Acute and Chronic Subcutaneous Administration of ZD100, a Novel pGC-A/cGMP Peptide Activator, Demonstrates Robust Antihypertensive Efficacy in Rodents

Abstract

Introduction Hypertension remains a prevalent challenge that induces high morbidity and mortality in the general population. It is also known to be an important risk factor for heart failure (HF) incidence. There remains an urgent need for the development of antihypertensive agents with novel mechanisms of action, particularly for resistant hypertension which markedly increases risk for HF. ZD100 (also called MANP) is a novel designer natriuretic peptide that potently activates particulate guanylyl cyclase A receptor (pGC-A) and its second messenger cGMP, is highly resistant to neprilysin degradation and mediates vasodilation with marked natriuresis and diuresis and inhibition of aldosterone, supporting its potential effectiveness for hypertension. The use of ZD100 for hypertension, however, is limited by its delivery method in which its activity to date was only tested with continuous intravenous infusion in short-term acute studies. Subcutaneous (SC) injection of peptide therapeutics has demonstrated impressive safety, greater convenience and lower medical cost. Importantly, the long term effects of ZD100 in experimental hypertension remain unknown. Hypothesis We hypothesize that ZD100 SC administration yields favorable cardiovascular (CV) and renal actions in normal rats and chronically ZD100 reduces blood pressure (BP) in a hypertensive rat model. Methods In normal Sprague Dawley rats, acute SC ZD100 (low: 1.94 mg/kg, high: 3.88 mg/kg, n=5) or vehicle (0.9% saline, n=5) were administered and BP, urine output, urinary sodium excretion, and plasma cGMP, ZD100, and aldosterone were measured. In sodium-deficient-diet induced hypertensive Sprague Dawley rats, daily SC injection for 7 days of ZD100 (3.88mg/kg, n=10) or vehicle (n=9) were performed and CV, renal and neurohumoral parameters were obtained at day 7. Data are presented as absolute changes from baseline values and expressed as Mean±SEM. *p Results Acute SC ZD100 induced potent and dose-dependent BP lowering effects over 360 min compared to vehicle in normal rats (high: -29.0±8.2*, low: -14.8±5.5, veh: -6.3±3.6 mmHg). In parallel, robust diuresis, natriuresis and GMP activation were seen with ZD100. Specifically, diuresis and natriuresis increased 3-5 fold by ZD100 compared to vehicle. We then determined its chronic CV and renal actions in a hypertensive model in rats. ZD100 SC daily for 7 days elevated plasma ZD100 levels and exhibited BP lowering effects compared to vehicle (ZD100: -6.1±4.9*, veh: +10.5±5.7 mmHg), with increased plasma levels of cGMP (ZD100: 112±18*, veh: 33±5 pmol/mL) and a trend for diuretic and natriuretic enhancement and aldosterone suppression. Conclusion Our study thus supports the effectiveness of chronic SC use of ZD100, a novel and best-in-class pGC-A/cGMP peptide activator in experimental hypertension and supporting its clinical development in hypertension.