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Biomedical subjects

Z W Yang

Publications and source records attributed to Z W Yang.

At least 19 recordsLinked to original sources
PubMed2004

Testicular phenotype in luteinizing hormone receptor knockout animals and the effect of testosterone replacement therapy.

The LH receptor knockout model, developed in our laboratory, was used in determining what FSH alone can do in the absence of LH signaling and whether any of the testicular LH actions are not mediated by androgens. The results revealed that null animals contained smaller seminiferous tubules, which contained the same number of Sertoli cells, spermatogonia, and early spermatocytes as wild-type siblings. The number of late spermatocytes, on the other hand, was moderately decreased, the number of round spermatids was dramatically decreased, and elongated spermatids were completely absent. These changes appear to be due to an increase in apoptosis in spermatocytes. While the number of Leydig cells progressively increased from birth to 60 days of age in wild-type animals, they remained unchanged in null animals. Consequently, 60-day-old null animals contained only a few Leydig cells of fetal type. The age-dependent increase in testicular macrophages lagged behind in null animals compared with wild-type siblings. Orchidopexy indicated that -/- testicular phenotype was not due to abdominal location. Rather, it was mostly due to androgen deficiency, as 21-day testosterone replacement therapy stimulated the growth of seminiferous tubules, decreased apoptosis, and increased the number of late spermatocytes and round spermatids and their subsequent differentiation into mature sperm. The therapy, however, failed to restore adult-type Leydig cells and testicular macrophage numbers to the wild-type levels. In summary, our data support the concept that FSH signaling alone can maintain the proliferation and development of Sertoli cells, spermatogonia, and early spermatocytes. LH actions mediated by testosterone are required for completion of spermatogenesis, and finally, androgen-independent actions of LH are required for the formation of adult-type Leydig cells and recruitment of macrophages into the testes.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

A stereological study of the effects of experimental inguinal cryptorchidism and subsequent orchiopexy on spermatogenesis in adult monkeys.

Our previous study demonstrated that experimental intra-abdominal cryptorchidism in adult rabbits for 13 weeks resulted in severe spermatogenic arrest: type A spermatogonia was the only germ cell type seen in the seminiferous epithelium and its number per testis was reduced by 84%. Seven weeks following orchiopexy, the type A spermatogonial number returned to the near-normal range in most animals and spermatogenesis partially recovered (Reproduction 2002, 124, 95-105). This study aimed to determine whether inguinal cryptorchidism would produce less-severe damage to spermatogenesis and whether subsequent orchiopexy would better restore spermatogenesis. Five normal adult male rhesus monkeys (Macaca mulatta) underwent bilateral artificial inguinal cryptorchidism. Half a year later, one testis together with the ipsilateral epididymis were removed from each animal and then unilateral orchiopexy was performed on the contralateral side, with the remaining testis and epididymis being removed another half a year later. A contemporary unbiased and efficient stereological tool, the optical disector, was used to estimate numbers of all types of spermatogenic cells in the testis and spermatozoa in the epididymis. Spermatogenic arrest was induced by cryptorchidism at the stage of spermatogonia (n = 1), spermatocytes (n = 2) or early spermatids (n = 1), with the type A spermatogonial numbers per testis being reduced to 14.8-57.2% of the control average; in one of the five cryptorchid animals, however, spermatogenesis remained normal. Subsequent orchiopexy, which was successfully performed on two animals with cryptorchidism-induced spermatogenic arrest, brought on a full or partial recovery of spermatogenesis. In conclusion, inguinal cryptorchidism induces less severe (in comparison with an intra-abdominal one) and variable damage to spermatogenesis, which is restored, at least in part, by subsequent orchiopexy.

Animals↗
PubMed2002

A quantitative (stereological) study of the effects of experimental unilateral cryptorchidism and subsequent orchiopexy on spermatogenesis in adult rabbit testis.

The aim of this study was to examine the controversial effects of experimental unilateral cryptorchidism and subsequent orchiopexy on the number of germ cells and other morphometric characteristics of testicular and epididymal structures in adult rabbits. Unilateral cryptorchidism was induced in 11 mature male New Zealand white rabbits by returning one testis, together with the ipsilateral epididymis, to the abdominal cavity via a surgical procedure. After 3 months, testes and epididymides were removed from six animals (and from six age-matched control animals that did not undergo the surgery). Orchiopexy was performed on the five remaining animals and the testes and epididymides of these animals (and an additional six age-matched control animals) were removed 7 weeks later. A contemporary, unbiased and efficient stereological tool, the optical disector, was used to estimate the number of nuclei in the testis and epididymis using methacrylate-embedded sections of 25 micron in thickness. Cryptorchidism resulted in severe testicular atrophy and spermatogenic arrest: type A spermatogonia and Sertoli cells only were seen in the seminiferous epithelium, and the number of type A spermatogonia per testis was reduced by 84%. After orchiopexy, the testis remained atrophied and the number of type A spermatogonia returned to the near-normal range in four of five animals, but spermatogenesis was recovered only partially at the stage of early primary spermatocytes (one animal), late primary spermatocytes (two animals) or spermatids (one animal). In conclusion, cryptorchidism caused severe spermatogenic arrest that was potentially recoverable (in view of the restoration of the number of type A spermatogonia), but orchiopexy failed to induce full recovery of spermatogenesis.

Animals↗
PubMed2002

Quantitative (stereological) study of the effects of vasectomy on spermatogenesis in rhesus monkeys (Macaca mulatta).

Vasectomy reversal by vasovasostomy after long-term vasectomy in men results in lower sperm counts and pregnancy rates compared with controls, and severe damage to spermatogenesis has been observed in some animal models such as mice. The primary aim of this study was to evaluate, using sophisticated stereological methods, whether vasectomy of 6 and 12 months in a non-human primate would lead to, among other morphometric changes, reduced numbers of germ cells in testes and spermatozoa in epididymides. Five normal adult male rhesus monkeys (Macaca mulatta) underwent bilateral vasectomy, with another three aged-matched normal monkeys not undergoing vasectomy. One testis together with the ipsilateral epididymis was removed from each animal at 6 months, and the other testis and epididymis, the prostate gland and seminal vesicles were removed at 12 months. Various morphometric data were obtained using stereological methods and an unbiased and efficient stereological tool, the optical disector, was used to estimate nuclear numbers of all types of spermatogenic cells in testes and spermatozoa in epididymides using methacrylate-embedded sections 25 microm in thickness. As shown by a two-way repeated measures analysis of variance, vasectomy or hemicastration (removal of the organs at 6 months) had no significant effects on all quantitative parameters of stereology obtained from the testis, epididymis, prostate gland and seminal vesicle, except that (i) sperm granuloma was observed from three of five vasectomized animals both at 6 and 12 months, and (ii) hemicastration significantly reduced the diameter of the seminiferous tubules and increased the number of type A spermatogonia per testis. In conclusion, vasectomy in the non-human primate is a safe procedure in terms of effects on the structures of the reproductive organs.

Animals↗
PubMed2001

Comparison of blood counts in venous, fingertip and arterial blood and their measurement variation.

We compared routine blood pictures in venous, fingertip and arterial blood and their measurement variation. A pair of venous and fingertip blood samples were simultaneously collected from 24 volunteers, and another pair of venous and arterial samples from another 12 volunteers. The volunteers were healthy adults, aged 20-22 years, with males and females in equal numbers. Three aliquots of blood were taken from each person for three measurements of blood counts, including haemoglobin concentration and haematocrit, using an automatic haematology analyser. Compared to arterial blood, there was a significant increase of erythrocyte count (2.7%) and haematocrit (3.1%) in the venous blood. The total and large leucocyte counts were significantly higher (9.2% and 12.6%, respectively) in the fingertip blood than in the venous blood. There were a decreasing number of leucocytes in the fingertip blood with repeated sampling. The intermeasurement variation for total leucocyte or haemoglobin measurement was significantly larger as measured with the fingertip blood or arterial blood than with the venous blood. The intermeasurement coefficients of variation of haemoglobin (1.3%) and small leucocyte ratio or platelet (approximately 4.0%) measurements with venous and arterial blood were the smallest and largest, respectively. Volume of arterial plasma was diminished by 2-3% after microcirculation. Elevation of total leucocyte count in the fingertip blood was mainly due to the increase of granulocytes. Measurement with venous blood was of better precision than with fingertip or arterial blood.

Adult↗
PubMed2001

Importance of PKC and PI3Ks in ethanol-induced contraction of cerebral arterial smooth muscle.

We investigated the relationships of two potential intracellular signaling pathways, protein kinase C (PKC) and phosphatidylinositol 3-kinases (PI3Ks), to ethanol-induced contractions in cerebral arteries. Ethanol (20-200 mM) induces concentration-dependent constriction in isolated canine basilar arteries that is inhibited in a concentration-dependent manner by pretreatment of these vessels with 10(-9)-10(-3) M Gö-6976 (an antagonist selective for PKC-alpha and PKC-betaI), 10(-10)-10(-4) M bisindolylmaleimide I (a specific antagonist of PKC), and 10(-10)-10(-4) M wortmannin or 10(-8)-10(-2) M LY-294002 (selective antagonists of PI3Ks). Ethanol-induced increases in intracellular Ca(2+) concentration (from approximately 100 to approximately 500 nM) in canine basilar smooth muscle cells are also suppressed markedly (approximately 20-70%) in the presence of a similar concentration range of Gö-6976, bisindolymaleimide I, wortmannin, or LY-294002. This study suggests that activation of PKC isoforms and PI3Ks appears to be an important signaling pathway in ethanol-induced vasoconstriction of cerebral blood vessels.

Androstadienes↗
PubMed2001

Ethanol-induced contractions in cerebral arteries: role of tyrosine and mitogen-activated protein kinases.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and stroke appears complex; moderate ingestion is associated with reduced stroke risk, while heavy intake is associated with increased stroke risk. Ethanol has been shown both experimentally and epidemiologically to induce hemorrhagic and ischemic strokes, which are associated with cerebral vasoconstriction. Ethanol is known to induce contraction in isolated cerebral arteries and intact microvessels from diverse mammalian animals. The relationships between ethanol-induced contractions in cerebral arteries, intracellular free Ca(2+) ([Ca(2+)](i)), tyrosine kinases (including the src family), and mitogen-activated protein kinases (MAPK) were investigated in the present study. METHODS: Cerebral arterial muscle tension and [Ca(2+)](i) were quantified by an isometric contraction technique and direct visualization of Ca(2+) in single cells. RESULTS: Ethanol induces concentration-dependent contractions in intact canine basilar arteries, which are attenuated significantly by pretreatment of the arteries with low concentrations of an antagonist of protein tyrosine kinases (genistein); an src homology 2 (SH2) domain inhibitor peptide; a highly specific antagonist of p38 MAPK (SB-203580); a potent, selective antagonist of MEK1/MEK2 (U0126); and a selective antagonist of mitogen-activated protein kinase kinase (MAPKK) (PD-98059). IC(50) levels obtained for these 5 antagonists are consistent with reported K:(i) values for these tyrosine kinase, MAPK, and MAPKK antagonists. Ethanol induces transient and sustained increases in [Ca(2+)](i) in primary single smooth muscle cells from canine basilar arteries, which are markedly attenuated in the presence of genistein, an SH2 domain inhibitor peptide, SB-203580, U0126, and PD-98059. Several specific antagonists of known endogenously formed vasoconstrictors do not inhibit or attenuate either the ethanol-induced contractions or the elevation of [Ca(2+)](i). CONCLUSIONS: The present study suggests that activation of protein tyrosine kinases (including the src family) and MAPK appear to play important roles in the ethanol-induced contractions and the elevation of [Ca(2+)](i) in smooth muscle cells from canine basilar arteries. The results could be used to suggest that selective antagonists of protein tyrosine kinases and MAPK may be useful both prophylactically and therapeutically in alcohol-induced strokes.

Animals↗
PubMed2000

Low [Mg(2+)](o) induces contraction of cerebral arteries: roles of tyrosine and mitogen-activated protein kinases.

The present study was designed to investigate the mechanism of action of low extracellular magnesium ion concentration ([Mg(2+)](o)) on isolated canine basilar arteries and single cerebral vascular smooth muscle cells from these arteries. Low-[Mg(2+)](o) medium (0-0.6 mM) produces endothelium-independent contractions in isolated canine basilar arteries in a concentration-dependent manner; the lower the concentration of [Mg(2+)](o), the stronger the contractions. The low-[Mg(2+)](o) medium-induced contractions are significantly attenuated by pretreatment of the arteries with low concentrations of either SB-203580, U-0126, PD-98059, genistein, or an Src homology 2 (SH2) domain inhibitor peptide. IC(50) levels obtained for these five antagonists are consistent with reported inhibitor constant (K(i)) values for these tyrosine kinase and mitogen-activated protein kinase (MAPK) antagonists. Low-[Mg(2+)](o) medium (0-0.6 mM) produces transient intracellular calcium ion concentration ([Ca(2+)](i)) peaks followed by a slow, sustained, and elevated plateau of [Ca(2+)](i) in primary single smooth muscle cells from canine basilar arteries. Low-[Mg(2+)](o) medium induces rapid and stable increases in [Ca(2+)](i); these increases are inhibited markedly in the presence of either SB-203580, U-0126, PD-98059, genistein or a SH2 domain inhibitor peptide. Several specific antagonists of known endogenously formed vasoconstrictors do not inhibit or attenuate either the low-[Mg(2+)](o)-induced contractions or the elevation of [Ca(2+)](i). The present study suggests that activation of several cellular signaling pathways, such as protein tyrosine kinases (including the Src family) and MAPK, appears to play important roles in low-[Mg(2+)](o)-induced contractions and the elevation of [Ca(2+)](i) in smooth muscle cells from canine basilar arteries.

Animals↗
PubMed2000

Low [Mg(2+)](o) induces contraction and [Ca(2+)](i) rises in cerebral arteries: roles of ca(2+), PKC, and PI3.

Removal of extracellular Ca(2+) concentration ([Ca(2+)](o)) and pretreatment of canine basilar arterial rings with either an antagonist of voltage-gated Ca(2+) channels (verapamil), a selective antagonist of the sarcoplasmic reticulum Ca(2+) pump [thapsigargin (TSG)], caffeine plus a specific antagonist of ryanodine-sensitive Ca(2+) release (ryanodine), or a D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)]- mediated Ca(2+) release antagonist (heparin) markedly attenuates low extracellular Mg(2+) concentration ([Mg(2+)](o))-induced contractions. Low [Mg(2+)](o)-induced contractions are significantly inhibited by pretreatment of the vessels with Gö-6976 [a protein kinase C-alpha (PKC-alpha)- and PKC-betaI-selective antagonist], bisindolylmaleimide I (Bis, a specific antagonist of PKC), and wortmannin or LY-294002 [selective antagonists of phosphatidylinositol-3 kinases (PI3Ks)]. These antagonists were also found to relax arterial contractions induced by low [Mg(2+)](o) in a concentration-dependent manner. The absence of [Ca(2+)](o) and preincubation of the cells with verapamil, TSG, heparin, or caffeine plus ryanodine markedly attenuates the transient and sustained elevations in the intracellular Ca(2+) concentration ([Ca(2+)](i)) induced by low-[Mg(2+)](o) medium. Low [Mg(2+)](o)-produced increases in [Ca(2+)](i) are also suppressed markedly in the presence of Gö-6976, Bis, wortmannin, or LY-294002. The present study suggests that both Ca(2+) influx through voltage-gated Ca(2+) channels and Ca(2+) release from intracellular stores [both Ins(1,4,5)P(3) sensitive and ryanodine sensitive] play important roles in low-[Mg(2+)](o) medium-induced contractions of isolated canine basilar arteries. Such contractions are clearly associated with activation of PKC isoforms and PI3Ks.

Androstadienes↗
PubMed2000

Mg(2+)-induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO.

In vitro extracellular Mg(2+) concentration ([Mg(2+)](0)) produces endothelium-dependent and endothelium-independent relaxations in rat aorta in a concentration-dependent manner. These relaxant effects of Mg(2+) on intact rat aortic rings, but not denuded rat aortic rings, were suppressed by either N(G)-monomethyl-L-arginine (L-NMMA), N(omega)-nitro-L-arginine methyl ester (L-NAME), or methylene blue. The inhibitory effects of L-NMMA and L-NAME could be reversed partly by L-arginine. [Mg(2+)](0)-induced dilatation in vivo in rat mesenteric arterioles and venules was almost completely inhibited by N(G)-nitro-L-arginine and L-NMMA. Removal of extracellular Ca(2+) concentration ([Ca(2+)](0)) or buffering intracellular Ca(2+) concentration in endothelial cells, with 10 microM 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM, markedly attenuated the relaxant effects of Mg(2+). Mg(2+) produced nitric oxide (NO) release from the intact aortic rings in a concentration-dependent manner. Removal of [Ca(2+)](0) diminished the increased NO release induced by elevated levels of [Mg(2+)](0). In vivo infusion of increasing doses (1-30 microM/min) of MgSO(4), directly into the femoral veins of anesthetized rats, elicited significant concentration-dependent sustained increases in serum total Mg and concomitant decreases in arterial blood pressure. Before and after employment of various doses of MgSO(4), intravenous administration of either L-NMMA (10 mg/kg) or L-NAME (10 mg/kg) increased (i.e., reversed) the MgSO(4)-lowered blood pressure markedly, and intravenous injection of L-arginine restored partially the increased blood pressure effects of both L-NMMA and L-NAME. Our results suggest that 1) small blood vessels are very dependent on NO release for Mg(2+) dilatations and 2) the endothelium-dependent relaxation induced by extracellular Mg(2+) is mediated by release of endothelium-derived relaxing factor-NO from the endothelium, and requires Ca(2+) and formation of guanosine 3',5'-cyclic monophosphate.

Animals↗
PubMed2000

Reversible effect of testosterone undecanoate injection on spermatogenesis in rats.

AIM: To study the effect of testosterone undecanoate (TU) injection on spermatogenesis in rats. METHODS: Twenty adult SD rats received vehicle or TU (8 mg/kg, 19 mg/kg or 625 mg/kg) injection, im, every 15 days for 60 days, and another 38 animals received similar treatments for 130 days with half of them undergoing a recovery phase of 120 days (5 rats for each treatment). At the end of the treatment, testes were removed and the diameter of the seminiferous tubules and the number of late elongated spermatids (steps 15-19) per testis were estimated with stereological methods as a measure of the spermatogenic efficiency. RESULTS: Low dose (8 mg/kg) TU treatment virtually had no effect on spermatogenesis. A dose of 19 mg/kg slightly suppressed spermatogenesis 60 days after treatment, and severe suppression occurred after another 70 days of dosing. Spermatogenesis was completely recovered at the end of the recovery phase. Large dose (625 mg/kg) TU treatment did not significantly affect spermatogenesis and was well tolerated by animals. CONCLUSION: TU injection reversibly suppresses spermatogenesis in rats.

Animals↗
PubMed2000

Quantitative (stereological) study on the spermatozoal storage capacity of epididymis in rats and monkeys.

AIM: To investigate the spermatozoal production rate of the testis and the spermatozoal storage capacity of the epididymis in monkeys and rats. METHODS: The number of the late spermatids (steps 13-14 in the monkey or steps 15-19 in the rat) per testis and the number of spermatozoa per epididymis were estimated in 6 normal adult monkeys (Macaca fascicularis) and 6 normal adult SD rats on 25 microns-thick methacrylate-embedded sections using a contemporary unbiased and efficient stereological method--the optical disector. The diameter and length of the efferent ductules and ductus epididymidis and the volume of the epididymal fluid in the tubules were also estimated. RESULTS: The total number of the late spermatids per testis was 2902 +/- 749 (million, x +/- s) in the monkey, or 179 +/- 31 in the rat; the number of spermatozoa per epididymis was 3235 +/- 1835 in the monkey, or 241 +/- 76 in the rat. CONCLUSION: A large number of spermatozoa was densely packed and stored in the ductus epididymidis; the epididymal transit time for spermatozoa was around 5 days in monkeys or 11 days in rats.

Animals↗
PubMed1999

Low extracellular Mg2+ contraction of arterial muscle: role of protein kinase C and protein tyrosine phosphorylation.

The effects of extracellular Mg2+ ion ([Mg2+]0) deficiency on basal tension of isolated rat aortae and rat aortic smooth muscle cell Ca2+ metabolism were investigated in the present study. The contractions of rat aortae induced by diverse concentrations of low [Mg2+]0 were potentiated, greatly, by removal of the endothelium or pre-incubation of intact rat aortic rings with L-N(G)-monomethyl-arginine (L-NMMA). [Mg2+]0 deficiency-induced contractions were inhibited, to different degrees, by pre-treatment of the vessels with low concentrations of Gö6976, bisindolymaleimide I, genistein or a combination of bisindolymaleimide I with genistein. IC50 levels found for these three agents were found to be not too different from Ki values for these drugs. Pre-treatment of rat aortic smooth muscle cells with Gö6976, bisindolymaleimide I, genistein or a combination of bisindolymaleimide I with genistein suppressed, significantly, or almost eliminated both the rapid and stable increments in [Ca2+]i induced by Mg2+-free medium. The present findings suggest that both protein kinase C and protein tyrosine phosphorylation appear to play important roles in Mg2+ deficiency-induced contractions of isolated rat aortic smooth muscle, most likely via phosphorylation of L-type Ca2+ channels.

Animals↗
PubMed1999

Hydrogen peroxide induces contraction and raises [Ca2+]i in canine cerebral arterial smooth muscle: participation of cellular signaling pathways.

The effects of hydrogen peroxide (H2O2) on isolated canine basilar arteries, and single smooth muscle cells isolated from these arteries, were investigated in the present study. Exposure of isolated endothelium-intact and denuded arterial rings to H2O2, at concentrations of 2.2x10(-5) M to 4.4x10(-3) M, produced concentration-dependent contractile responses. Removal of the endothelium attenuated, but did not eliminate the contractions. H2O2-induced contractions were inhibited, to different degrees, by preincubation of the vessels with low concentrations of staurosporine or bisindolylmaleimide I HCl [antagonists of protein kinase C (PKC)], Gö6976 (a PKCalpha and PKCbeta1 selective antagonist), genistein (an antagonist of protein tyrosine kinase), PD-98059 (an antagonist of mitogen-activated protein kinase), wortmannin [an antagonist of phosphatidylinositol 3 (PI3)-kinases], and LY-294002 (an antagonist of PI3-kinases). These agents were also found to relax arteries precontracted by H2O2. Removal of extracellular Ca2+ or pretreatment of the vessels with 5.0 microM verapamil markedly attenuated the contractions. Complete inhibition of the contractile response was obtained after buffering intracellular Ca2+ with BAPTA-AM. A variety of specific pharmacological antagonists of several known vasoconstrictors neither inhibited nor attenuated the H2O2-induced contractions. Exposure of smooth muscle cells to H2O2 (4.4x10(-6) M to 4.4x10(-4) M) significantly raised intracellular Ca2+ ([Ca2+]i) within 20 s. This was abolished in the absence of extracellular Ca2+ or after application of 5.0 microM verapamil. Pretreatment of the cells with low concentrations of staurosporine, bisindolylmaleimide I, Gö6976, genistein, PD-98059, wortmannin, and LY-294002 markedly suppressed the H2O2-mediated [Ca2+]i elevation. The present findings suggest that hydrogen peroxide, in vitro, produces endothelium-dependent and independent contractions of canine basilar arteries, which are clearly Ca2+-dependent and are not associated with release of endogenous vasoconstrictors. Several intracellular signal transduction systems, such as PKC (both Ca2+-dependent and Ca2+-independent), protein tyrosine phosphorylation, IP3, mitogen-activated protein kinase and PI3 kinase appear to play a role in the H2O2-induced contractions in cerebral arterial muscle.

Animals↗
PubMed1999

The role of humic substances in drinking water in Kashin-Beck disease in China.

We conducted in vitro and in vivo assays in a selenium-deficient system to determine if organic matter (mainly fulvic acid; FA) is involved in a free radical mechanism of action for Kashin-Beck disease. Cartilage cell culture experiments indicated that the oxy or hydroxy functional groups in FA may interfere with the cell membrane and result in enhancement of lipid peroxidation. Experiments with rats demonstrated that toxicity from FA was reduced when the hydroxy group was blocked. Induction of lipid peroxidation by FA in liver and blood of rats was similar to that exhibited by acetyl phenyl hydrazine. FA accumulated in bone and cartilage, where selenium rarely concentrates. In addition, selenium supplementation in rats' drinking water inhibited the generation of oxy-free radicals in bone. We hypothesized that FA in drinking water is an etiological factor of Kashin-Beck disease and that the mechanism of action involves the oxy and hydroxy groups in FA for the generation of free radicals. Selenium was confirmed to be a preventive factor for Kashin-Beck disease.

Animals↗
PubMed1998

Mechanisms of hydrogen peroxide-induced contraction of rat aorta.

It has been suggested that reactive oxygen species may be involved in the regulation of vascular tone. However, the underlying mechanisms remain to be elucidated. The present studies were designed to investigate the contractile effects of hydrogen peroxide (H2O2), one of the reactive oxygen species, on isolated ring segments of rat aorta with and without endothelium. H2O2 induced an endothelium-independent contraction in isolated rat aorta ring segments in a concentration-dependent manner at concentrations from 5 x 10(-6) to 5 x 10(-3) M. H2O2-induced contractions of denuded rat aorta rings were stronger than those on intact rat aorta segments. The contractile effects of H2O2 were inhibited completely by 1200 u/ml catalase. The presence of 1.0 microM Fe2+ or 10 microM proadifen, a cytochrome P450 monooxygenase inhibitor, potentiated the contractile effect of H2O2 on isolated rat aorta segments. 1 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (a hydroxyl radical scavenger) significantly attenuated the vessel contractions induced by hydrogen peroxide plus Fe2+ or hydrogen peroxide itself. Removal of extracellular Ca2+ ([Ca2+]0), addition of 5 microM verapamil, administration of a protein kinase C inhibitor (staurosporine), treatment with an inhibitor of protein tyrosine phosphorylation (genistein) or employment of 5.0 microM indomethacin resulted in a significant attenuation of the contractile responses of the vessels to H2O2. Pharmacological antagonists (e.g. a muscarinic acetylcholine receptor antagonist (atropine), an antagonist of histamine H1 receptors (diphenhydramine), an antagonist of histamine H2 receptors (cimetidine), an alpha-adrenoceptor antagonist (phentolamine), a beta-adrenoceptor antagonist (propranolol) and an antagonist of serotonin receptor (methysergide)) did not inhibit or attenuate the contractions induced by H2O2. Exposure of primary aortic smooth muscle cells to H2O2 (5 x 10(-6) to 5 x 10(-3) M) produced significant rises of intracellular Ca2+ ([Ca2+]i) within 20 s. Employment of 1.0 microM Fe2+ markedly enhanced the increment in [Ca2+]i in the smooth muscle cells. 10 microM proadifen treatment failed to alter the hydrogen peroxide-induced increment in [Ca2+]i of the smooth muscle cells. However, the presence of 5 microM indomethacin significantly attenuated the rise in [Ca2+]i in smooth muscle cells. The present results suggest that H2O2 can induce contractions of rat aorta segments, at pathophysiological concentrations, which are Ca2+-dependent. Hydroxyl radicals (.OH), cyclooxygenase products, protein kinase C and products of protein tyrosine phosphorylation appear to play some role in hydrogen peroxide-induced contractions. Metabolites catalyzed by cytochrome P450-dependent enzymes (upon treatment with hydrogen peroxide) appear to exert a vasodilator effect on rat aorta segments. Lastly, some unidentified mediators, produced by a cytochrome P450 inhibitor (proadifen), during hydrogen peroxide treatment, appear to play some role in contraction of vascular smooth muscle of rat aorta segments in vitro.

Animals↗
PubMed1998

Endothelium-dependent relaxation to hydrogen peroxide in canine basilar artery: a potential new cerebral dilator mechanism.

In prostglandin F2alpha(PGF2alpha)-precontracted isolated canine basilar arterial rings, hydrogen peroxide (H2O2) produced endothelium-dependent relaxations at concentrations of from 4.4 x 10(-7) - approximately 4.4 x 10(-5) M. Removal of extracellular Ca2+ ([Ca2+]0) attenuated the relaxant effects of H2O2. Complete inhibition of H2O2 relaxant action was obtained after buffering intracellular Ca2+ ([Ca2+]i), in the endothelial cells, with 10 microM 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). The H2O2-induced relaxations could be abolished completely by 1200 u/ml catalase and was suppressed significantly by 0.5 microM atropine, 150 microM NG-monomethyl-arginine (L-NMMA), 50 microM NG-nitro-L-arginine methyl ester (L-NAME), 1 microM Fe2+, or 5 microM methylene blue. These inhibitory effects of L-NMMA, L-NAME, or atropine could be reversed partly by 50 microM L-arginine. The Fe2+ inhibition of H2O2-stimulated relaxation was reduced significantly by either 1 mM deferoxamine (a Fe2+ chelator) or 100 microM dimethyl sulfoxide (DMSO, a *OH scavenger). Such relaxant effects of H2O2 were enhanced, significantly, by an acetylcholinesterase antagonist, neostigmine. A variety of pharmacological antagonists (of diverse vasodilator agents) could not inhibit the relaxant action of H2O2. Our observations suggest that at suitable pathophysiological concentrations, H2O2 could induce release of an endothelium-derived relaxing factor (EDRF), probably nitric oxide (NO), from endothelial cells of the canine cerebral artery. The H2O2 relaxant effects are clearly Ca2+-dependent, require formation of cyclic guanosine monophosphate (cGMP), and may be associated with release of endogenous acetylcholine (ACh).

Acetylcholine↗