Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis.

Ping-Chung Kuo,Yi-Ching Lo,Sheng-Nan Wu,Yen-Chin Liu

doi:10.3390/ijms21041268

Abstract

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. Methods: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14β-dihydroxykaur-16-en-15-one] and croton-03 [ent-1β-acetoxy-7α,14β-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. Results: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 μM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 μM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 μM). The Ih in INS-1 cells was also depressed effectively by croton-03. Conclusion: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.

Highlights

The genus croton (Euphorbiaceae) includes about 300 species that are widely distributed throughout tropical regions
Previous studies have demonstrated that intravenous injection with the essential oil of C. zehntneri or nepetaefolius could induce rapid and dose-dependent hypotension and bradycardia [2,3,4]
Findings from the present results provide the evidence to unravel that these compounds can effectively interact with the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel to inhibit Ih in a concentration, time, and state-dependent manner

Summary

Introduction

The genus croton (Euphorbiaceae) includes about 300 species that are widely distributed throughout tropical regions. (Euphorbiaceae), known as Kho sam cho la in Vietnamese, is a tropical shrub native to northern Vietnam and has been used in Vietnam for the treatment of various types of disorders [1]. Previous phytochemical investigations have shown that C. tonkinensis is a rich source of diterpenoids [1]. Anti-inflammatory and cancer chemopreventive activities of C. tonkinensis extracts have been recently reported. Those effects are thought to be linked to their ability to depress the transcription nuclear factor κB [1]. Previous studies have demonstrated that intravenous injection with the essential oil of C. zehntneri or nepetaefolius could induce rapid and dose-dependent hypotension and bradycardia [2,3,4]

Objectives

Methods

Results