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. 2024 Feb 14:11:1348897.
doi: 10.3389/fcvm.2024.1348897. eCollection 2024.

Anti-hypertensive effect of a novel angiotensin II receptor neprilysin inhibitor (ARNi) -S086 in DSS rat model

Jingchao Sun  1   2 , Ying Xiao  1 , Wenjie Xu  1 , Wei Xing  1 , Frank Du  3 , Maozhi Tian  3 , Danqi Xu  3 , Yihua Ren  3 , Xin Fang  3
Affiliations

Anti-hypertensive effect of a novel angiotensin II receptor neprilysin inhibitor (ARNi) -S086 in DSS rat model

Jingchao Sun et al. Front Cardiovasc Med. .

Abstract

Introduction: Angiotensin receptor-neprilysin inhibitor (ARNi), comprised of an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has established itself as a safe and effective intervention for hypertension. S086 is a novel ARNi cocrystal developed by Salubris for the treatment of heart failure and hypertension.

Methods: Dahl Salt Sensitive (DSS) hypertensive rat model and telemetry system were employed in this study to investigate the anti-hypertensive efficacy of S086 and compare it with the first ARNi-LCZ696.

Results and discussion: The study showed that oral administration of S086 dose-dependently lowered blood pressure (P < 0.001). The middle dosage of S086 (23 mg/kg) exhibited efficacy comparable to LCZ696 (68 mg/kg), while also demonstrating superiority at specific time points (P < 0.05). Notably, water consumption slightly decreased post-treatment compared to the vehicle group. Furthermore, there were significant increases in natriuresis and diuresis observed on the first day of treatment with 23 mg/kg and 68 mg/kg S086 (P < 0.001). However, over the course of treatment, the effects in all treatment groups gradually diminished. This study demonstrates the anti-hypertensive efficacy of S086 in DSS hypertensive rat model, offering promising avenues for the clinical development of S086 as a hypertension treatment.

Keywords: angiotensin receptor blocker (ARB); angiotensin receptor-NEP inhibitor (ARNi); diuresis; hypertension; natriuresis; neprilysin inhibitor.

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Conflict of interest statement

S086 is Salubris’ developing product, and Salubris is the patent owner. JS, YX, WXu, and WXi were employed by Shenzhen Salubris Pharmaceutical Co., Ltd. FD, MT, DD, YR and XF were employed by WuXi AppTec (Shanghai) Co., Ltd.

Figures

Figure 1
Figure 1
Schematic design of the study. The study was divided into three stages. Firstly, telemetry devices were implanted into rats. Secondly, DSS rat hypertension model was created by administering high salt diets for 7 days and sham group animals were administered low salt diets. Thirdly, rats were treated with the designated interventions for 4 weeks, and body weight, blood pressure, heart rate, water consumption, natriuresis, and diuresis were measured during the treatment period.
Figure 2
Figure 2
The 24-h systolic blood pressure (SBP) and time curve. The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt group (n = 8/group) was used as sham control. The vehicle model group rats that received solvent. SBP was tested every week.
Figure 3
Figure 3
The 24-h diastolic blood pressure (DBP) and time curve. The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt sham group (n = 8/group) was used as sham control. The vehicle model group rats that received solvent. DBP was tested every week.
Figure 4
Figure 4
The 24-h mean arterial pressure (MAP) and time curve. MAP is calculated using the following formula: MAP = (SBP + 2×DBP)/3. †P < 0.05 vs. LCZ696-68 mg/kg.
Figure 5
Figure 5
Heart rate (HR). The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt sham group (n = 8/group) was used as sham control. The vehicle model group rats that received solvent. HR was tested every week.
Figure 6
Figure 6
Water consumption. The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt sham group (n = 8/group) was used as sham control. The vehicle model group rats that received solvent. Water consumption was tested every week. ###P < 0.001 vs. Sham.
Figure 7
Figure 7
Natriuresis. The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt sham group (n = 8/group) was used as sham control. The vehicle model group rats that received solvent. Natriuresis was tested on days 1, 4 and 28, 6 hours after dosing. ###P < 0.001 vs Sham; *P < 0.05, **P < 0.01, ***P < 0.001 vs Vehicle; ^^P < 0.01 vs EXP3174; &P < 0.05, &&P < 0.01 vs Sacubitril.
Figure 8
Figure 8
Diuresis. The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt sham group (n = 8/group) was used as sham control. The vehicle model group rats that received solvent. Diuresis was tested on days 1, 4 and 28, 6 hours after dosing. ###P < 0.001 vs Sham; *P < 0.05, **P < 0.01, ***P < 0.001 vs Vehicle; ^^P < 0.01 vs EXP3174.
Figure 9
Figure 9
Body weight. The successfully established DSS rats were randomly divided into seven groups (n = 7/group), with each group receiving different drugs or the same drug with different doses, as indicated in the figure. The low salt sham group (n = 8/group) was used as sham control. Body weight was measured pre-dosing and daily after dosing.
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