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Dimitrios Tsikas

Publications and source records attributed to Dimitrios Tsikas.

48 records · Page 3Linked to original sources
PubMed2003

Effects of various nitric oxide-donating drugs on adrenergic tension of human seminal vesicles in vitro.

OBJECTIVES: To evaluate the effects of the nitric oxide (NO)-donating compounds sodium nitroprusside (SNP), S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (SNAC), S-nitroso-N-acetylcysteine-ethylester (SNACET), and linsidomine (SIN-1) on the adrenergic tension of isolated human seminal vesicle strip preparations. The significance of the NO-cyclic guanosine monophosphate (cGMP) pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established. However, information on the significance of NO-mediated signal transduction in the functional control of the mammalian seminal vesicles is still sparse. METHODS: Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Tension was induced by the addition of 10 microM norepinephrine. After stable tension plateaus had been reached, the drugs were added in a cumulative manner (0.01 to 100 microM) and the isometric responses of the tissue registered. The effects of the compounds on the phasic contractility of the tissue preparations were also evaluated. The adenylyl cyclase-stimulating agent forskolin was used as a reference compound known to interfere with the cyclic adenosine monophosphate pathway. RESULTS: Adrenergic tension was dose dependently attenuated by the drugs. The rank order of potency, from greater to lesser, was GSNO, SNAC, SNP, SIN-1, forskolin, and SNACET. The rank order (from greater to lesser) with regard to the inhibitory effects of the compounds on the frequency of phasic contractions of the tissue induced by the addition of norepinephrine was GSNO, SNAC, SNP, and SIN-1; the effects of SIN-1, forskolin, and SNACET on the frequency of contractions were nearly equipotent. CONCLUSIONS: Our results strongly support the hypothesis that the contractility of the human seminal vesicle is under the control of the NO-cGMP pathway. This finding may give a rationale for the use of S-nitrosothiols, such as GSNO and SNAC, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation (premature ejaculation).

Adrenergic alpha-Agonists↗
PubMed2003

Lack of oxidative stress during sustained therapy with isosorbide dinitrate and pentaerythrityl tetranitrate in healthy humans: a randomized, double-blind crossover study.

The mechanisms by which tolerance to organic nitrates develops are still poorly understood. Enhanced oxidative stress, i.e., increased free radical production following organic nitrate administration, has been recently suggested as a possible mechanism. A randomized, double-blind, crossover study assessed in 18 healthy young volunteers at baseline and 1 and 5 days after oral administration with therapeutically relevant doses of isosorbide dinitrate (ISDN, 30 mg TID) or pentaerythrityl tetranitrate (PETN, 80 mg TID) the effect on two index parameters of oxidative stress in vivo, i.e., urinary 8-iso-prostaglandin (PG)F2alpha and circulating 3-nitrotyrosine and their major urinary metabolites, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha and 3-nitro-4-hydroxyphenylacetic acid. In addition, urinary cGMP and serum and urinary nitrate and nitrite were determined. All parameters were quantified by gas chromatography-mass spectrometry or gas chromatography-tandem mass spectrometry except for cGMP, which was analyzed by radioimmunoassay. Serum and urinary nitrite levels increased significantly following 5-day administration of ISDN and PETN. Neither urinary excretion of 8-iso-PGF2alpha and plasma 3-nitrotyrosine nor their respective metabolites changed significantly after ISDN or PETN administration. There were no significant differences between ISDN and PETN regarding these parameters. Urinary cGMP increased significantly only after ISDN. This study is compatible with a stimulation of cGMP by ISDN, but neither ISDN nor PETN enhances systemic oxidative stress in healthy volunteers.

Adult↗
PubMed2002

Measurement of S-nitrosoalbumin by gas chromatography--mass spectrometry. III. Quantitative determination in human plasma after specific conversion of the S-nitroso group to nitrite by cysteine and Cu(2+) via intermediate formation of S-nitrosocysteine and nitric oxide.

Highly contradictory data exist on the normal plasma basal levels in humans of S-nitrosoproteins, in particular of S-nitrosoalbumin (SNALB), the most abundant nitric oxide (.NO) transport form in the human circulation with a range of three orders of magnitude (i.e., 10 nM-10 microM). In previous work we reported on a GC-MS method for the quantitative determination of SNALB in human plasma. This method is based on selective extraction of SNALB and its 15N-labeled SNALB analog (S(15)NALB) used as internal standard on HiTrapBlue Sepharose affinity columns, HgCl(2)-catalysed conversion of the S-nitroso groups to nitrite and [15N]nitrite, respectively, their derivatization to the pentafluorobenzyl derivatives and quantification by GC-MS. By this method we had measured SNALB basal plasma levels of 181 nM in healthy humans. It is generally accepted that HgCl(2)-catalysed conversion of S-nitroso groups into nitrite is specific. In consideration of the highly divergent SNALB plasma levels in humans reported so far, we were interested in an additional method that would allow specific conversion of S-nitroso groups into nitrite. We found that treatment with cysteine plus CuSO(4) is as effective and specific as treatment with HgCl(2). The principle of the cysteine/CuSO(4) procedure is based on the transfer of the S-nitroso group from SNALB to cysteine yielding S-nitrosocysteine, and its subsequent highly Cu(2+)-sensitive conversion into nitrite via intermediate.NO formation. Similar SNALB concentrations in the plasma of 10 healthy humans were measured by GC-MS using HgCl(2) (156+/-64 nM) and cysteine/CuSO(4) (205+/-96 nM). Our results strongly suggest that SNALB is an endogenous constituent in human plasma and that its concentration is of the order of 150-200 nM under physiological conditions.

Animals↗
PubMed2002

Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179.

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.

Angiotensin II↗
PubMed2002

Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro.

OBJECTIVES: To evaluate the effects of the nitric oxide (NO)-donating drugs sodium nitroprusside, S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteineetylester (SNACET), and linsidomine (SIN-1), as well as the adenylyl cyclase-stimulating agent forskolin, on electrically induced contractions and on tissue levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) of isolated human seminal vesicle strip preparations. The significance of the L-arginine-NO-cGMP pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established; however, information on the relevance of NO-mediated signal transduction in the functional control of mammalian seminal vesicles is still sparse. METHODS: Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Phasic contractions were induced by electrical field stimulation (frequency 80 Hz, amplitude 10 V, single pulse 1 ms, total pulse duration 1 second, pause 90 seconds). After stable contraction amplitudes had been reached, the drugs were added in a cumulative manner (0.001 to 10 microM), and the isometric responses were registered. After drug exposure, freezing, tissue homogenization, and extraction of cyclic nucleotides, cAMP and cGMP were measured by means of enzyme-linked immunosorbent assays. RESULTS: Electrical field stimulation-induced amplitudes were attenuated by the drugs in a dose-dependent manner. The rank order of potency was GSNO > sodium nitroprusside > forskolin > SNACET > or = SIN-1. The relaxing effect of GSNO was antagonized in the presence of 10 microM of guanylyl cyclase inhibitor methylene blue. The inhibitory effects of GSNO, sodium nitroprusside, and forskolin on the contractile activity were paralleled by an increase in tissue cGMP (2 to 100-fold) and cAMP (7 to 9-fold). CONCLUSIONS: Our results strongly support the hypothesis that the contractility of human seminal vesicles is in part regulated by the NO-cGMP-cascade. This may give a rationale for the use of S-nitrosothiols, such as GSNO, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation.

Aged↗
PubMed2002

In vitro effects of a novel class of nitric oxide (NO) donating compounds on isolated human erectile tissue.

OBJECTIVES: The discovery of nitric oxide (NO) as one of the major effectors in penile erectile function has led to the development of various drugs which are able to elevate intracellular levels of cGMP. Recently, a novel class of NO donors have been developed, exemplified by S-nitroso-glutathione (GSNO) and S-nitroso-N-acetylcysteine-ethylester (SNACET), as well as compounds combining both phosphodiesterase inhibitory and NO donating activity, such as NCX 911 (sildenafil nitrate). In our study, we assessed the effects of GSNO, SNACET and NCX 911 on adrenergic tension and electrically induced relaxation of isolated human corpus cavernosum (HCC) and the in vitro formation of cGMP. Effects were compared to those of sodium nitroprusside (SNP) and sildenafil citrate. MATERIALS AND METHODS: Using the organ bath technique, drug effects were investigated on norepinephrine-induced tension and electrically induced relaxation of HCC. HCC strips were exposed to increasing concentrations of the compounds (0.01/0.1-10/100 microM) and the accumulation of cGMP was determined by means of a radioimmunoassay. RESULTS: Relaxation of HCC induced by means of electrical field stimulation (EFS) was abolished by tetrotodoxin, guanylyl cyclase inhibitor ODQ and nitric oxide synthase inhibitor L-NNA. Adrenergic tension of HCC strips was dose-dependently reversed by the drugs. The rank order of potency was: SNP > GSNO > NCX911 > sildenafil > SNACET. Compounds also dose-dependently increased EFS-induced amplitudes of relaxation (SNP > NCX911 > sildenafil > SNACET/GSNO). Relaxing effects of the drugs were paralleled by an increase in tissue levels of cGMP. CONCLUSION: Our results provide a rationale for future use of NCX 911 and S-nitrosothiols in the pharmacotherapy of erectile dysfunction (ED). Since the compounds are assumed to exert no considerable hemodynamic effects, they might be developed into new oral treatments for ED.

Adult↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗