摘要:

Various attempts to developing antagonists for substance P (SP) and related peptides, based on our past experience with angiotensin, kinins, and neurotensin, were unsuccessful. The particular features of SP, namely the high activity of C-terminal partial sequences in some pharmacological tests were used to develop one hexa and several octapeptide antagonists. Weak antagonists were obtained with a single modification, namely the replacement of Leu10 with trp in the sequences SP (6–11), SP (4–11) and SP (1–11). The affinity of octa and undecapeptide antagonists could be increased by using two (in positions 7 and 9 or 7 and 10) or 3 (in position 7, 9 and 10) substitutions of the natural residues with trp. Affinity of antagonists was further increased by replacing Met11 with either Nle or Phe. These new compounds showed some selectivity, [pro4, trp7’9, Nleπ]-SP (4–11) being more potent in the rabbit mesenteric vein than all other octapeptides described in the present study; on the other hand, [pro4, trp7’9’10, Phe11]-SP (4–11) was found to be the most potent antagonist of SP and related peptides in the guinea pig ileum and the guinea pig trachea. Both compounds were similarly active in the dog carotid artery. Undecapeptide antagonists, bearing the same structural modifications as the octapeptides, were found to be stimulant in the guinea pig trachea and relaxant in the dog carotid artery. The agonistic property was eliminated by repeated applications of the compounds in guinea pig tracheae, and therefore the compounds could be tested as antagonists. The undecapeptides were found to be much more active antagonists against kassinin and eledoisin than against SP and physalaemin. The data obtained with the octa and undecapeptide antagonists of SP have been used for identification and characterization of SP receptors in various smooth muscles. It appears that SP and related peptides may exert their numerous pharmacological effects by activating more than o

ISSN:0031-7012    

DOI:10.1159/000137979

出版商:S. Karger AG    

年代:1984

数据来源: Karger

摘要:

The epoxide hydrolase activity with styrene oxide as substrate was investigated in the nuclear fraction of human fetal and adult liver specimens. All investigated liver fractions catalyzed the hydration of styrene oxide and the average epoxide hydrolase activities were 0.37 and 1.90 nmol/min/mg protein in fetal and adult specimens, respectively. The enzyme followed Michaelis-Menten kinetics in fetal nuclear fraction and biphasic kinetics in adult livers. The nuclear/microsomal enzyme activity ratios of epoxide hydrolase were 0.09 and 0.11 for fetal and adult livers, respectively.

ISSN:0031-7012    

DOI:10.1159/000137980

出版商:S. Karger AG    

年代:1984

数据来源: Karger

摘要:

The anticonvulsant effect of primidone was determined in gerbils, in which seizures were elicited by a blast of compressed air, over the time range of 30 min to 18 h after oral administration. ED50s remained fairly constant from 1 to 12 h after administration: 46–73 µmol/kg with the minimal value at 6 h. Of the metabolites, phenobarbital was maximally effective at 2 h after administration (ED50 35 µmol/kg), whereas phenylefhylmalondiamide (PEMA) only had a weak anticonvulsant effect (ED50 1.55mmol/kg at 2 h). By determination of primidone and its active metabolites in plasma and brain at 1 4 and 12 h after administration of the respective ED50s, it could be shown that unchanged primidone is mostly responsible for the anticonvulsant effect of the first hours, but, at 12 h, only phenobarbital could be detected in both tissues. PEMA could not be detected in brain. From the effective brain concentrations at different times it could be calculated that primidone and phenobarbital have the same anticonvulsant potency on a molar base in the gerbil. The concentrations necessary to control seizures in this model were considerably lower than those needed to suppress convulsions in maximal seizure models in mice and r

ISSN:0031-7012    

DOI:10.1159/000137981

出版商:S. Karger AG    

年代:1984

数据来源: Karger

摘要:

We studied the influence of a perfluorochemical (PFC) emulsion on the ultrastructure and function of the isolated perfused guinea pig heart compared to a Krebs-Henseleit solution. The PFC perfusion enhanced the force of contraction and reduced the coronary flow rate, but had no influence on the frequency and the oxygen consumption. The positive inotropic action of K-strophanthin and isoproterenol was slightly strengthened, whereas the β-adrenergic antagonism by propranolol and the vasodilatation by glycerol trinitrate remained unchanged. The positive chronotropic action of isoproterenol was reduced during PFC perfusion. No histological differences depending on the perfusion medium were observed. It is concluded that PFC perfusion improves the functional state of the Langendorff preparation

ISSN:0031-7012    

DOI:10.1159/000137982

出版商:S. Karger AG    

年代:1984

数据来源: Karger

摘要:

Indogs, a single dose of quinine led to a redistribution of digoxin in tissues, which was reflected by an acute and biphasic change in plasma and blood concentrations.

ISSN:0031-7012    

DOI:10.1159/000137983

出版商:S. Karger AG    

年代:1984

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000137984

出版商:S. Karger AG    

年代:1984

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000137985

出版商:S. Karger AG    

年代:1984

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000137978

出版商:S. Karger AG    

年代:1984

数据来源: Karger