Kinetics of oxytocin and deaminooxytocin displacement from the OXTR -receptor compartment in rat uterus ex vivo

Pliška, V.; Jutz, Guido

doi:10.1016/j.bcp.2018.01.006

Cited by 3 publications

(17 citation statements)

References 31 publications

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“…In the case of membrane‐bound receptors, the ligand–receptor interaction space is limited to the interstitial space close to the outer part of the cell membrane, which appears to be very narrow. Its topology in rat myometrium based on histometric data has been discussed in more detail in our previous communication 22 . The concentration gradient of an amphiphilic substance—like peptides—near a biological membrane follows the Gouy–Chapman particle distribution around the negatively charged membrane surface 56 and causes an inhomogeneity of the interstitium just on the ligand–receptor interaction site.…”

Section: Discussionmentioning

confidence: 99%

“…The suggested compartment structure itself and the employed methodical approach require some additional comments. First, a receptor compartment is currently defined as a structural unit in which the concentration of a stimulating agent regulates a specified response 22–24 . In this sense, it belongs to the pharmacologically formulated group of “fluid compartments.” These are conventionally considered as space elements of biological entities (organisms, tissues, cells, etc.)…”

Section: Discussionmentioning

confidence: 99%

“…Measurements were carried out at 30°C under continuous ventilation with Carbogen gas (25% O 2 + 5% CO 2 ). The protocol of time–response measurements was presented in detail in our precedent communication 22 . Each strip used for stimulation by a single peptide (for concentration of stimulating agents, cf.…”

Section: Methodsmentioning

confidence: 99%

“…The intrinsic relaxation dynamics of the stimulated tissue is another factor of the muscle state change, potentially overlapping with the "pure" drug effect. A recent kinetic analysis of the uterotonic response to oxytocin and deaminooxytocin 22 indicates that such additional dynamic processes in myometrium are not rate determining.…”

Section: Response Kinetics: Combined Steady State With Exponential Termsmentioning

confidence: 99%

“…Second, besides the transport and clearance processes, the time course of a response to a drug stimulation can possibly be influenced by the kinetics of drug-receptor interaction, and/or by the internal contraction-relaxation dynamics of the responding smooth muscle tissue. As for oxytocin, the influence of the receptor kinetics was investigated in more detail in our previous report, by using k on , k off data for binding of oxytocin to myometrium membranes in in vitro preparations reported by various laboratories (summary in Pliska and Jutz 22 ).…”

Section: Pharmacokinetic Aspectsmentioning

confidence: 99%

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Clearance of oxytocin and its potentially enzyme resistant analogues in the OXT‐receptor compartment of the potassium depolarized rat myometrium

Pliška

Jutz

2021

Journal of Peptide Science

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The time–response behaviour of a group of oxytocin analogues structurally modified on potential sites of oxytocin splitting by tissue inactivation enzymes (“enzyme probes”) was investigated ex vivo on the potassium depolarized rat myometrium (at 30°C) and compared with the data obtained in the in vivo experiments. The modified oil‐immersion method by Kalsner and Nickerson was used to record time profiles after cessation of a steady state myometrium contraction triggered by analogues in a high potassium tissue medium. An exchange of the aqueous medium for mineral oil enables to suppress return diffusion of the peptide and to record its irreversible clearance near the corresponding receptor compartment. Response records were analysed by a nonlinear numeric procedure based on combination of steady state and kinetic terms that allows concomitant estimations of affinities from time–response measurements, in the given case for analogues on depolarized myometrium. Potential inactivation‐sensitive sites in the oxytocin chain are the Ν‐terminal peptide bond Cys1‐Tyr2 (aminopeptidase splitting), the intramolecular disulphide bridge (reduction and formation of the practically inactive linear peptide) and the C‐terminal Leu8‐GlyNH29 or the Pro7‐Leu8 (postprolin cleaving enzyme) bond, respectively. Clearance rate constants of single peptides in the OXT‐receptor compartment were in an interval of 0.025 to 0.28 min−1. The fragment contribution analysis reveals a significant linear additivity of individual structural changes and thus a predictivity of irreversible inactivation rate in the receptor compartment. The most potent inactivation of oxytocin is associated with aminopeptidase splitting; other enzymes may play some though nondecisive role. Less significant differences within the peptide group were found for rate constants for peptide transport between receptor compartment and its external aqueous medium. Besides rate constants, the evaluation of time–response data yields affinity values of the tested peptides and indicates a 25‐times desensitation of depolarized compared with a native state.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Response Kinetics: Combined Steady State With Exponential Termsmentioning

confidence: 99%

Section: Pharmacokinetic Aspectsmentioning

confidence: 99%

See 3 more Smart Citations

Clearance of oxytocin and its potentially enzyme resistant analogues in the OXT‐receptor compartment of the potassium depolarized rat myometrium

Pliška

Jutz

2021

Journal of Peptide Science

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Based on UPLC/MS/MS and Bioinformatics Analysis to Explore the Difference Substances and Mechanism of Curcumae Radix (Curcuma wenyujin) in Dysmenorrhea

Qin

Fei

Zhang

et al. 2022

Chemistry & Biodiversity

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Background: Curcumae Radix (CW) is traditionally used to treat dysmenorrhea caused by uterine spasm. However, the changes of its composition and anti-uterine spasms during vinegar processing and the mechanism in treating dysmenorrhea are not clear. Objective: To elucidate the changes of anti-uterine spasm and its substance basis, and the mechanism of treating dysmenorrhea before and after vinegar processing. Methods:The uterine spasm contraction model was established, and the uterine activity and its inhibition rate were calculated to evaluate the differences. The main chemical constituents of CW were quickly analyzed by UPLC-Q-TOF-MS/MS technology, and the differences between them were explored by multivariate statistical analysis. Then, the regulatory network of "active ingredients-core targets-signal pathways" related to dysmenorrhea was constructed by using network pharmacology, and the combination between differential active components and targets was verified by molecular docking. Results: CW extract relaxed the isolated uterine by reducing the contractile tension, amplitude, and frequency. Compared with CW, the inhibitory effect of vinegar products was stronger, and the inhibition rate was 70.08 %. 39 compounds were identified from CW and 13 differential components were screened out (p < 0.05). Network pharmacology screened 11 active components and 32 potential targets, involving 10 key pathways related to dysmenorrhea. The results of molecular docking showed that these differentially active components had good binding activity to target. Conclusion: It was preliminarily revealed that CW could treat dysmenorrhea mainly through the regulation of inflammatory reaction, relaxing smooth muscle and endocrine by curcumenone, 13-hydroxygermacrone, (+)-cuparene, caryophyllene oxide, zederone, and isocurcumenol.

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Histological Features of Uterine Myometrial Dysfunction: Possible Involvement of Localized Inflammation

Zhu,

Zhang,

et al. 2024

CURR MED SCI

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Kinetics of oxytocin and deaminooxytocin displacement from the OXTR -receptor compartment in rat uterus ex vivo

Cited by 3 publications

References 31 publications

Clearance of oxytocin and its potentially enzyme resistant analogues in the OXT‐receptor compartment of the potassium depolarized rat myometrium

Clearance of oxytocin and its potentially enzyme resistant analogues in the OXT‐receptor compartment of the potassium depolarized rat myometrium

Based on UPLC/MS/MS and Bioinformatics Analysis to Explore the Difference Substances and Mechanism of Curcumae Radix (Curcuma wenyujin) in Dysmenorrhea

Histological Features of Uterine Myometrial Dysfunction: Possible Involvement of Localized Inflammation

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