Excavatolide B Modulates the Electrophysiological Characteristics and Calcium Homeostasis of Atrial Myocytes

Abstract

Severe bacterial infections caused by sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction, and finally death. The lipopolysaccharide (LPS) provokes an inflammatory response under sepsis, which may increase propensity to arrhythmogenesis. Excavatolide B (EXCB) possesses potent anti-inflammatory effects. However, it is not clear whether EXCB could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes. This study investigated the effects of EXCB on the atrial myocytes exposed to lipopolysaccharide. A whole-cell patch clamp and indo-1 fluorimetric ratio technique was employed to record the action potential (AP), ionic currents, and intracellular calcium ([Ca2+]i) in single, isolated rabbit left atrial (LA) cardiomyocytes, with and without LPS (1 μg/mL) and LPS + EXCB administration (10 μM) for 6 ± 1 h, in order to investigate the role of EXCB on atrial electrophysiology. In the presence of LPS, EXCB-treated LA myocytes (n = 13) had a longer AP duration at 20% (29 ± 2 vs. 20 ± 2 ms, p < 0.05), 50% (52 ± 4 vs. 40 ± 3 ms, p < 0.05), and 90% (85 ± 5 vs. 68 ± 3 ms, p < 0.05), compared to the LPS-treated cells (n = 12). LPS-treated LA myocytes showed a higher late sodium current, Na+/Ca2+ exchanger current, transient outward current, and delayed rectifier potassium current, but a lower l-type Ca2+ current, than the control LA myocytes. Treatment with EXCB reversed the LPS-induced alterations of the ionic currents. LPS-treated, EXCB-treated, and control LA myocytes exhibited similar Na+ currents. In addition, the LPS-treated LA myocytes exhibited a lower [Ca2+]i content and higher sarcoplasmic reticulum calcium content, than the controls. EXCB reversed the LPS-induced calcium alterations. In conclusion, EXCB modulates LPS-induced LA electrophysiological characteristics and calcium homeostasis, which may contribute to attenuating LPS-induced arrhythmogenesis.

Marine natural products

“…602 The same diterpene also inhibits osteoclastogenesis 603 and can modulate the electrophysiology and calcium ion homeostasis of rabbit atrial myocytes. 604 The cytotoxicity of Sarcophyton sp. extracts towards androgen-dependent and androgen-independent tumour cell lines does not correlate with diterpene levels as measured by NMR metabolomics methods.…”

Briarane Diterpenoids Isolated from Octocorals between 2014 and 2016

“…Compounds of this type of diterpenoid have been demonstrated to possess various bioactivities in vitro, such as anti-inflammatory activity, antibacterial activity, and cytotoxicity towards cancer cells. For example, one of the compounds of this type, excavatolide B [ 13 ], has been proven to possess extensive biomedical bioactivities, such as anti-inflammatory, analgesic, the attenuation of rheumatoid arthritis activities, anticancer, and the modulation of the electrophysiological characteristics and calcium homeostasis in atrial myocytes [ 64 , 65 , 66 , 67 ]. Due to the structural diversity and biomedical bioactivities, there has been little synthetic work on briarane analogues [ 68 , 69 ].…”

Marine Pharmacology in 2016–2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…depsipeptide coibamide A ( 240 ) [ 262 ]; sponge Theonella aff. swinhoei cyclic peptide cyclotheonellazole A ( 241 ) [ 263 ]; bacterium SNA-024 N 6 , N 6 -dimethyladenosine ( 242 ) [ 264 ]; gorgonian Briareum excavatum briarane-type diterpene excavatolide B ( 150 ) [ 265 ]; brown algae Undaria pinnatifida, Ecklonia stolonifera and/or Sargassum horneri marine carotenoid fucoxanthin ( 51 ) [ 266 ]; sponge Phorbas sp. diterpenoid gagunin D ( 243 ) [ 267 ]; bacterium Bacillus sp.…”

“…Also presented in Table 3 is the pharmacological activity (IC 50 for enzyme or receptor inhibition) of marine-derived compounds , although their respective mechanisms of action remained undetermined and will require further investigation: sponge Aaptos aaptos alkaloid 9-methoxyaaptamine (261) [285]; mangrove-derived fungus Ascomycota sp. SK2YWS-L polyketide ascomindone A (262) [286]; mudflat-derived fungus Aspergillus niger polyketide aurasperone B (263) [287]; alga-derived fungi Penicillium thomii and Penicillium lividum meroterpenoid austalide H acid ethyl ester (264) [288]; fungus Biscogniauxia mediterranea peptide biscogniauxone (265) [289]; fungus Aspergillus ustus sesterpenoid cerebroside D (266) [290]; sponge Spongia ceylonensis diterpene ceylonin A (267) [291]; sponge-derived fungus Stachybotrys chartarum sesquiterpene chartarene D (268) [292]; sponge-associated fungus Talaromyces stipitatus KUFA 0207 anthraquinone citreorosein (269) [293]; fungus Aspergillus sp. SCSIOW3 polyketide cordyol (270) [294]; fungus Chaetomium cristatum dioxopiperazine alkaloid cristazine (271) [295]; sponge-associated fungus Emericella variecolor polyketides diasteltoxins A-C (272)(273)(274) [296]; sponge Latrunculia sp.…”