Background: Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors improve heart failure (HF) associated-outcomes in patients with type 2 diabetes (T2D). In patients with HF, SGLT2 inhibitors will likely be co-prescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics. Methods: The RECEDE-CHF trial (NCT03226457) was a randomized, double-blind, placebo-controlled, cross-over trial of patients with T2D and HF with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline at week 6. Results: Twenty-three participants (mean age 69.8 years, 73.9% male, mean furosemide dose of 49.6±31.3mg/day, mean HbA1c 7.9±3.8%) were recruited. Compared to placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference 535 ml, 95% CI 133 to 936, p =0.005) and week 6, (mean difference 545 ml, 95% CI 136 to 954 p = 0.005) after adjustment for treatment order, baseline 24-hour urine volume and percentage change in loop diuretic dose. At 6 weeks empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference -7.85 mmol/L, 95% CI -2.43 to 6.73, p = 0.57). Empagliflozin caused a non-significant increase in fractional excretion of sodium at day 3 which was absent at week 6 (mean difference day 3: 0.30%, 95% CI -0.03 to 0.63, p=0.09; week 6 0.11%, 95% CI -0.22 to 0.44, p > 0.99) and a significant increase in electrolyte-free water clearance at week 6 (mean difference 312 ml, 95% CI 26 to 598, p=0.026) compared to placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6. Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03226457

Abstract:Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. It is increasingly recognised that this is related to hypertension, although whether it predates hypertension or is a consequence of it is still unknown. In this review we explore the mechanisms of endothelial dysfunction in hypertension, its prognostic significance and methods of pharmacological reversal. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation CONDENSED ABSTRACTEndothelial dysfunction is prevalent in hypertension and has a recognised association with the condition. In this article we review the pathophysiology of endothelial dysfunction in human hypertension, its prognostic significance and methods of pharmacological reversal. We appreciate the opportunity to revise this manuscript again and particularly would like to thank Reviewer whose constructive criticism has certainly improved the manuscript. We have addressed the minor comments suggested as attached to this letter.We are extremely grateful once again to the reviewers and the editors for their detailed critique which has undoubtedly improved the quality of the manuscript.We thank you once again for the opportunity to resubmit our manuscript and look forward to your decision. Yours sincerely Dr Ify Mordi Submission letterReviewer #2:I thank you the author for their last revision: the paper improved quite a lot! Just few points should be still addressed:We thank the reviewer for their positive appraisal of our revised manuscript -we agree that the comments provided have substantially improved the review. We agree with the reviewer that this sentence is out of place. Given the length of the review and the fact that this is covered elsewhere we have now deleted the sentence.-Please move the description of micromyography to the invasive methods as tissue biopsies are necessary.We thank the reviewer for pointing out this error. We have now moved the description of myography to the invasive methods section (page 5). We have no conflict of interest. Endothelial Dysfunction in Human Essential Hypertension Manuscript 2 ABSTRACTAlthough the endothelium has a number of important functions, the term endothelial