Natriuretic peptide analogues with distinct vasodilatory or renal activity: integrated effects in health and experimental heart failure. Issue 2 (13th March 2020)

• Record Type: Journal Article
• Authors: Rademaker, Miriam T; Scott, Nicola J A; Koh, Cho Yeow; Kini, R Manjunatha; Richards, A Mark
• Is Part Of: Cardiovascular research. Volume 117:Issue 2(2021)
• Page Start: 508
• Page End: 519
• Publication Date: 2020-03-13
• Subjects: Atrial natriuretic peptide analogues -- Acute decompensated heart failure -- Vasodilation -- Diuresis; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvaa052
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body–fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DR D) or diuretic (ANP-DG D) activities, in normal health and experimental ADHF. Methods and results: We compared the effects of incremental infusions of ANP analogues ANP-DR D and ANP-DG D with native ANP, in normal ( n = 8) and ADHF ( n = 8) sheep. ANP-DR D administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and heart failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DG D induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DR D-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF—suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DG D in HF. Conclusion: These ANP analogues exhibit distinct vasodilatory (ANP-DR D) and diuretic/natriuretic (ANP-DG D) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure–volume homeostasis. Graphical Abstract: