Possible involvement of kinins in muscle energy metabolism.
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Adenine Nucleotides↗
Biomedical subjects
R Geiger
Publications and source records attributed to R Geiger.
[Peptide chemistry today].
Peptide chemistry has reached a plateau on which more work is devoted to the improvement of known basic principles than to the development of really new methods. As a consequence, routine syntheses of peptides concentrate on few protecting groups and coupling procedures only. The recent progress in purification of peptides by liquid chromatography helped to promote this trend. Meanwhile, recombinant technology permits the synthesis of proteins and possibly of some lower peptides, too. It cannot compete, however, with chemical solid-phase synthesis of a newly discovered peptide with up to about 40 amino acids in speed but may take over the synthesis for large-scale production. Peptides containing modified or non-natural structures, which are often superior to the natural compounds as drugs, will remain subject of chemical synthesis, too. Present research focuses on the role of peptide and protein factors in the immune response and on structure and biological activities of neuropeptides.
Adrenocorticotropic Hormone↗
Chemistry of the inhibitors of the renin-angiotensin system.
The enzyme renin splits a single peptide bond in the plasma glycoprotein angiotensinogen liberating the biologically inactive decapeptide angiotensin I (ANG I). A second enzyme, angiotensin converting enzyme (CE), releases the strong vasoconstricting octapeptide ANG II via degradation of a C-terminal dipeptide. The effect of this compound on blood pressure can be attenuated by interference with the enzyme-controlled peptide cascade of the renin-angiotensin system (RAS). This is accomplished by inhibition of renin and CE, respectively. Orally active CE inhibitors are valuable drugs in the treatment of renal and essential hypertension and of heart failure. Strong inhibitors of renin have also been synthesized, however, peptide moieties which have still to be present in these compounds impede oral absorption. Finally, antagonistic analogues of ANG II are able to block its effect on the receptor level. Their application is limited by the still existing partial agonistic activity.
Angiotensin II↗
Synthesis of a highly active angiotensin converting enzyme inhibitor: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).
The convergent, diastereoselective synthesis of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe acid (Hoe 498), a new ACE-inhibitor with improved bioavailability and pharmacokinetics, is described.
Angiotensin-Converting Enzyme Inhibitors↗
Kinin receptors and angiotensin converting enzyme in rabbits basilar arteries.
Bradykinin (BK) initially produced concentration related relaxations of the rabbit basilar artery in vitro under resting tension and when contracted with 5-hydroxytryptamine. Concentration-effect (C-E) curves to BK repeated at 2 h intervals over an 8-10 h period resulted in the production of progressively increased contractile responses. The induction of these contractile responses to BK was prevented by pre-incubation of these tissues with cycloheximide. On tissues which had been challenged with BK at 2 h intervals for 8 h in the absence of cycloheximide the rank order of potency of three kinins to produce contraction was methionyl-lysyl-BK (M-L-BK) greater than BK greater than des-Arg9-BK. On the same tissues the specific B1-receptor antagonist des-Arg9-Leu8-BK inhibited the contractile effects of BK. These results suggest the presence of a B1-receptor mediating contraction. The rank order of potency of the kinins to produce relaxation of tissues preincubated with cycloheximide was BK greater than M-L-BK greater than des-Arg9-BK which suggests the presence of a B2-receptor mediating these responses. Angiotensin I (AI) and angiotensin II (AII) produced concentration related contractions of the tissue. The angiotensin converting enzyme inhibitors captopril, BPP5a and BPP9a inhibited responses to AI but had no effect on contractile C-E curves to BK, AII and 5-HT or on relaxant C-E curves to BK. These results suggest that the rabbit basilar artery in vitro contains two BK receptors, a B1 receptor mediating contraction and a B2 receptor mediating relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin I↗
Human tissue kallikrein. I. Isolation and characterization of human pancreatic kallikrein from duodenal juice.
Human pancreatic kallikrein was purified from duodenal juice by ion exchange chromatography on DEAE-Sepharose and immunoaffinity chromatography. Thus, an enzyme preparation with a specific activity (using Ac-Phe-Arg-OEt as substrate) of 1 000 U/mg protein was obtained. A specific biological activity of 1310 KE/mg protein was measured in the dog blood pressure assay and of 0.361 HMW kininogen-U/mg, corresponding to the liberation of 383 micrograms bradykinin-equivalents per mg enzyme per min from HMW kininogen in the rat uterus assay. In dodecyl sulfate gel electrophoresis one protein band corresponding to a molecular mass of 27 kDa was obtained. Using gel filtration on Ultrogel AcA-44 a molecular mass of 40 kDa was measured. The amino-acid composition was determined and isoleucine and alanine were identified as the only N-terminal amino-acid residues. On isoelectric focusing four protein bands with isoelectric points of 5.60, 5.65, 5.70 and 5.85 were separated. The bimolecular velocity constant for the inhibition by diisopropyl fluoro phosphate was determined as 10.5 l x mol-1 x min-1. The dissociation constant Ki of the human pancreatic kallikrein-aprotinin complex was calculated to be 1.5 x 10(-10)M. The kinetic constants for the kallikrein-catalysed hydrolysis of Ac-Phe-Arg-OEt and D Val-Leu-Arg-Nan were determined. Immunological studies showed a close relationship between the human pancreatic kallikrein and other human tissue kallikreins, especially with human urinary kallikrein. Detergents such as Triton X-100, Tween 20 and lysolecithin, as well as human serum albumin, activated the human pancreatic kallikrein preparation.
Detergents↗
Human tissue kallikrein. II. Isolation and characterization of human salivary kallikrein.
Human salivary kallikrein was isolated from saliva using affinity chromatography on aprotinin-Sepharose and anti-human urinary kallikrein IgG-Sepharose followed by ion exchange chromatography on DEAE-Sepharose. The enzyme preparation had a specific activity of 950 U/mg protein towards the synthetic substrate Ac-Phe-Arg-OEt, a specific biological activity of 2000 KE/mg protein (measured in the dog blood pressure assay) and 0.64 HMW-kininogen-U/mg, corresponding to the liberation of 679 micrograms bradykinin equivalents per mg enzyme per min from HMW-kininogen (using the rat uterus test). In sodium dodecyl sulfate gel electrophoresis one protein band corresponding to a molecular mass of 32 kDa was obtained. The amino-acid composition was determined and isoleucin was found as the only N-terminal residue. The bimolecular velocity constant for the inhibition by diisopropyl fluorophosphate was determined as 8 l x mol-1 x min-1. The dissociation constant Ki of the human salivary kallikrein-aprotinin complex was calculated to be 0.7 x 10(-10)M. The Km and Vmax values for the hydrolysis of the synthetic substrates Ac-Phe-Arg-OEt and D Val-Leu-Arg-Nan were determined. In the enzyme immunoassay for human urinary kallikrein parallel binding curves were obtained.
Humans↗
Central and peripheral action of enkephalin analogues.
Chemical modifications of enkephalins led to analogues with strongly increased biological potency. Compounds such as H-Tyr-DLys(CHO)-Gly-Phe-L-homocysteinethiolactone (Hoe 825) additionally show a remarkable split between central and peripheral action, favouring the stimulation of gastrointestinal contractions. Hoe 825 could, therefore, be useful in the treatment of conditions where gut motility is lacking in humans, especially in adynamic ileus.
Animals↗
Biochemistry of human tissue kallikrein.
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Amino Acids↗
Mediator studies in skin blister fluid from patients with dual skin reactions after intradermal allergen injection.
Skin blister fluid (SBF) samples obtained after allergen skin testing in a total of 26 patients with late cutaneous reactions (LCRs) were examined for the presence of various vasoactive mediators. Histamine was predominant during the early phase of the wheal and flare reaction(206 +/- 40 ng/ml) and decreased with the development of the LCR toward normal SBF levels (around 20 ng/ml). Kallikrein activity was measurable in low amounts (around 5 ng/ml) in three out of 13 SBF samples taken 30 min after skin testing and in five of 13 SBF samples taken 6 hr after allergen testing. The thromboxane B2 content of SBF showed an increase with the development of LCR (control skin 976 +/- 483 ng/ml; allergen-tested skin 30 min after allergen injection, 1465 +/- 1566 ng/ml; allergen-tested skin 6 hr after antigen injection, 1775 +/- 731 ng/ml). SBF obtained from normal skin as well as from allergen-tested skin showed significant platelet-activating property as measured in an in vitro serotonin-release assay from washed human platelets. It is concluded that during the development of late-phase reactions a complex interaction of various mediator systems takes place.
Adolescent↗
Comparison of immunological and enzymatic properties of human urinary and pancreatic kallikrein.
Human urinary and human pancreatic kallikreins were compared by radioimmunoassay, immunoelectrophoresis, by their enzymatic activity using the substrate Ac-Phe-Arg-OEt and by their biological activity employing the dog blood pressure assay. The only significant difference observed was a higher anodal mobility of the urinary kallikrein under the conditions of immunoelectrophoresis.
Animals↗
Enzyme immunoassay of human urinary kallikrein. Determination of human urinary kallikrein, III.
An enzyme immunoassay for the determination of human urinary kallikrein has been developed and is compared with other human urinary kallikrein assays such as radioimmunoassay, dog blood pressure assay, rat uterus test after kinin liberation and synthetic substrate(20) tests (AcPheArgOEt and S-2266). The usable range of the standard curve is from 0.05 to 12 ng kallikrein per test. The intraassay coefficient of variation is between 2 and 4%, the interassay coefficient of variation is between 4 and 12%, and the recovery of authentic kallikrein added to urine samples is 95%. Human saliva and human pancreatic kallikrein show the same binding curves as purified human urinary kellikrein. Kallikrein from urine of rats, dogs and rabbits as well as boar acrosin and pig pancreatic kallikrein, bovine trypsin and chymotrypsin show no cross-reactivity.
Animals↗
[Exchange of A1-glycine in bovine insulin with L- and D-tryptophan].
Substitution of A1-glycine of insulin by L-amino acids yields in analogues with low biological activity. With D-amino acids in A1 biological activity is essentially retained. Synthesis of [A1-L-tryptophan]- and [A1-D-tryptophan]-insulin should provide information about the position of the side chains of L- and D-amino acids relative to A19-tyrosine, e.g. by evaluation of intramolecular resonance energy transfer between the fluorescent side chains. [A1-D-Tryptophan]-insulin exhibits full biological activity.
Adipose Tissue↗
Determination of bradykinin, kallidin and Met-Lys-bradykinin by high performance liquid chromatography.
A high performance liquid chromatography system was developed for the quantitative separation and determination of bradykinin, kallidin and Met-Lys-bradykinin using a reversed-phase column (Nucleosil 5 C8) and an isocratic buffer system. The lower limit of detection is 20 pmol for bradykinin. The intra-variation coefficient of the assay is between 1.8 and 5.7%. The recovery of bradykinin is higher than 96%. Addition of human serum albumin to the assay system in a concentration of 40% lead to a remarkable reduction of the detectable kinin level, which indicates an adsorption of kinins to serum albumin.
Amino Acid Sequence↗
Human urinary kallikrein.
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Chemical Phenomena↗
Progressive inhibition of human glandular (urinary) kallikrein by human serum and identification of the progressive antikallikrein as alpha 1-antitrypsin (alpha 1-protease inhibitor).
Human urinary kallikrein was inhibited by human alpha 1-antitrypsin (alpha 1-protease inhibitor) in a similar way as by equivalent amounts of human serum. The inhibitor present in the kallikrein-inhibitor complex formed was identified as alpha 1-antitrypsin by two-dimensional immunoelectrophoresis. Under the experimental conditions applied, 90 mIU (= 185 microgram) alpha 1-antitrypsin inhibits about 9 microgram of human urinary kallikrein in 24 h at 37 degrees C, 1 ml of human serum, containing 2-4 mg alpha 1-antitrypsin, inhibits about 70 microgram kallikrein. At an incubation temperature of 25 degrees C, the rate of inactivation is significantly lower than at 37 degrees C. No inhibition was observed at 0 degrees C or when alpha 1-antitrypsin was presaturated with trypsin.
Humans↗
[Synthesis of an insulin-like growth factor I hybrid insulin (author's transl)].
Stepwise Edman degradation of the insulin B chain is achieved after reversible protection of the amino groups in A1 and B29 with the acid-stable methylsulfonylethyloxycarbonyl residue. Condensation of the protected N-terminal tetrapeptide of insulin-like growth factor I with the degraded insulin yields an hybrid insulin whose synthesis and biological properties are discussed.
Amino Acid Sequence↗
Isolation of an enzymatically active tissue kallikrein from human seminal plasma by immunoaffinity chromatography.
A tissue kallikrein from human seminal plasma was isolated by immunoaffinity chromatography and characterized. Its molecular mass was determined by gel filtration to be approximately 40000 Da. The enzyme preparation liberates kinin from human HMW kininogen (specific activity: 0.594 HMW kininogen-U/mg), lowers the blood pressure of dogs after intravenous injection (specific activity: 1740 biol. kallikrein unit/mg) and is strongly inhibited by aprotinin but not by soybean trypsin inhibitor. N alpha-Acetyl-L-phenylalanyl-L-arginine ethyl ester, D-valyl-L-leucyl-L-agrine ethyl ester and N-benzyloxycarbonyl-L-tyrosine p-nitrophenyl ester are cleaved with identical rates by the enzyme from human seminal plasma and human urinary kallikrein.
Animals↗