摘要:

Angiotensin-II (AII) receptors have been classified as AT1 and AT2 subtypes based on selective antagonists. AII binding sites in bovine ovary membranes were characterized using the radiolabeled AII antagonist, [125I]SarAIIe8-AII ([125I]SIA). The binding was specific and saturable with dissociation constant (Kd) and maximum binding (Bmax) of 0.18 ± 0.08 nmol/l and 32.5 ± 1.3fmol/mg, respectively. Pretreatment of ovarian membranes with dithiothreitol (10 μmol/l) doubled the specific binding of [125I]SIA twofold to 63.5 ± 2.8 fmol/mg. Guanine nucleotide had no significant effect on the affinity of agonist (AII) to compete for [125I]SIA binding. All and a series of All-related analogs were used in competition binding experiments, and the data were compared with those obtained with membranes prepared from bovine adrenal cortex and bovine cerebellum. The membranes from ovary and cerebellum showed similar binding characteristics, but they differed from those of adrenal cortex. CGP42112A and WL-19, AT2-subtype selective antagonists, inhibited [125I]SIA binding to ovarian membrane with IC50 values of 28 ± 4 and 26.7 ± 2.8 nmol/l, respectively. SK&F 108566 and DuP 753, AT1-subtype-selective antagonists, had very little effect on [125I]SIA binding to ovarian membranes. These data directly demonstrate that bovine ovary membranes have predominantly AT2-subtype AII rece

ISSN:0031-7012    

DOI:10.1159/000139022

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The density and distribution of dopamine D1 and D2 receptors visualized by in vitro autoradiography were investigated in adult and senescent BL C57 mice. A significant decrease was observed in regions of the basal ganglia of senescent animals, which was more pronounced for the D1 subtype. Chronic treatment with cinnarizine, an organic Ca2+ channel antagonist, alters both D1 and D2 receptor densities, with a higher sensitivity of the Dl subtype. These results could indicate that the interactions between dopamine receptor subtypes may be necessary for the full expression of behavioral events mediated by the D2 receptors.

ISSN:0031-7012    

DOI:10.1159/000139023

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 μmol/l, respectively. In a rat ex vivo assay, orally administered RG 12561 lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91 %, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16 %, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent

ISSN:0031-7012    

DOI:10.1159/000139024

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Tricyclic antidepressant drugs may affect the cardiovascular system, principally in patients with preexisting cardiac disease. The present study was undertaken to compare the effects of amitriptyline and mianserin with those of tianeptine, an atypical tricyclic antidepressant drug, in rat isolated working heart subjected to a local myocardial ischemia. Coronary, aortic and cardiac flows, and heart rate remained stable during the whole pre-ischemic period in control hearts. Ligation of the left main coronary artery induced a 50% decrease in coronary, aortic and cardiac flow without any change in heart rate. Reperfusion was characterized by the occurrence of ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) and by a marked reduction in cardiodynamic parameters. Amitriptyline (1 and 10 μmol/l) and mianserin (1 and 10 μmol/l) exhibited an anti-arrhythmic activity against reperfusion arrhythmias. Tianeptine (1 and 10 μmol/l) was not able to reduce the incidence of reperfusion arrhythmias. Although tianeptine did not change heart rate, mianserin and amitriptyline induced a bradycardia. Mianserin and amitriptyline improved the cardiac recovery of cardiac function during reperfusion. The cardiodynamic parameters (coronary, aortic and cardiac flows) were not altered by tianeptine during the preischemic period. Furthermore, these parameters were similar to those observed in the control group both during ischemia and reperfusion. The beneficial effects of amitriptyline and mianserin observed in the setting of myocardial reperfusion were not associated with a reduced lipoperoxidation investigated by using an in vitro model in the presence or absence of a free-radical-generating system. The results of the present study indicate that the pronounced antiarrhythmic activities of mianserin and amitriptyline cannot be explained by an antiperoxidative action of these dru

ISSN:0031-7012    

DOI:10.1159/000139025

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

L-Carnitine (oral route) signiñcantly corrects the muscle hypocontractility and hypoexcitability induced in the rat after 5 consecutive days of fasting. This effect is interpreted on the basis of the dual role of L-carnitine as cofactor in the transport of long-chain fatty acids into the mitochondria and as a detoxifying agent of intracellular acyl-CoA. The activity of L-carnitine is increased with the concomitant administration (oral route) of an equimolar dose of L-lysine. In the present experimental conditions, there is a threefold potentiation by comparison with L-carnitine alone. This result is discussed on the basis of the combined effects of an exogenous supply of L-carnitine and endogenous synthesis of L-carnitine from the L-lysine administered at the same time

ISSN:0031-7012    

DOI:10.1159/000139026

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Iterative administrations of glipizide (2 μmol/l) for 10 min each to perifused rat pancreatic islets provoked at low glucose concentration (2.8 mmol/l) rapid and rapidly reversible decreases in 86Rb outflow, rapid and rapidly reversible increases in 45Ca outflow and modest stimulations of insulin release. In the presence of Ca2+, the reascension in 86Rb outflow was preceded by a transient fall in effluent radioactivity upon withdrawal of the sulfonylurea. At a higher concentration of D-glucose (8.3 mmol/l), glipizide provoked, each time, biphasic and rapidly reversible increases in both 86Rb and 45Ca outflow, as well as in insulin release. These results are compatible with the view that glipizide decreases K+ conductance, leading to depolarization of the B-cell plasma membrane and gating of voltage-sensitive Ca2+ channels. In the presence of 8.3 mmol/l D-glucose, however, the inhibitory effect of glipizide on effluent K+ permeability may be masked by activation of Ca2+-sensitive K+ channels. The present data also indicate that glipizide is able to evoke, at the occasion of iterative administrations, biphasic ionic and secretory responses, without evidence of tachyphylaxis

ISSN:0031-7012    

DOI:10.1159/000139027

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

An analog of somatostatin, SMS 201-995 (SMS; Sandostatin®), has been shown to have increased potency in the inhibition of hormone secretion in vivo. In this study, the effect of SMS on the secretion of immunoreactive insulin, gastrin and gastric somatostatin was examined in the rat using in situ vas-cularly perfused organ preparations. The analog was found to inhibit both basal somatostatin and gastrin secretion from the perfused stomach in a concentration-dependent manner. SMS (9.4 × 10–8 mol/l) also inhibited somatostatin release stimulated by gastric inhibitory polypeptide (GIP), but did not suppress gastrin release under the same conditions; an opposite effect was obtained when /-isoproterenol was used to stimulate somatostatin release. In the perfused pancreas both SS-14 (6.1 × 10–9 mol/l) and SMS (9.4 × 10–9 mol/l) inhibited the GIP (2 × 10–9 mol/l) or acetylcholine (1 × 10–6 mol/l), but not 17.8 × 10–9 mol/l glucose-stimulated insulin secretion. Insulin secretion stimulated by 17.8 × 10–3 mol/l glucose was unaffected by either peptide at this concentration. These results show that SMS is a potent inhibitor of gastric and pancreatic endocrine secretion. However, the inhibitory effect of SMS on gastric endocrine secretion was uncoupled in the presence of different secretagogues, suggesting that the action of SMS was dependent on the activation of different mechanisms or pathways in the stomach. In the pancreas, SMS appears to be acting on the β-cell via a similar mech

ISSN:0031-7012    

DOI:10.1159/000139028

出版商:S. Karger AG    

年代:1993

数据来源: Karger