Acta pharmacologica et toxicologica最新文献

The aim of the present study was to examine the effect of glyceryltrinitrate (GTN) and 8-Br-cGMP on tension and cytosolic calcium concentration in pre-contracted bovine mesenteric arteries (BMA). The activity of glycogen phosphorylase a was used as a measure of the cytosolic calcium concentration. The activity of this enzyme is regulated by the cytosolic calcium concentration and/or cAMP. Since the cAMP level was not found to be affected by GTN-treatment, the use of phosphorylase a activity to monitor changes in the cytosolic calcium concentration can be justified. The vessels were contracted with phenylephrine (10 microM) or 100 mM K+-depolarization, which caused an increase in phosphorylase a activity. Addition of 1 microM GTN to the phenylephrine-contracted vessels resulted in a 3-4-fold rise in intracellular cGMP level, which was accompanied by a large decrease in tension and phosphorylase a activity. The K+-depolarized vessels, on the other hand, were largely resistant to the relaxant action of GTN, and there was only a slight reduction of the phosphorylase a activity. In phenylephrine-contracted vessels, made tolerant to GTN by incubation at elevated pH in the presence of GTN (0.44 mM), no changes in tension and phosphorylase a activity were seen after stimulation with a test dose of GTN (1 microM). The cGMP response was also markedly blunted in the tolerant vessels. Relaxation of phenylephrine-contracted BMA induced by 8-Br-cGMP (0.5 mM) was also accompanied by a reduction in phosphorylase a activity.(ABSTRACT TRUNCATED AT 250 WORDS)

An experimental long-term hepatotoxicity study of cyanamide in Sprague-Dawley and Wistar rats has been carried out. After six months oral administration of cyanamide (2.7 and 25 mg/kg/day) no significant histological changes have been observed in the liver. Similarly, a one year intraperitoneal administration of 8 and 16 mg/kg/day has not induced any hepatic change. Specifically, no inclusion bodies in any cyanamide treated rat have been detected. Moreover, hepatic biochemical parameters have shown no significant impairment of hepatic function at doses used in human therapy (0.5-1 mg/kg).

The principal aim of the present investigation was to examine in detail individual and combined actions on airways of four antiasthmatic drugs with different mechanisms of action. They were theophylline (THEO), the beta 2-adrenoceptor agonist terbutaline (TER), the antimuscarinic ipratropium bromide (IPRA), and the glucocorticoid betamethasone (BM). The respiratory measurements (intratracheal pressure in rats and lung resistance and dynamic lung compliance in guinea pigs) were performed in anaesthetized, mechanically ventilated animals. Mild, moderate, and submaximal obstruction of mainly large or small airways were induced by a cumulative administration of either methacholine (MeCh) or leukotriene D4 (LTD4), both i.v. The antiasthmatic drugs were given acutely i.v., but THEO and BM also as intraperitoneal pretreatments. Moreover, actions of the antiasthmatic drugs were studied ex vivo on lung beta-adrenoceptors in rats and guinea pigs. 3H-dihydroalprenolol was used as a ligand in the beta-receptor binding assay. A detailed evaluation of the lung resistance and dynamic lung compliance responses to MeCh and LTD4 suggested that MeCh induced obstruction in more proximal airways than LTD4. THEO attenuated both airway challenges, being about 2-4 times more efficient on LTD4 than on MeCh. TER inhibited both MeCh- and LTD4-induced airway obstruction about equally, whereas IPRA was effective on the MeCh-induced obstruction only. In most cases, treatment with THEO+TER or THEO+IPRA attenuated the MeCh-induced mild or moderate obstruction of large airways additively, and the submaximal airway response to MeCh synergistically. The relatively good effect of THEO on small airway obstruction caused by MeCh was not augmented by TER or IPRA. In contrast to these results, combination of subefficient doses of THEO and TER, but not of THEO and IPRA, resulted in an antagonistic interaction on the MeCh challenge in rats and guinea pigs. The combined action of THEO+TER was at its best additive on large and small airways obstruction caused by LTD4. Addition of IPRA to THEO treatment did not modify the effects on LTD4 challenge. Neither TER nor IPRA enhanced the cardiovascular effects of THEO in rats or guinea pigs. THEO administration to rats and guinea pigs resulted in plasma concentrations (7.5-32 micrograms/ml) that were roughly comparable to clinically relevant values. The respective lung tissue concentrations were 53-81% of the plasma values. In rats, but not in guinea pigs, combined treatment with THEO+TER increased the THEO concentration in lung tissue.(ABSTRACT TRUNCATED AT 400 WORDS)