Neutral Endopeptidase Up-Regulation in Isolated Human Umbilical Artery: Involvement in Desensitization of Bradykinin-Induced Vasoconstrictor Effects

Pelorosso, Facundo Germán; Halperin, Ana; Palma, Alejandro; Nowak, W; Errasti, Andrea Emilse; Rothlin, Rodolfo Pedro

doi:10.1124/jpet.106.113381

Cited by 4 publications

(3 citation statements)

References 46 publications

(58 reference statements)

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“…This sensitization process is dependent on the de novo synthesis of receptors (Sardi et al, 1998(Sardi et al, , 1999. Within human tissues, the in vitro induction of kinin B 1 receptor in colon, ileum, and coronary and umbilical arteries has been reported (Couture et al, 1981;Drummond and Cocks, 1995;Zuzack et al, 1996;Pelorosso et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In other series of experiments, HUV were snap-frozen after a 30-minute in vitro incubation in the presence of either BIX02188 (10 mM), SB203580 (10 mM), VX-702 (200 nM), SP600125 (3 mM), or PD184352 (1 mM). Western blot was performed after the protocols described in the online Supplemental Material and in our previous studies Pelorosso et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

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Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins

Kilstein

Nowak

Errasti

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The upregulated kinin B 1 receptors exert a pivotal role in modulating inflammatory processes. In isolated human umbilical veins (HUVs), kinin B 1 receptor is upregulated as a function of in vitro incubation time and proinflammatory stimuli. The aim of this study was to evaluate, using functional and biochemical methods, the involvement of extracellular signal-regulated kinase 5 (ERK5), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/ 2) on the kinin B 1 receptor upregulation process in HUV. Real-time polymerase chain reaction analysis revealed for the first time that kinin B 1 receptor mRNA expression closely parallels the functional sensitization to kinin B 1 receptor selective agonist des-Arg 10 -kallidin (DAKD) in HUV. Moreover, the selective inhibition of ERK5, p38 MAPK, and JNK, but not ERK1/2, produced a dosedependent rightward shift of the concentration-response curves to DAKD after 5-hour incubation and a reduction in kinin B 1 receptor mRNA expression. Biochemical analyses showed that ERK5, p38 MAPK, and JNK phosphorylation is maximal during the first 2 hours postisolation, followed by a significant reduction in the last 3 hours. None of the treatments modified the responses to serotonin, an unrelated agonist, suggesting a specific effect on kinin B 1 receptor upregulation. The present work provides for the first time pharmacologic evidence indicating that ERK5 plays a significant role on kinin B 1 receptor upregulation. Furthermore, we confirm the relevance of p38 MAPK and JNK as well as the lack of effect of ERK1/2 in this process. This study may contribute to a better understanding of MAPK involvement in inflammatory and immunologic diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins

Kilstein

Nowak

Errasti

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Human umbilical cords (n= 24) were collected from healthy and normotensive women after full-term vaginal or caesarean deliveries [33,34]. Artery preparations with intact endothelium were cut in rings of approximately 3 mm width and mounted in 10 ml organ baths in modified Krebs solution of the following composition (mmol/l): NaCl: 119, KCl: 4.7, NaHCO 3 : 25, KH 2 PO 4 : 1.2, CaCl 2 : 2.5, MgSO 4 :1.0, EDTA: 0.004 and D-glucose: 11.…”

Section: Preparation Of Human Umbilical Artery Ringsmentioning

confidence: 99%

EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin

Sakariassen¹,

Femia

Daray

et al. 2012

Thrombosis Research

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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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Neutral Endopeptidase Up-Regulation in Isolated Human Umbilical Artery: Involvement in Desensitization of Bradykinin-Induced Vasoconstrictor Effects

Abstract: Previous reports show that bradykinin B 2 receptors mediate contractile responses induced by bradykinin

Cited by 4 publications

References 46 publications

Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins

Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins

EV-077 in vitro inhibits platelet aggregation in type-2 diabetics on aspirin

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

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