Rademaker Miriam T, Scott Nicola J A, Koh Cho Yeow, Kini R Manjunatha, Richards A Mark
Department of Medicine, Christchurch Heart Institute, University of Otago-Christchurch, PO Box 4345, Christchurch 8011, New Zealand.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Cardiovasc Res. 2021 Jan 21;117(2):508-519. doi: 10.1093/cvr/cvaa052.
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-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF.
We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD 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-DGD 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-DRD-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-DGD in HF.
These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.
急性失代偿性心力衰竭（ADHF）的治疗需要根据全身/外周灌注状态以及体液容量是否扩张采取不同的治疗方法。目前对于能分别针对各方面进行治疗的药物仍有需求未得到满足。心房利钠肽（ANP）在血压和容量调节中起重要作用。我们首次研究了经修饰具有专属血管舒张（ANP-DRD）或利尿（ANP-DGD）活性的人ANP类似物在正常健康状态和实验性ADHF中的综合血流动力学、内分泌和肾脏效应。
我们比较了在正常（n = 8）和ADHF（n = 8）绵羊中，递增输注ANP类似物ANP-DRD和ANP-DGD与天然ANP的效果。与ANP反应相似，给予ANP-DRD会使正常和心力衰竭（HF）绵羊的血浆环磷酸鸟苷（cGMP）增加，同时动脉压呈剂量依赖性降低。与ANP不同，ANP在HF中会产生利尿/利钠作用，而该类似物对肾脏无显著影响。相反，ANP-DGD在HF中可使尿cGMP、尿量和钠排泄量显著逐步增加，与ANP相当，但无伴随的血管舒张作用。在两种状态下，所有肽类相对于对照组均增加了血细胞比容，在HF中降低了左心房压力。对于ANP-DRD诱导的血压降低，仅在正常绵羊高剂量时血浆肾素活性相对于对照组升高，而在HF中则完全没有升高，提示相对肾素抑制，两种状态下醛固酮均未增加，而在HF中ANP-DGD可使肾素和醛固酮均显著降低。
这些ANP类似物表现出不同的血管舒张（ANP-DRD）和利尿/利钠（ANP-DGD）活性，因此有可能为压力-容量稳态存在不同病理生理紊乱的ADHF患者提供精准治疗。
