Totum-854 reduction of blood pressure is associated with tissue remodeling in aorta and heart of SHR rat

Abstract

Abstract Introduction and purpose Arterial Hypertension (AHT) is a major cause of premature death worldwide. We have developed Totum-854 (T-854), a polyphenol-rich botanical composition to reduce the risk of developing AHT. We assessed the acute and chronic effects on blood pressure in spontaneous hypertensive rats (SHR). Method Acute protocol: 12-week-old SHR rats received randomly in a cross-over design, a dose of vehicle (VEH, 1% Tween 20), Captopril (50mg/kg) and T-854 (1250mg/kg) per os with at least 48h-wash-out interval between two gavages. Arterial pressure was recorded during 24h post-gavage, thanks to a radio-telemetry device (HD-S10, DSI) directly into the abdominal aorta. Baseline arterial pressure was measured before oral gavage during 90 min. Chronic study 18-week-old SHR rats received vehicle (VEH, 1% Tween 20) or T-854 (1000mg/kg) per os once a day for 8 weeks. Arterial pressure was recorded before the oral gavage for 90 min once a week with a radio-telemetry device (HD-S10, DSI). Delta (Δ) SBP and ΔDBP were calculated by subtracting baseline blood pressure (before the start of oral gavage) to measured blood pressure every week. At the end of supplementation, rats were euthanized, and aorta and heart were sampled. Aorta was embedded in paraffin and Masson's trichrome staining was performed in slides obtained by a microtome. Media thickness was measured with ImageJ. For the heart, mRNA was extracted using Trizol and cardiac hypertrophy/fibrosis gene expression was evaluated by RT-qPCR. Results Acute supplementation with T-854 exhibited an intermediate profile between VEH and Captopril response for change in SBP and DBP curves. SBP and DBP were reduced in comparison to VEH with 24h-AUC decreased by 93.6±67.8 mmHg h and 70.8±54.6 mmHg h for captopril and T-854, respectively. When T-854 was administered chronically during 8 weeks, ΔSBP and ΔDBP evolution were significantly different in comparison to VEH group (p<0.05). These curves were maintained under vehicle curves from the 2nd week of supplementation and until the end of the study. After 8 weeks of T-854 supplementation, tissue analysis showed a decrease of 10% on the aorta media thickness in T-854 supplemented rats (p<0.05). Cardiac MMP-2 gene expression was also lower in T-854 group compared to VEH (p=0.059). Conclusion T-854 24h-post-gavage acute effect on blood pressure in hypertensive SHR rats suggests a rapid effect, with a decrease in blood pressure few hours after oral administration. Moreover, chronic T-854 supplementation prevents AHT development in SHR. In conclusion, T-854 appears as an efficient strategy to prevent HTA suggesting also a protective role of T-854 on vascular and heart structure and function. Funding Acknowledgement Type of funding sources: None.