Inhibition of neurogenic contractions in renal arteries and of cholinergic contractions in coronary arteries by the presumed inhibitor of ADP-ribosylation factor 6, NAV2729

Ru Huang,Bingsheng Li,Raphaela Waidelich,Martin Hennenberg,Christian G Stief,Alexander Tamalunas

doi:10.1007/s00210-022-02218-2

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 α1-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.

Highlights

ADP ribosylation factor 6 (ARF6) belongs to the superfamily of monomeric GTPases
Average KCl-induced contractions were similar before application of DMSO and NAV2729 in both vessel types, i.e., in renal interlobar arteries and in coronary arteries (Fig. 1A)
The findings of the present study suggest that NAV2729, a small molecule inhibitor with previously supposed specificity for ARF6 (Wang et al 2021; Yamauchi et al 2017; Yoo et al 2016), inhibits neurogenic smooth muscle contractions of pig renal interlobar arteries and

Summary

Introduction

ADP ribosylation factor 6 (ARF6) belongs to the superfamily of monomeric GTPases. Major known functions of ARF6 encompass promotion of actin polymerization, roles in vesicular trafficking, regulation of internalized cargo, cell adhesion, migration, and completion of mitotic cytokinesis (D'Souza-Schorey and Chavrier 2006; Donaldson 2002; Humphreys et al 2013; Schafer et al 2000; SchweitzerAcknowledging the role of vascular smooth muscle contraction for cardiovascular homeostasis and diseases, together with their high prevalence, burden, and mortality,1 3 Vol.:(0123456789)Naunyn-Schmiedeberg's Archives of Pharmacology (2022) 395:471–485 it might be adequate to assess effects of NAV2729 or to understand a driving role of ARF6 in vascular smooth muscle contraction. Diseases and conditions imparted by aberrant vascular smooth muscle contraction include arterial hypertension, coronary artery disease, diabetic nephropathy, and others. Elevated systolic blood pressure has been estimated to account for 7.7 to 10.4 million annual deaths (Zhou et al 2021), which is outnumbered by the number of deaths due to any cardiovascular disease, including ischemic heart disease, estimated to 18.6 million cases for the year 2019 (Roth et al 2020). Drugs to inhibit vascular smooth muscle contraction belong to the gold standard options in medical treatment of hypertension and cardiovascular diseases (Brouwers et al 2021). Impaired renal function in diabetic nephropathy is related to increased glomerular capillary pressure and increased smooth muscle tone in efferent glomerular arterioles, which, in turn, is closely coupled to systemic blood pressure and hypertension (DeFronzo et al 2021; Khavandi et al 2009). Strategies for treatment of diabetic nephropathy include drugs to reduce intrarenal vascular resistance and antihypertensive drugs, in addition to glucose-lowering sodium-glucose cotransporter 2 (SGLT2) inhibitors (Cosentino et al 2020)

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Conclusion