter's syndrome and activated neurohormonal systems such as the renin-angiotensin system, cardiac and vascular remodeling can be observed in the absence of hypertension. In analogy to the results of experimental studies showing that angiotensin II and noradrenaline act as growth factors on cardiac and vascular cells, cardiovascular remodeling present in our patient with Bartter's syndrome may be explained by increased activity of angiotensin II and/or noradrenaline.

Arteries↗
PubMed1994

Iron-deficiency anemia as the sole manifestation of celiac disease.

We report on a 40-year-old woman with a 2-year history of iron-deficiency anemia of unknown origin. Repeated endoscopic investigations in the past had revealed no abnormality of the gastrointestinal system on macroscopic examination. Oral iron supplementation was shown to have no effect on serum iron levels and had no influence on the anemia. Upper gastrointestinal endoscopy performed at our hospital confirmed normal macroscopic findings. However, jejunal biopsies revealed subtotal villous atrophy of the mucosa of the small intestine. A strict gluten-free diet led to an increase in serum iron, resolution of the anemia, and restitution of normal mucosal architecture. Thus iron-deficiency anemia may be the lone manifestation of celiac disease.

Adult↗
PubMed1994

Oxymetazoline enhances epidermal- and platelet-derived growth factor-induced DNA synthesis.

In the present study, the effect of 10(-9) to 10(-6) M epinephrine (alpha- and beta-agonist), norepinephrine (alpha- and beta 1-antagonist) isoproterenol (beta-agonist) salbutamol (beta 2-agonist), phenylephrine (alpha 1-agonist) and oxymetazoline (mainly alpha 2-agonist) on DNA synthesis in vascular smooth muscle cells (VSMCs) from rat aorta has been investigated. Our results show that only oxymetazoline induced a moderate dose-dependent elevation of [3H]thymidine incorporation into cell DNA (10(-6) M, 100-300%). Epidermal growth factor (EGF) (50 ng/ml) and platelet-derived growth factor (PDGF)-BB induced an elevation of the [3H]thymidine incorporation into cell DNA from 154 +/- 7 (basal value) to 1270 +/- 95 and 1552 +/- 178 cpm/microgram protein (mean +/- S.D., n = 3). Oxymetazoline (10(-6) M) and phenylephrine induced an increase of [3H]thymidine incorporation to 368 +/- 53 and 205 +/- 27 cpm/microgram protein, respectively. In contrast to phenylephrine, oxymetazoline caused an elevation of the PDGF-BB- and EGF-induced [3H]thymidine incorporation to 1561 +/- 143 and 2086 +/- 235 (means S.D., n = 3), respectively. In addition, EGF (1 to 50 ng/ml) induced a dose-dependent increase of [3H]thymidine incorporation from 154 +/- 7 (basal value) to 486 +/- 35 (1 ng/ml), 912 +/- 74 (5 ng/ml), 1019 +/- 40 (25 ng/ml) and 1270 +/- 95 (50 ng/ml) cpm/microgram protein (mean +/- S.D.). In the presence of 10(-6) M oxymetazoline, 1, 5, 25 and 50 ng/ml EGF caused an increase of [3H]thymidine incorporation to 633 +/- 101, 1124 +/- 87, 1231 +/- 101, and 1561 +/- 89 cpm/microgram protein (mean +/- S.D.).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Agonists↗