31 Tetramethoxystilbene-loaded liposomes potentiate small coronary arterial dilator function, in an acute hypertension murine model, ex vivo

Introduction The methylated analogue of the polyphenol Resveratrol (RV), 2, 3’, 4, 5’-Tetramethoxystilbene (TMS), displays significantly more antioxidant effects than RV and is a potent inhibitor of CYP1B1, shown to contribute to the development of hypertension. While TMS bioavailability is low1, liposomes are a promising modality for TMS encapsulation and delivery to improve uptake into tissues2. The objective of this study was to determine the effect of TMS, delivered via liposomes, on endothelial cell viability and vasodilator responses of isolated coronary arteries, after acute pressure elevation, ex vivo, and assess mechanisms involved. Methods Liposomes were synthesised using a thin-lipid film process and characterised using UV-Vis and fluorescence spectroscopy, Dynamic Light Scattering and Fourier-transform infrared spectroscopy. The effect of TMS-loaded liposomes on human coronary artery endothelial cell viability was determined in vitro using Alamar Blue assay. Small coronary arteries were isolated from male Wistar rats (in accordance with Home office guidelines and institutional ethics approval) and their function assessed at 60mmHg and following acute pressure elevation (150 mmHg, 30 minutes) to mimic a hypertensive environment. Endothelial-dependent (acetylcholine, ACh 1.0 nM – 1.0 mM) and independent (Sodium nitroprusside -SNP, 100 μM, Papaverine –PAPA, 100 μM) responses were measured in the presence/absence of TMS and TMS-loaded liposomes, using pressure myography. Data are expressed as mean percent dilation ± SEM. Results TMS-loaded liposomes (157 ± 6 nm diameter; zeta potential -13.13 ± 0.67 mV) maintained cell viability without toxicity, following 48h incubation. Acute pressure elevation significantly reduced endothelial-dependent dilator responses but did not affect endothelial-independent vasodilation. Co-incubation with TMS liposomes significantly improved endothelial-dependent vasodilation (@ ACh 100 μM: 86.06 ± 5.63% and 89.84 ± 3.05% for TMS liposomes and TMS solution respectively, compared to control PSS 38.52 ± 6.34; n = 5; p ≤ 0.01). The potentiated dilator response was sustained over a longer period (4h) with TMS liposomes, when compared to TMS solution (@ ACh 100 μM: 77.32 ± 8.70% vs 41.70 ± 8.70%; n = 4; p ≤ 0.05). Conclusion TMS-loaded liposomes have the potential to restore attenuated coronary endothelial-dependent dilator responses in an acute hypertensive environment. Our findings will help establish whether TMS-loaded liposomes are a valid therapeutic drug-delivery strategy in hypertension. References Nawaz et al., 2017. Nutrients, 9(11), p.1188. Hu et al., 2018. Molecular Pharmaceutics, 15(12), pp.5493-5500. Conflict of Interest None