摘要:

Sn-mesoporphyrin is considerably more effective than Sn-protoporphyrin in inhibiting bilirubin production in vivo, in the experimental animal. In this study the effects of Sn-mesoporphyrin, administered in doses ranging from 1 to 20 μmol/kg b.w., on the developmental patterns of hepatic cytochrome P450 content and cytochrome P450-dependent drug metabolism in rat neonates were examined at various time points during the 5-week period immediately after birth. No detrimental alterations in cytochrome P450 content or in cytochrome P450-dependent drug metabolism were observed. In addition no deleterious effects were noted on total glutathione content in brain of Sn-mesoporphyrin-treated animals. After single doses of Sn-protoporphyrin of 20, 50 or 100 μmol/kg b.w. were administered at birth, transient decreases in hepatic cytochrome P450 content (days 1 and 2), and ethylmorphine demethylase (days 2 and 5) and 7-ethoxycoumarin deethylase (days 1 2 and 5) activities were observed in the period immediately after birth. However no sustained alterations in the developmental patterns of these enzymes were observed even at the highest dose (100 μmol/kg b.w.) of Sn-protoporphyrin administered. These findings indicate that in the doses utilized in this study both metalloporphyrins have no long-term effects on cytochrome P450-dependent drug metabolism. Furthermore, in doses up to 20 μmol/kg b.w., neither compound produced any short-term effects on hepatic cytochrome P450 content or functional activity in newborn r

ISSN:0031-7012    

DOI:10.1159/000138610

出版商:S. Karger AG    

年代:1989

数据来源: Karger

摘要:

The mianserin (MIS) distribution in 12 brain regions was investigated after 2-and 14-day continuous MIS infusion, starting with 19 mg/kg/day on the first day. There was no significant difference between the 2nd and 14th day with respect to MIS concentration, brain/serum concentration ratio in whole brain or MIS serum level. The MIS distribution was heterogenous on the 2nd and 14th day and did not change with time. The concentrations were highest in cortex and hippocampus and lowest in cerebellum, hypothalamus, and bul-bus olfactorious and septum. This distribution pattern differs from those found with tricyclic antidepressant drugs.

ISSN:0031-7012    

DOI:10.1159/000138611

出版商:S. Karger AG    

年代:1989

数据来源: Karger

摘要:

The vasodepressor responses to intravenous injections of arachidonic acid, and the formation of its metabolites, were studied in rats made diabetic 1 or 2 weeks after a 1-dose alloxan treatment. Arachidonic acid dose-dependently decreased the diastolic blood pressure in normal animals, but this hypotensive effect was significantly weaker in 2-week postalloxan-treated rats. Indometacin abolished arachidonic-acid-induced depressor responses in both normal and diabetic animals. Hypotension induced by sodium nitroprusside was of the same magnitude in non-diabetic and insulin deficient rats. Plasma levels of thromboxane B2 were significantly increased in both the 1- and 2-week diabetic rats, being greater in the latter group; those of 6-keto-PGF1α remained unchanged during the 2-week diabetic period. It is concluded that the attenuation by diabetes of depressor responses to arachidonic acid could be due to changes in the thromboxane/prostacyclin balance, with thromboxane formation being elevated whereas prostacyclin generation remains unaffected

ISSN:0031-7012    

DOI:10.1159/000138612

出版商:S. Karger AG    

年代:1989

数据来源: Karger

摘要:

The cortex and medulla were isolated from kidneys whose donors (5 men and 1 woman, aged between 44 and 68 years) were undergoing nephrectomy to remove a tumor. Kidneys with normal architecture for at least two thirds of the organ were included in the study. Tissue specimens used in our experiments were free from pathological changes. The activities of the following enzymes of phase INADPH cytochrome c reductase, aminopyrine N-demethylase, ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase, microsomal and cytosolic epoxide hydrolases, glutathione reductase and glutathione peroxidase, and those of the following enzymes of phase II glutathione transferase, glucuronyl transferase, sulphotransferase, acetyltransferase, thiomethyltransferase, thiopurinemethyltransferase, thioltransferase and glyoxalase were measured. The activity in renal cortex was significantly higher than in medulla for NADPH cytochrome c reductase, cytosolic epoxide hydrolase, glutathione reductase and glutathione peroxidase (phase I enzymes), and glutathione transferase, acetyltransferase, thiomethyltransferase, thiopurinemethyltransferase, thioltransferase and glyoxalase (phase II enzymes). The other enzymes had similar activity in cortex and medulla. The distribution pattern of drug-metabolizing enzymes in the human kidney cannot be considered as a single pattern because of the observed enzyme-dependent differences between cortex and medulla.

ISSN:0031-7012    

DOI:10.1159/000138613

出版商:S. Karger AG    

年代:1989

数据来源: Karger

摘要:

The stimulatory effect of the dihydropyridine derivative, Bay K 8644, on the isolated pregnant human uterus, and its interactions with the calcium channel blockers, nifedipine, verapamil and diltiazem and with the calmodulin inhibitor trifluoperazine were investigated. In uterine preparations showing spontaneous activity, Bay K 8644 (1 nmol/l – 1 μmol/l) produced an increase in the frequency of contractions without effects on their amplitude. However, strong phasic contractions were induced in quiescent preparations. The stimulatory action of Bay K 8644 proved to be insensitive to calcium withdrawal, but was completely prevented in the presence of 1 mmol/l EGTA. Bay K 8644 shifted the inhibitory concentration-response curve of verapamil and nifedipine to the right, leaving the diltiazem-and trifluoperazine-induced effect virtually unchanged. Schild plot analysis revealed a competitive interaction of Bay K 8644 with nifedipine, while the interaction with verapamil was of the nonlinear type. These data demonstrated that the dihydropyridine derivative Bay K 8644 possesses calcium agonistic properties also in the isolated human uterus. Furthermore, the competitive interaction with nifedipine showed the existence of specific dihydropyridine receptors closely associated with the calcium chann

ISSN:0031-7012    

DOI:10.1159/000138614

出版商:S. Karger AG    

年代:1989

数据来源: Karger

摘要:

To study the selectivity of calmodulin antagonists it was assumed that they should inhibit noradrenaline (NA)- and K+-induced contractions similarly without an accompanying inhibition of 45Ca uptake. Therefore, in isolated rat aorta the effects of W-7, calmidazolium and trifluoperazine on contraction and 45Ca uptake elicited by K+ and NA were investigated. Calmidazolium (10–5–10–4 mol/l) elicited an incomplete inhibition of K+-and NA-induced contraction and 45Ca uptake. Trifluoperazine inhibited the NA-induced contractions at lower concentrations (10–8–10–6 mol/l) than the K+-induced contraction (10–6–10–4 mol/l). The K+- and NA-induced 45Ca uptake was blocked by trifluoperazine (10–5 mol/l). W-7 (10–5–10–4 mol/l) inhibited the K+- and NA-induced contraction, however, in the same concentration range W-7 diminished the K+- and NA-induced 45Ca uptake. In conclusion, the results indicate that calmidazolium and trifluoperazine are hardly useful as calmodulin antagonists because of their additional properties, whereas W-7 seems to be the least unspecific of the calmo

ISSN:0031-7012    

DOI:10.1159/000138615

出版商:S. Karger AG    

年代:1989

数据来源: Karger

摘要:

The pharmacologic profile of the novel β-adrenoceptor antagonist/vasodilator, carvedilol, has been investigated in vitro. Carvedilol produced competitive antagonism of the β1-adrenoceptor mediated positive chronotropic response to isoproterenol in guinea pig atria, and the β2-adrenoceptor mediated relaxation to isoproterenol in carbachol (1 μmol/l) precontracted guinea pig trachea, with a dissociation constant (KB) for β1-adrenoceptors of 0.8 nmol/l and β2-adrenoceptors of 1.3 nmol/l. At slightly higher concentrations, carvedilol produced competitive inhibition of the α1-adrenoceptor mediated contractile response to norepinephrine in rabbit aorta with a Kb of 11 nmol/l. Carvedilol had no significant effect on the contractile response to angiotensin II in rabbit aorta at concentrations up to 10 μmol/l, thus demonstrating the lack of nonspecific vasodilator actions in arteries. In canine saphenous vein, carvedilol produced noncompetitive blockade of α2-adrenoceptor mediated vasoconstriction, indicative of some additional activity. In estrogen-primed rat uterus precontracted by depolarization with KC1 (70 mmol/l), carvedilol produced concentration-dependent relaxation (IC50 of 7.6 μmol/l), consistent with the notion that carvedilol may be a calcium channel antagonist. Support for this hypothesis was obtained in KCl (70 mmol/l) depolarized rabbit aorta where carvedilol (10 μmol/l) produced a 10-fold parallel rightward shift in the concentration-response curve to calcium chloride. These studies demonstrate that carvedilol is a potent β1, β2- and α1-adrenoceptor antagonist, and a moderately potent calcium channel antagonist. These multiple activities of carvedilol may contribute to the antihypertensive activity of

ISSN:0031-7012    

DOI:10.1159/000138616

出版商:S. Karger AG    

年代:1989

数据来源: Karger