International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

Halls, Michelle L.; Bathgate, Ross A. D.; Sutton, Steve W.; Dschietzig, Thomas

doi:10.1124/pr.114.009472

Cited by 117 publications

(123 citation statements)

References 498 publications

(786 reference statements)

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“…The immediate response of relaxin-2 signaling in blood vessels involves activation of phosphoinositide 3-kinase via G ␤␥ , activation of protein kinase B/Akt, phosphorylation of endothelial NO synthase (eNOS), and release of NO (Ref. 21 and references therein). Therefore, region-specific differential activation of one of these mediators is most likely responsible for the observed differences in CBF.…”

Section: Discussionmentioning

confidence: 99%

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Bischoff

Schmidt

Irintchev

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Serelaxin, recombinant human relaxin-2, modulates endothelial vasodilatory functionality and is under evaluation for treatment of acute heart failure. Little is known about acute effects on cerebral perfusion. We tested the hypothesis that Serelaxin might also have effects on the cerebral microcirculation in a sheep model, which resembles human brain structure quite well. We used laser Doppler flowmetry and sidestream dark-field (SDF) imaging techniques, which are reliable tools to continuously assess dynamic changes in cerebral perfusion. Laser Doppler flowmetry shows that bolus injection of 30 g Serelaxin/kg body wt induces an increase (P ϭ 0.006) to roughly 150% of cortical cerebral blood flow (CBF), whereas subcortical CBF remains unchanged (P ϭ 0.688). The effects on area-dependent CBF were significantly different after the bolus injection (P ϭ 0.042). Effects on cortical CBF were further confirmed by SDF imaging. The bolus injection of Serelaxin increased total vessel density to 127% (P ϭ 0.00046), perfused vessel density to 145% (P ϭ 0.024), and perfused capillary density to 153% (P ϭ 0.024). Western blotting confirmed the expression of relaxin receptors RXFP1 and truncated RXFP2-variants in the respective brain regions, suggesting a possible contribution of RXFP1 on the effects of Serelaxin. In conclusion, the injection of a high dose of Serelaxin exerts quick effects on the cerebral microcirculation. Therefore, Serelaxin might be suitable to improve cortical microcirculation and exert neuroprotective effects in clinically relevant scenarios that involve cortical hypoperfusion. These findings need to be confirmed in relevant experimental settings involving cerebral cortical hypoperfusion and can possibly be translated into clinical practice. RELAXIN-2 IS A HUMAN HORMONE that mediates cardiovascular adaptations during pregnancy and particularly systemic and renal vasodilatation (7). Moreover, these effects are observed in nonpregnant animals and in ex vivo studies following the artificial administration of the substance as well (33). An intravenous bolus injection of a recombinant form of human relaxin-2, Serelaxin (Novartis Pharma, Basel, Switzerland), modulates a sustained endothelial vasodilatory function. Serelaxin mediates systemic hemodynamic changes and increases renal blood flow through a fall in systemic intravascular resistance with a concomitant increase in arterial compliance (15,22,31,38,39). In the RELAX-AHF study, cardiovascular and all-cause mortality was reduced 37% in patients treated with Serelaxin (42). Furthermore, initial positive studies on the cerebral effects of this peptide hormone in a stroke model (47) and in a high blood pressure situation (6) have already been published. Serelaxin induces a nitric oxide-mediated vasodilatation (40) and can particularly reduce the infarction size of the cerebral cortex, suggesting a neuroprotective effect (47).Nonetheless, studies on the influence of Serelaxin on the cerebral blood flow (CBF) have not been performed to this day. Moreover, desp...

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Section: Discussionmentioning

confidence: 99%

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Bischoff

Schmidt

Irintchev

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Несмотря на общий план строения, первич-ная структура цепей релаксина и инсулина существенно отличается, что и обусловливает различную направленность их биологических эффектов. При этом синтез релаксина, так же как и инсулина, осуществляется в форме пред-шественника -препрорелаксина (preprorelaxin (ppRLX)), который превращается в зрелый гормон в результате отщепления конвертаза-ми сигнального пептида и соединения двух цепей [8][9][10]. …”

Section: структура и синтезunclassified

“…Известно, что релаксин является плейотроп-ным гормоном и оказывает влияние на функ-ции многих органов и систем, но основной его биологический эффект направлен на преобра-зование органов-мишеней (тела и шейки мат-ки, молочных желез), играющих наиболее важ-ную роль при беременности, родах и лактации [9,10,13,14].…”

Section: роль релаксина в репродуктивной системеunclassified

Prognostic possibilities of relaxin as a marker of preterm birth

et al. 2018

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Premature birth is one of the most important problems of modern obstetrics because it is a leading cause of childhood morbidity and mortality in all countries. Annually, > 1 million premature newborns worldwide die from various types of complications, and most of the survivors become disabled. Moreover, according to WHO analysis, most of these children can be saved by developing measures for the early identification of preterm births, which will provide additional time for effective intervention. Currently, available diagnostic methods do not adequately assess the risks of premature delivery owing to the low predictive value of the methods. This makes it necessary to search for predictors of preterm labor that can improve the accuracy of diagnostic techniques. The desired predictors should have a pathogenetic basis, and most importantly, they must contribute to the early detection of life-threatening premature births. The hormone relaxin could be considered to be a promising marker of premature birth because its role in the pathogenesis of premature birth is unquestionable, and the evaluation of its levels is possible during the early stages of pregnancy.

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“…It is primarily expressed in reproductive tissues (for details see Bathgate et al 2013;Halls et al 2015) and also influences bone metabolism (Ferlin et al 2010). RXFP2 signaling also involves adenylyl cyclase (AC) activation and cAMP generation, utilizing a subset of the G proteins used by RXFP1 (Halls et al 2006).…”

Section: Historical Background: Relaxin Family Peptides and Their Recmentioning

confidence: 99%

Ral

Pollock¹,

Kashatus²

2018

Encyclopedia of Signaling Molecules

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International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

Cited by 117 publications

References 498 publications

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model

Prognostic possibilities of relaxin as a marker of preterm birth

Ral

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