摘要:

Cyclosporin A (CsA) is widely used as the immunosuppressant of choice for preventing graft rejection. However, its clinical use is hampered by certain side effects, especially its nephrotoxicity and other cardiovascular side effects. CsA for intravenous infusion contains cremophor (Cre) and this vehicle has significant adverse effects on endothelial function and vascular muscle. The present study was aimed at investigating the direct effects of CsA and Cre on isolated and perfused rat hearts in the dosage that closely approximates the peak level achieved for the prevention of graft rejection in the rat. Transplantation is a clinical setting in which the myocardium may be exposed to transient ischemia. In this study, we have shown that the vehicle of CsA, namely Cre, has significant adverse effects on cardiac function. We observed a reduction in coronary flow and aortic output. Addition of CsA appeared to induce a further reduction of aortic flow. We have also shown that a significant increase of thiobarbituric acid reactive substances, considered as an index of lipid peroxidation, occurred in the reperfused heart in the presence of Cre + CsA. Our experimental study shows that Cre turned out to be toxic to myocardium by itself. In the heart, potential Cre-CsA interactions possibly potentiating CsA toxicity could not be excluded. The increase of lipid peroxidation in the heart perfused with CsA suggests that reactive oxygen species may be involved in the detrimental effects of this substance on the heart.

ISSN:0031-7012    

DOI:10.1159/000139354

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The effects of cloricromene on plasma endothelin-1 (ET-1) levels and on microcirculatory function in 9 patients with peripheral atherosclerotic arteriopathy (PAA) and in healthy control subjects were studied. ET-1 levels and microcirculatory function were evaluated both under basal conditions and 30, 60, and 90 min after acute administration of cloricromene (30 mg i.v.). PAA patients had significantly increased levels of ET-1 and impaired vascular parameters (studied by means of Winsor’s Index, Gosling’s Index, postischemic perfusion index and recovery time) when compared to control subjects. The acute administration of cloricromene (30 mg i.v.) did not change plasma ET-1 both in control subjects and in patients with PAA. In contrast, cloricromene produced a significant improvement in the postischemic perfusion index and in recovery time in arteriopathic patients. Control subjects and patients with PAA also underwent a cold pressor test (CPT) under basal conditions and (72 h later) 30 min after an acute intravenous administration of cloricromene (30 mg i.v.). CPT caused a higher increase in ET-1 in the patients with PAA compared to the control group, and a reduction in the vascular flow at the femoral level, while the pretreatment with cloricromene prevented both the increase in the levels of ET-1 and the reduction of the femoral vascular flow observed after the cold stimulus in patients with PAA. Our data show that cloricromene, besides ameliorating the microcirculatory function, is able to interfere with dynamic mechanisms, such as those induced by the CPT, capable of stimulating the release of ET-1 at the vascular le

ISSN:0031-7012    

DOI:10.1159/000139355

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

To study the effects of aging on the blood pressure potency of phenylephrine, 6-, 10- and 40-week-old rats were used. In anesthetized rats, the potency (pD2 value) of phenylephrine on the blood pressure tended to increase with age from 6 to 10 weeks, but significantly decreased thereafter with age from 10 to 40 weeks. Similarly, in pithed rats, the potency of phenylephrine significantly increased, but decreased thereafter. In isolated rat thoracic aorta, the pD2 value of phenylephrine from the contractile responses significantly increased with age from 6 to 10 weeks, but decreased thereafter from 10 to 40 weeks. The change in the potency of phenylephrine on the blood pressure was proportional to the pD2 value of phenylephrine estimated in aortic preparations. The specific binding of [3H]prazosin to single smooth muscle cells of thoracic aorta from different aged rats was saturable. The maximum number of binding sites (Bmax) significantly increased with age from 6 to 10 weeks, but decreased thereafter from 10 to 40 weeks. However, the dissociation constant of [3H]prazosin (Kd) did not alter with age. The changes in the potencies (pD2 values) of phenylephrine on the pressure responses and on the contractile responses were proportional to the logarithm of the maximum number of binding sites. The present study suggests that age-related changes in blood pressure are due to changes in the maximum number of binding sites (receptor density) of α1-adrenoceptors

ISSN:0031-7012    

DOI:10.1159/000139356

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The pharmacokinetics and pharmacodynamics of EXP3174 {2-n-butyl-4-chloro-1- [(2’-(1H-tetrazole-5-yl)biphenyl-4-yl-)methyl]imidazole-5-carboxylic acid), an angiotensin II receptor antagonist, were studied in conscious rats. Elimination half-life, systemic clearance, and apparent volume of distribution of EXP3174 at a dose of 10 mg/kg i.v. were 2.9 h, 1.8 ml/ min/kg, and 0.25 l/kg, respectively. Inhibition of the angiotensin II pressor response correlated with the log of the steady state plasma EXP3174 concentration in a sigmoidal fashion with an IC50 of about 200 ng/ml. When corrected for plasma protein binding, the IC50 (free) for EXP3174 was 0.4 ng/ml (0.9 nmol/l). This study indicates a predictable plasma concentration-effect relationship of EXP3174 in rats which would be helpful in designing more rational dosing schemes for pharmacodynamic studie

ISSN:0031-7012    

DOI:10.1159/000139357

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The first step in the conversion of spironolactone (SP) to its biologically active metabolites is deacetylation to 7α-thiospirolactone (7α-thio-SL). Studies were done to evaluate the effects of reduced glutathione (GSH) on SP deacetylation by adrenal microsomal preparations. In the absence of GSH, adrenal microsomes catalyzed the conversion of SP to 7α-thio-SL at low rates. Addition of GSH to the incubation medium caused a concentration-dependent stimulation of SP deacetylation. At a concentration of 10 mM, GSH caused a 4- to 5-fold increase in the rate of 7α-thio-SL production. The results suggest that GSH may have an important role in the overall disposition of SP, including the formation of active metaboli

ISSN:0031-7012    

DOI:10.1159/000139358

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Experiments were performed in the longitudinal muscle strip of the guinea pig ileum to characterize the receptors involved in the contractile response of this preparation to neurokinins. Antagonists for the NK-1 (CP 96345, CP 99994) and NK-2 (SR 48968) receptors, atropine for NK-3 receptors, as well as diphenhydramine (histamine H1 receptor antagonist) and indometacin (cyclooxygenase inhibitor) were used to determine the relative contribution of neurokinin receptors and some endogenous agents to the myotropic effects of substance P (SP) and neurokinin receptor selective agonists. The present findings indicate that the three neurokinin receptor types take part in the contractile activities of SP-related peptides. NK-1 receptors, probably localized in the smooth muscle, are inhibited only by the two CP compounds and not by atropine or the other agents. NK-2 receptors contribute to the contraction by 5-10% and are blocked by SR 48968. NK-3 receptors act indirectly through the release of acetylcholine from the myenteric plexus, since activities of [MePhe7]NKB and senktide are blocked by atropine. Septide behaves as a selective NK-1 receptor agonist and does not show any difference with SP, except for higher sensitivity to CP antagonists. The same is observed with Ac[Arg6, Sar9, Met(02)π]SP(6-l 1), another NK-1-selective fragment. Discrepancies between antagonist pA2 values obtained against undeca- and hexapeptide agonists are interpreted as due to a stronger binding affinity of undecapeptide agonists as compared with the hexapeptides. Results of binding assays confirm data from the literature by showing that undecapeptide agonists have higher affinities than hexapeptides, particularly septide, and such discrepancies (with the biological assays) can also be explained by the reduction or absence of the cationic charge at the N terminal of septide

ISSN:0031-7012    

DOI:10.1159/000139359

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The protective effect of ‘chemical vagotomy’ (atropine given in three doses: 0.1, 0.5 and 1.0 mg/kg i.p.) was examined on indomethacin (IND, 20 mg/kg s.c.)-induced macroscopic gastrointestinal (GI) mucosal erosions and changes of vascular permeability in the stomach and three equal parts of small intestine and colon in rats. The different doses of atropine were administered at 0, 5, 10, 15 and 20 h after IND administration, then the number and severity of lesions were noted and the vascular damage was measured by Evans blue extravasation into the mucosa and intraluminal juice at 24 h after the IND treatment. Our results indicate that atropine (‘chemical vagotomy’) dose-dependently and significantly decreases the IND-induced mucosal erosions and vascular permeability in the vagal nerve-innervated parts of GI tract (i.e. the stomach, small intestine and proximal colon). Atropine in 0.5 and 1.0 mg/kg doses has a significantly higher protective effect on the vascular damage than on the macroscopic mucosal lesions in the stomach, small intestine and proximal colon. The vascular permeability is only one of those factors which have a role in the appearance of the GI mucosal erosions after IND treatment. These results suggest that the decrease of vascular permeability is involved in the protective effect of atropine against IND-induced GI mucosal

ISSN:0031-7012    

DOI:10.1159/000139360

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

The effects of intraperitoneal and intracerebroventricular administration of the inhibitor of endopeptidase EC 24.11 (enkephalinase), thiorphan, and the synthetic enkephalin analogue [D-Ala2-Met5]enkephalinamide (DALA) were investigated in cold-restraint-stressed rats. Drugs were administered alone or after pretreatment with naloxone or naloxone methiodide given 20 min prior to the drugs. Thiorphan and DALA, administered centrally (4 µg i.c.v./rat) or peripherally (400 µg/kg), induced a significant gastric protection. Prior treatment with naloxone s.c. (1 mg/kg) inhibited the effect induced by i.e.v. or i.p. injections of thiorphan or DALA. In contrast, s.c. administration of naloxone methiodide (1 mg/ kg) did not affect the response induced by central administration of thiorphan or DALA, but was able to prevent that of thiorphan or DALA when they were administered i.p. These data strongly support the hypothesis of a central and peripheral involvement of endogenous opioid peptides in gastric protection in stressed rat

ISSN:0031-7012    

DOI:10.1159/000139361

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Copper-zinc superoxide dismutase was purified from Ascαris suum (Nematoda). Four benzimidazole derivatives, six recently synthesized pyrimidine derivatives and eleven recently synthesized glycine derivatives were shown to inhibit: (1) purified extracts of A. suum superoxide dismutase; (2) superoxide dismutase from host liver, and (3) purified extracts of superoxide dismutase from living A. suum incubated in the presence of these drugs. Thiabendazole compounds, with a documented effect against helminth parasites, were found to affect the superoxide dismutase. The inhibitory effects of some pyrimidine and glycine derivatives were higher than those of benzimidazoles, and the pyrimidine compounds failed to inhibit the host’s enzyme. These derivatives are candidate anthelmintics, acting as inhibitors of certain metalloenzymes in parasit

ISSN:0031-7012    

DOI:10.1159/000139362

出版商:S. Karger AG    

年代:1996

数据来源: Karger