Antiangiogenic effect of sulindac sulfide could be secondary to induction of apoptosis and cell cycle arrest.

BACKGROUND: The development of colon cancer is probably angiogenesis-dependent. Recently, sulindac sulfide was shown to possess anti-angiogenic activity. In the present work, the question of whether this activity reflects a specific interaction with angiogenesis or is secondary to the effect of sulindac sulfide on the survival of endothelial cells was addressed. MATERIALS AND METHODS: Endothelial and normal mouse fibroblast cell lines were incubated with non-steroidal anti-inflammatory drugs (NSAIDs), arachidonic acid (AA) and prostaglandin E2 (PGE2). Cell viability (survival), PGE2 synthesis, cell cycle and apoptosis were measured. Western blotting and semi-quantitative RT-PCR multiplex methods verified the changes in the levels of pro-apoptotic proteins and their expressions, respectively. RESULTS: Sulindac sulfide and celecoxib inhibited the survival of endothelial cells, whereas other NSAIDs were ineffective. In contrast to celecoxib, sulindac sulfide did not affect the survival of normal fibroblast cells. Both agents inhibited the production of PGE2 from AA and arrested the cell cycle in the S-phase. Moreover, sulindac sulfide activated caspases 3 and 8, decreased the levels of Bax and Bid proteins, caused cleavage of PARP and increased the expressions of the bax and caspase 3 genes. CONCLUSION: The results suggest that the anti-angiogenic activity of sulindac sulfide is secondary to the inhibition of endothelial cell survival resulting from cell cycle arrest and apoptosis.

Pharmacokinetics of selol, a new agent containing selenium, in rats.

The pharmacokinetic properties of selol, a new organoselenium compound, were evaluated in rats. Each animal was given a single oral or subcutaneous dose of selol 12 mg/kg. The selenium concentration was determined in whole blood and tissues by non flame carbon furnace atomic-absorption spectrometry. The pharmacokinetic parameters Cmax and tmax differed statistically between oral (p.o.) and subcutaneous (s.c.) treatment. The selenium average peak concentrations in the blood were 494 +/- 8 ng/ml after oral and 322 +/- 5 ng/ml after subcutaneous administration. They were reached after 1.9 +/- 0.1 h and 2.4 +/- 0.1 h, respectively. For the AUC0 mean values of 1373 +/- 56 ng.h/ml (p.o.) and 1273 +/- 137 ng.h/ml (s.c.) were found. The mean residence time (MRT) was significantly longer after subcutaneous administration. Selenium distributes quickly to the main organs with prevalence to the adrenal gland. Moreover, its concentrations in the examined organ were evidently higher after subcutaneous treatment as compared to the oral route. Our data suggest that Selol may be used as a possible source of selenium for the treatment of selenium-deficient patients, particularly via the subcutaneous route.

Activation of GABA-A receptor by hypotensive drugs.

Chronic antihypertensive treatment with clonidine and beta-adrenoceptor blockers leads to a significant increase in GABA-A receptor number in the hypothalamus, the pons-medulla and the striatum. The enhancement of receptor number after two beta-blockers was associated with the decrease of Kd factor in the pons-medulla and the striatum. There was no change in receptor affinity after clonidine. We conclude that neurotransmission via GABA-A receptors is important for the hypotensive effects of clonidine and some beta-adrenoceptor blockers.

Clonidine hypotension in spontaneously hypertensive rats (SHR) depends on the functional state of GABAergic and glutamatergic systems.

The effect of gamma-aminobutyric acid (GABA)A receptors and of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor blockade on clonidine hypotension was studied. The experiments were performed on spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. We found that the blockade of GABAA receptors line significantly (P < 0.01) reduced hypotensive responses to clonidine. Similarly, the NMDA receptor antagonist dizocilpine (MK-801) completely abolished the blood pressure lowering effect of clonidine. Our findings support the conclusion that clonidine hypotension is closely related to the functional state of both inhibitory GABAergic and excitatory glutamatergic systems.

On the role of NMDA receptors in blood pressure regulation in spontaneously hypertensive rats (SHR).

In the present study the binding of [(3)H]MK-801 to glutamatergic receptors of the NMDA type was compared in spontaneously hypertensive (SHR) and normotensive (WKY) rats in various brain structures (including nucleus tractus solitarii) by quantitative receptor autoradiography. Additionally, blood pressure changes after treatment with the NMDA antagonist MK-801 were studied in both strains. There were no differences between SHR and WKY rats either in the level of [(3)H]MK-801 binding or in the hypertensive reaction to MK-801.

Antihypertensive treatment with beta blockers and gabaergic transmission in rat brain.

The effects of chronic oral administration of propanolol and metoprolol on blood pressure and GABAergic function were investigated in spontaneously hypertensive rats (SHR) and compared with the effect of dihydralazine. Under the experiment conditions employed all drugs reduced significantly (p < 0.01) arterial pressure. The beta blockers elevated GABA turnover in the hypothalamus and the pons-medulla. Dihydralazine, however had not such an effect. Our result suggest that the antihypertensive action of beta blockers may be related in part to the enhanced cerebral GABAergic transmission.

Enhancement of GABAergic system activity by metoprolol in spontaneously hypertensive rats.

The relevance of the GABAergic system for the antihypertensive action of metoprolol in spontaneously hypertensive rats was studied by comparing the effect of metoprolol with the effect of dihydralazine. Chronic oral treatment with metoprolol produced the maximum effect after 49 days (-delta 34 mm Hg). This effect persisted on the same level for up to 55 days. The measurements of gamma-aminobutyric acid (GABA) synthesis and specific [3H]GABA binding were performed in the hypothalamus, the pons-medulla, the hippocampus and the striatum. Significant stimulation of GABA synthesis and turnover appeared in the hypothalamus and the pons medulla. In contrast, chronic administration of dihydralazine had no influence on GABA synthesis rate. It was also shown that metoprolol elevated significantly (P < 0.01) specific [3H]GABA binding in the hypothalamus and the pons-medulla. In the striatum this effect of metoprolol was less pronounced. Binding constant analysis revealed changes in both the receptor density and affinity. Our results suggest that the hypotensive response to chronic treatment with metoprolol might be attributed to an enhancement of GABAergic system activity.

Intracellular accumulation of cytosine arabinoside in murine normal and neoplastic lymphocytes following their exposure to sodium 2-mercaptoethanesulphonate.

The effect of mesna on intracellular accumulation of cytosine arabinoside (Ara-C) in murine normal and neoplastic lymphocytes was studied. Simultaneous exposure of cells to mesna at concentrations ranging from 0.25 to 1.0 mM and 3H-Ara-C (40.0 nM) resulted in a strong inhibition of Ara-C uptake in normal lymphocytes. Under the same experimental conditions, mesna did not affect the Ara-C uptake in neoplastic cells (cultured L5178Y mouse leukaemia cells and neoplastically transformed thymus cells). It was found that the inhibitory effect of mesna was not cell cycle-dependent, since mesna reduced the Ara-C uptake in both normal quiescent and PHA-stimulated cells. We therefore concluded that mesna may selectively reduce Ara-C uptake by normal cells in vitro.

Systemic toxicity and dermal irritation of Tolpa Peat Preparation.

The systemic toxicity of the peat preparation in rats and rabbits was assessed. Dermal irritation tests were conducted on rabbits. In acute and chronic toxicity studies TPP was well tolerated in both animal species. Laboratory findings revealed no hematologic abnormalities as well as disturbances in liver and kidney function. No local irritancy of TPP was found. The results show that TPP may be considered as practically non toxic.

Increased activity of the GABAergic system in selected brain areas after chronic propranolol treatment in spontaneously hypertensive rats.

The influence of chronically administered propranolol on the functional state of the gamma-aminobutyric acid-ergic (GABAergic) system in spontaneously hypertensive rats was studied and compared with the effect of dihydralazine. GABA content, synthesis and turnover rate in selected brain areas were assessed. Hypotensive activity of propranolol and dihydralazine after injection of GABA antagonist pictrotoxin was examined in acute experiment. Prolonged administration of propranolol increased GABA content, synthesis and turnover rate in the hypothalamus and the pons-medulla. After chronic injections of dihydralazine there was no change in GABA indices. Antihypertensive activity of dihydralazine in picrotoxin-treated animals remained unchanged. On the contrary, picrotoxin suppressed the propranolol-induced decrease in blood pressure. Our results indicate that propranolol increases GABAergic system activity. Therefore, we conclude that down-regulation of the GABAergic system in hypertension may be compensated by the regulatory action of propranolol.

[Naphthalenesulfonate compounds of alkylaminoalkyl drugs]. / Naftalenosulfoniany wybranych leków pochodnych alkiloaminoalkili.

New compounds of alkylaminoalkyl with some naphthalenosulphonate (Na) were obtained and some of their physicochemical properties have been determined. Ability to formation of these compounds was utilised in qualitative and quantitative analysis of the above drugs.

Pharmacological effects of Ukrain in rats and rabbits.

The effect of Ukrain administered in various doses on mean blood pressure (MAP) and breathing rate in rats and rabbits was evaluated. It was found that MAP was reduced and breathing rate increased significantly in both animal species. Maximum tolerated dose (MTD) of Ukrain was 10-fold higher in rats than in rabbits, and it amounted to 3.5 mg x kg(-1) and 0.35 mg x kg(-1), respectively. Possible clinical implications of these findings were discussed.

Effect of clonidine on blood pressure and GABAergic mechanisms in spontaneously hypertensive rats.

The action of clonidine on blood pressure and on the functional state of the gamma-aminobutyric acid-ergic (GABAergic) system was studied. A single injection of clonidine (1, 5, 10, 20 micrograms.kg-1) induced a dose-dependent decrease of blood pressure. Chronic administration of clonidine, 10 micrograms.kg-1, produced the maximum effect after the third injection. The effect was maintained for the duration of the study. Single or chronic clonidine injections, at the dose of 10 micrograms.kg-1 enhanced the GABA content in the brain and hypothalamus. This effect was less pronounced in the hippocampus. The drug administered according to the same regimen stimulated glutamic acid decarboxylase activity only in the hypothalamus. Clonidine caused a marked enhancement of specific [3H]GABA binding in the hypothalamus. These data suggest that the hypotensive action of clonidine is related to stimulation of the GABAergic system.

Propranolol effect on GABA synthesis rate estimated by two different methods.

The propranolol effect on GABA synthesis rate in some brain structures using two different method was assessed. Both methods gave comparable results. Evaluation of the synthesis rate in vivo after inhibition of GABA degradation supplied more adequate information indicating that the availability of GABA precursor in the hypothalamus and the hippocampus is limited.

Down-regulation of the GABA-ergic system in selected brain areas of spontaneously hypertensive rats (SHR).

The relevance of GABA-ergic system in hypertensive state has been studied. GABA content, GAD activity and GABA-A receptor binding in various brain areas in age-matched spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY) was compared. Out of 9 brain areas studied the GABA content was significantly lower in the substantia nigra, hypothalamus, hypothalamus posterior and hippocampus of SHR rats. GAD activity was lowered in the hypothalamus and hippocampus of young SHR and adult SHR rats (4, 8, 14 weeks old). Scatchard analysis of the binding isotherms indicated a lower Bmax of the binding sites in the hypothalamus and hippocampus of 8 and 14 weeks old SHR rats. These results suggest that activity of GABA-ergic system differs substantially in SHR and WKY rats brain. Furthermore, these differences appear already in young prehypertensive SHR rats as well as in the early stages of hypertension.