Inhibition of Neurogenic Contractions in Renal Arteries and of Cholinergic Contractions in Coronary Arteries by the Presumed Inhibitor of ADP-ribosylation Factor 6, NAV2729

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2022 Feb 10

PMID 35141760

Authors

Ru Huang

Bingsheng Li

Alexander Tamalunas

Raphaela Waidelich

Christian G Stief

Martin Hennenberg

Affiliations

Soon will be listed here.

Abstract

NAV2729 is a presumed inhibitor of the monomeric GTPase ADP ribosylation factor 6 (ARF6) and inhibits smooth muscle contraction outside the cardiovascular system. Its effects on vascular smooth muscle contraction or a possible role of ARF6 in vasocontraction have not yet been examined. Here, we report effects of NAV2729 on neurogenic and agonist-induced contractions in renal interlobar and coronary arteries. Contractions of pig interlobar and coronary arteries were induced in an organ bath by agonists or by electric field stimulation (EFS). Owing to divergent characteristics of both vessel types, EFS-induced contractions were only examined in interlobar arteries, and contractions by agonists acting on muscarinic receptors only in coronary arteries. NAV2729 inhibited frequency-dependent EFS-induced contractions of interlobar arteries. The degree of inhibition was similar using 5 µM and 10 µM NAV2729. Inhibition of EFS-induced contractions was resistant to a nitric oxide synthase inhibitor and to diclofenac. The neurogenic and adrenergic character of EFS-induced contractions was confirmed by inhibition by tetrodotoxin and prazosin. In coronary arteries, NAV2729 (5 µM) inhibited concentration-dependent contractions induced by carbachol and methacholine. Contractions induced by α-adrenergic agonists, endothelin-1, the thromboxane receptor agonist U46619, or serotonin remained unchanged by NAV2729 in both vessel types. NAV2729 inhibits neurogenic contractions in interlobar arteries and contractions induced by cholinergic agonists in coronary arteries. In both vessel types, NAV2729 does not inhibit contractions induced by receptor agonists other than those acting on muscarinic receptors. Addressing effects in other vessels and in other smooth muscle-rich organs merits further attention.

Citing Articles

Smooth muscle contractility of laser-enucleated prostate tissues and impacts of preoperative α-blocker treatment in patients with and without catheterization.

Keller P, Hu S, Berger L, Nicola P, Schierholz F, Tamalunas A Sci Rep. 2025; 15(1):4985.

PMID: 39929919 PMC: 11811036. DOI: 10.1038/s41598-025-88884-7.

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle.

Hu S, Trieb M, Huang R, Tamalunas A, Keller P, Gotz M Naunyn Schmiedebergs Arch Pharmacol. 2023; 397(2):1219-1231.

PMID: 37658212 PMC: 10791718. DOI: 10.1007/s00210-023-02664-6.

Does coupling to ADP ribosylation factor 6 explain differences between muscarinic and other receptors in interaction with β-adrenoceptor-mediated smooth muscle relaxation?.

Erdogan B, Michel M Naunyn Schmiedebergs Arch Pharmacol. 2022; 395(4):381-386.

PMID: 35175382 PMC: 8873149. DOI: 10.1007/s00210-022-02221-7.

References

Herlemann A, Keller P, Schott M, Tamalunas A, Ciotkowska A, Rutz B . Inhibition of smooth muscle contraction and ARF6 activity by the inhibitor for cytohesin GEFs, secinH3, in the human prostate. Am J Physiol Renal Physiol. 2017; 314(1):F47-F57. DOI: 10.1152/ajprenal.00125.2017. View

Wang R, Schneider S, Keppler O, Li B, Rutz B, Ciotkowska A . ADP Ribosylation Factor 6 Promotes Contraction and Proliferation, Suppresses Apoptosis and Is Specifically Inhibited by NAV2729 in Prostate Stromal Cells. Mol Pharmacol. 2021; 100(4):356-371. DOI: 10.1124/molpharm.121.000304. View

Zhou B, Perel P, Mensah G, Ezzati M . Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nat Rev Cardiol. 2021; 18(11):785-802. PMC: 8162166. DOI: 10.1038/s41569-021-00559-8. View

Humphreys D, Davidson A, Hume P, Makin L, Koronakis V . Arf6 coordinates actin assembly through the WAVE complex, a mechanism usurped by Salmonella to invade host cells. Proc Natl Acad Sci U S A. 2013; 110(42):16880-5. PMC: 3801044. DOI: 10.1073/pnas.1311680110. View

Li B, Huang R, Wang R, Liu Y, Stief C, Hennenberg M . Picotamide inhibits a wide spectrum of agonist-induced smooth muscle contractions in porcine renal interlobar and coronary arteries. Pharmacol Res Perspect. 2021; 9(3):e00771. PMC: 8085950. DOI: 10.1002/prp2.771. View

Benabdi S, Peurois F, Nawrotek A, Chikireddy J, Caneque T, Yamori T . Family-wide Analysis of the Inhibition of Arf Guanine Nucleotide Exchange Factors with Small Molecules: Evidence of Unique Inhibitory Profiles. Biochemistry. 2017; 56(38):5125-5133. DOI: 10.1021/acs.biochem.7b00706. View

Yoo J, Shi D, Grossmann A, Sorensen L, Tong Z, Mleynek T . ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell. 2016; 29(6):889-904. PMC: 5027844. DOI: 10.1016/j.ccell.2016.04.015. View

DSouza-Schorey C, Chavrier P . ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol. 2006; 7(5):347-58. DOI: 10.1038/nrm1910. View

Hongu T, Kanaho Y . Activation machinery of the small GTPase Arf6. Adv Biol Regul. 2013; 54:59-66. DOI: 10.1016/j.jbior.2013.09.014. View

10.

Schweitzer J, DSouza-Schorey C . A requirement for ARF6 during the completion of cytokinesis. Exp Cell Res. 2005; 311(1):74-83. DOI: 10.1016/j.yexcr.2005.07.033. View

11.

Cosentino F, Grant P, Aboyans V, Bailey C, Ceriello A, Delgado V . 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2019; 41(2):255-323. DOI: 10.1093/eurheartj/ehz486. View

12.

Somlyo A, Somlyo A . Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev. 2003; 83(4):1325-58. DOI: 10.1152/physrev.00023.2003. View

13.

Dale P, Cernecka H, Schmidt M, Dowling M, Charlton S, Pieper M . The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease. Curr Opin Pharmacol. 2014; 16:31-42. PMC: 4071415. DOI: 10.1016/j.coph.2014.03.003. View

14.

Curtis M, Alexander S, Cirino G, Docherty J, George C, Giembycz M . Experimental design and analysis and their reporting II: updated and simplified guidance for authors and peer reviewers. Br J Pharmacol. 2018; 175(7):987-993. PMC: 5843711. DOI: 10.1111/bph.14153. View

15.

Michel M, Murphy T, Motulsky H . New Author Guidelines for Displaying Data and Reporting Data Analysis and Statistical Methods in Experimental Biology. Mol Pharmacol. 2019; 97(1):49-60. DOI: 10.1124/mol.119.118927. View

16.

Brouwers S, Sudano I, Kokubo Y, Sulaica E . Arterial hypertension. Lancet. 2021; 398(10296):249-261. DOI: 10.1016/S0140-6736(21)00221-X. View

17.

Curtis M, Bond R, Spina D, Ahluwalia A, Alexander S, Giembycz M . Experimental design and analysis and their reporting: new guidance for publication in BJP. Br J Pharmacol. 2015; 172(14):3461-71. PMC: 4507152. DOI: 10.1111/bph.12856. View

18.

Khavandi K, Greenstein A, Sonoyama K, Withers S, Price A, Malik R . Myogenic tone and small artery remodelling: insight into diabetic nephropathy. Nephrol Dial Transplant. 2008; 24(2):361-9. DOI: 10.1093/ndt/gfn583. View

19.

Schafer D, DSouza-Schorey C, Cooper J . Actin assembly at membranes controlled by ARF6. Traffic. 2001; 1(11):892-903. DOI: 10.1034/j.1600-0854.2000.011108.x. View

20.

Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel M . EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013; 64(1):118-40. DOI: 10.1016/j.eururo.2013.03.004. View