Pharmacological characterization of muscarinic receptor subtypes mediating vasoconstriction of human umbilical vein

Pujol-Lereis, Virginia; Hita, Francisco Javier; Gobbi, Mauro Darío; Verdi, Marcela Gomez; Rodríguez, María Cecilia; Rothlin, Rodolfo Pedro

doi:10.1038/sj.bjp.0706654

Cited by 23 publications

(10 citation statements)

References 46 publications

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“…Then we used specific receptor antagonists on umbilical vessels before applying ACh, the results showed that MR1 and MR3 antagonists could partially inhibit the vasoconstrictions. Although the contractile response related to MR subtypes was complex, the results in rat umbilical vessels supported the finding from previous studies in human umbilical vessels [28]. It is known that the muscarinic receptor type 3 is the main subtype of muscarinic receptors in endothelium of intact vessels.…”

Section: Discussionsupporting

confidence: 85%

“…Following previous reports on ACh-mediated umbilical vaso-constriction in human [28], recently, our team not only provided additional new evidence regarding ACh’s effects on human umbilical arteries and veins, but also found that ACh-induced umbilical contraction in rats and sheep [7], as the first time to demonstrate ACh-mediated umbilical vasoconstrictions in various animals. The present study extended the study and was the first to show that ACh could reliably cause contraction in umbilical vessels in rabbits too.…”

Section: Discussionmentioning

confidence: 65%

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Roles of ion channels in regulation of acetylcholine-mediated vasoconstrictions in umbilical cords of rabbit/rats

Zhu

Tang

Zhou

et al. 2016

Reproductive Toxicology

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We recently demonstrated that acetylcholine (ACh) produced reliable vasoconstrictions in the umbilical cords. This study investigated the possible mechanisms with different antagonists. ACh-mediated vasoconstrictions were decreased by voltage-operated calcium (Ca2+) channels antagonist nifedipine or inositol-1,4,5-trisphosphate-mediated Ca2+ release antagonist 2-aminoethyl diphenylborinate, indicating that both extracellular and intracellular calcium modulated the ACh-stimulated umbilical contraction. Intracellular Ca2+ concentrations were increased simultaneously with vasoconstrictions by ACh in the umbilical vessels. Inhibiting large-conductance calcium-dependent potassium (BK) channels enhanced ACh-mediated contraction, whereas inhibiting voltage dependent potassium (K+), inward rectifier K+ and ATP-sensitive K+ channels had no effects. Incubation with specific K+ channel inhibitors showed that ACh suppressed BK currents rather than 4-aminopyridine-sensitive K+ channels currents. The results suggested that blood vessels in umbilical cords had special characteristics in response to cholinergic signals. ACh-stimulated umbilical vasoconstrictions were mediated via muscarinic receptor subtype 1/3–protein kinase C/cyclooxygenase-BK channel pathways.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 65%

Roles of ion channels in regulation of acetylcholine-mediated vasoconstrictions in umbilical cords of rabbit/rats

Zhu

Tang

Zhou

et al. 2016

Reproductive Toxicology

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“…In other words, ACh did not cause vasoconstriction from the basal tone, but induced further additional constriction after KCl‐, 5‐HT‐ or PGE 2 ‐mediated vasoconstriction. Although a previous study has shown that ACh causes vasoconstriction in the resting state in human umbilical cords, it did not show that ACh produced further vascular constriction above the maximum vessel tension generated by KCl, 5‐HT or PGE 2 . This provides important information for clinical practice, because any factor that can increase cholinergic activation during pregnancy may alter blood flow or oxygen supply to the fetus.…”

Section: Discussionmentioning

confidence: 62%

“…Unless endothelial function is damaged, ACh has a relaxant effect on most intact blood vessels . However, ACh has been shown to cause vasoconstriction in human umbilical arteries (HUAs) and human umbilical veins (HUVs) . .…”

Section: Introductionmentioning

confidence: 99%

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Muscarinic‐mediated vasoconstriction in human, rat and sheep umbilical cords and related vasoconstriction mechanisms

Chen

et al. 2014

BJOG

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Objective The umbilical cord provides nutrition and oxygen to the fetus. The aim of this study was to determine the effects of acetylcholine (ACh) on umbilical cords from humans and other mammals, and the mechanisms of ACh-mediated vasoconstriction in the human umbilical cord.Design Human and animal umbilical cords used in vascular and cellular experiments.Setting Institute for Fetology, First Hospital of Soochow University, Suzhou, China.Population A total of 85 pregnant women, 16 Sprague Dawley rats and seven pregnant sheep.Methods Umbilical cord veins and arteries from humans, rats and sheep, aortas and mesenteric arteries from rats, and mesenteric, carotid and femoral arteries from ovine fetuses were used to compare vascular functions in response to ACh and to determine the mechanisms of ACh-mediated umbilical vasoconstriction. Vascular tension and ion channel currents were measured on isolated vessels and smooth muscle cells from human umbilical cords.Main outcome measures Provision of new evidence to conclude that ACh-stimulated vasoconstriction is common to all umbilical cords, and cellular mechanisms are linked to potassium channels.Results ACh caused reliable vasoconstriction in umbilical veins/ arteries in humans, rats and sheep, but not in any other vessels, including fetal vessels. Atropine inhibited the effects of ACh. The mRNA of ACh-muscarinic receptor subtypes M 1 -M 5 was expressed in human umbilical vessels. The protein kinase C antagonist GF109203X and the calcium inhibitor nifedipine decreased ACh-induced vasoconstriction in human umbilical vessels. ACh also caused a reduction in whole-cell potassium channel currents and the single-channel current of largeconductance calcium-activated potassium (BKca) channels.Conclusion Umbilical vessels are significantly different from other vessels in their response to ACh. BKca channels in smooth muscle cells may play important roles in ACh-mediated vasoconstriction in human umbilical cords. This information may be important for fetal medicine and practice with regard to the effect on fetal development of umbilical vascular functions.Keywords Acetylcholine, BKca current, muscarinic receptor, umbilical cord vessels, vascular constriction.

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Functional evidence of des-Arg10-kallidin enzymatic inactivating pathway in isolated human umbilical vein

Nowak

Goldschmidt

Georgina

et al. 2007

Naunyn-Schmied Arch Pharmacol

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It has been known for many years that plasma and tissues contain a variety of enzymes capable of metabolizing kinins. The aim of the present study was to evaluate, by means of functional studies in a capacitance vessel such as the human umbilical vein (HUV), the possible role played by the metallopeptidases angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and aminopeptidase M (APM) as an inactivating pathway of the B(1) receptor endogenous agonist des-Arg(10)-kallidin (DAKD). In HUV rings with and without endothelium, concentration-response curves (CRCs) to DAKD were determined after a 300-min incubation period, and enzymatic inhibitors were added to the organ baths 30 min before construction of the CRC. Presence of endothelial layer was confirmed by histological studies. There was a significant leftward shift observed in control HUV rings devoid of endothelium compared with intact tissues. Exposure to 1 microM captopril (ACE inhibitor) potentiated DAKD-elicited vasoconstrictor responses in HUV rings with endothelium while no such effect was observed in tissues devoid of endothelium. Application of 10 microM amastatin (APM inhibitor) induced a leftward shift of DAKD-elicited contractile responses in HUV with and without endothelium. On the other hand, 10 microM phosphoramidon (NEP inhibitor) showed no potentiating effect in HUV rings either with or without endothelium. However, under concurrent inhibition of ACE, NEP and APM, there was a higher potentiation of DAKD-elicited contractile responses compared with the effect observed with combined inhibition of ACE and APM. Moreover, when we evaluated contractile responses induced by Sar(0)-D-Phe(8)-des-Arg(9)-BK (a metabolically protected B(1) receptor agonist), no potentiating effect was observed under triple enzymatic inhibition. In conclusion, in the present study for the first time, we demonstrated in a capacitance vessel, HUV, that metallopeptidases ACE, NEP and APM represent a relevant functional inactivation pathway of DAKD.

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Pharmacological characterization of muscarinic receptor subtypes mediating vasoconstriction of human umbilical vein

Cited by 23 publications

References 46 publications

Roles of ion channels in regulation of acetylcholine-mediated vasoconstrictions in umbilical cords of rabbit/rats

Roles of ion channels in regulation of acetylcholine-mediated vasoconstrictions in umbilical cords of rabbit/rats

Muscarinic‐mediated vasoconstriction in human, rat and sheep umbilical cords and related vasoconstriction mechanisms

Functional evidence of des-Arg10-kallidin enzymatic inactivating pathway in isolated human umbilical vein

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