Open Veterinary Journal, (2026), Vol. 16(2): 1038-1047

Research Article

10.5455/OVJ.2026.v16.i2.24

The protective effects of Spirulina platensis hydromethanolic extract against deoxycorticosterone acetate-salt-induced spontaneously hypertensive rats

Putut Har Riyadi^1* , Eko Susanto¹, Tri Winarni Agustini¹, Apri Dwi Anggo¹ and Mochammad Fitri Atho’illah²

¹Department of Fishery Product Technology, Faculty of Fisheries and Marine Science, Diponegoro University, Semarang, Indonesia

²Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Malang, Indonesia

*Corresponding Author: Putut Har Riyadi. Department of Fishery Product Technology, Faculty of Fisheries and Marine Science, Diponegoro University, Semarang, Indonesia. Email: putut.riyadi [at] live.undip.ac.id

Submitted: 03/08/2025 Revised: 05/01/2026 Accepted: 21/01/2026 Published: 28/02/2016

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Abstract

Background: Spirulina platensis is a blue-green microalga known for its health benefits, including treating cardiovascular disease. However, research on the functional properties of S. platensis extracted via sonication remains limited.

Aim: To investigate the efficacy of S. platensis hydromethanolic extract (SPE) on controlling blood pressure, renin–angiotensin–aldosterone system hormones, including renin, angiotensin-converting enzyme (ACE), and angiotensin II (Ang II), and pro-inflammatory cytokines in the spontaneously hypertensive rats (SHRs) model.

Methods: Twenty-five male Wistar rats were divided into five groups (n=5), and the 20 rats were administered deoxycorticosterone acetate-salt for 5 weeks to induce SHR and treated orally with SPE for 28 days. Blood pressure was evaluated three times: initial, middle, and final treatment. The rats were then sacrificed, and the blood serum was collected. The serum was then analyzed for renin, Ang II, ACE, tumor necrosis factor-α, and interleukin (IL)-6 using enzyme-linked immunosorbent assay. Malondialdehyde was determined based on a colorimetric assay.

Results: Our results demonstrated that SPE could reduce hypertensive, inflammatory, and lipid peroxidation markers significantly (p < 0.05).

Conclusion: Our finding suggested that SPE improves hypertension by maintaining inflammation and antioxidants. Spirulina platensis may be regarded as a potential nutraceutical supplement S. platensis may be regarded as a potential nutraceutical supplement from fishery product for managing hypertension and other diseases associated with inflammation disturbances.

Keywords: Angiotensin II, Angiotensin-converting enzyme, Hypertension, Renin, Spirulina platensis.

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Introduction

Hypertension is a major global health issue affecting a significant portion of the world's population. Global statistics recorded that approximately 1.28 billion adults aged 30–79 years worldwide have hypertension, with about 46% population in the latent phase (Farhadi et al., 2023). Asia has a high prevalence of hypertension and has increased drastically over the past few decades (Loo et al., 2024; Rahman et al., 2024). Approximately one-third of the adult population in many Asian countries is affected by hypertension. Indonesia has the greatest prevalence of hypertension in Southeast Asia, with around 42.7% of men and 39.2% of women affected, representing a growth rate of 29% over four years (Mashuri et al., 2022; Shadiqa et al., 2025). Several factors contribute to the development of hypertension, including age, genetic predisposition, obesity, lack of physical activity, poor diet (high in salt and low in potassium), excessive alcohol consumption, and stress (Rios et al., 2023). Hypertension is a primary risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure and is also linked to chronic kidney disease and dementia (Song et al., 2021).

Hypertension is associated with oxidative stress, an imbalance between free radicals and antioxidants in the body. Malondialdehyde (MDA) is generated during lipid peroxidation and is often utilized as a biomarker to assess oxidative stress and oxidative damage in different tissues. MDA contributed to the pathophysiology of hypertension. Elevated MDA levels increase oxidative stress, impair endothelial function, and may lead to the progression of hypertension (Verma et al., 2019). Several studies have shown that patients with hypertension have higher serum concentrations of MDA compared to normotensive individuals, suggesting an increased oxidative stress burden in these patients (Yu et al., 2018; Bastawy et al., 2025). Furthermore, oxidative stress promotes inflammation within the vascular system that involves pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 (Zhang et al., 2022). TNF-α increases the expression of adhesion molecules on endothelial cells, which supports the recruitment of inflammatory cells to the vessel wall and is associated with vascular inflammation (Griffin et al., 2012; Dinh et al., 2014). This inflammation can lead to vascular remodeling characterized by increased stiffness, fibrosis, and reduced elasticity, further contributing to elevated blood pressure (Kim, 2023).

On the other hand, hypertension is associated with a complex interplay of various physiological factors, including the renin–angiotensin–aldosterone system (RAAS) hormones. Chronic inflammation induces the formation of reactive oxygen species (ROS), leading to oxidative stress, with both conditions complementing each other in a detrimental cycle. Further, if these conditions are unresolved, it might enhance the activity of the RAAS, including increased angiotensin II (Ang II) levels, which plays a role in vasoconstriction in the blood vessels (Zheng et al., 2020; Triebel and Castrop, 2024). The mechanism of action of RAAS, particularly through Ang II, is pivotal in promoting oxidative stress and inflammation, which in turn are involved in vascular remodeling and the pathogenesis of diseases like atherosclerosis (Koh et al., 2008; Zhao et al., 2025). Various medications have been developed to treat hypertension, including angiotensin-converting enzyme (ACE) inhibitors, Ang II receptor blockers, renin inhibitors, aldosterone antagonists, and others (Riet et al., 2015). Unfortunately, medications using synthetic drugs contribute to long-term side effects, including dry cough, hyperkalemia (Al-Janabi et al., 2025), renal dysfunction, and angioedema (Ameer et al., 2023). Nowadays, herbal medications are used as an alternative safe therapy, including for hypertension (Lai et al., 2022; Choi et al., 2024).

Spirulina platensis is a blue-green microalga known for its rich nutritional profile and various bioactive compounds. Spirulina platensis contains 60%–70% of protein, including essential amino acids (Ramírez-Amaro et al., 2020). Spirulina platensis contains phycocyanin pigment, which is reported to have strong antioxidant content. Moreover, S. platensis is also rich in various active compounds, including chlorophyll, beta-carotene, vitamin E, phenolic compounds, and gamma-linolenic acid, commonly consumed as processed fishery food products for improving health and well-being (Athiyappan et al., 2024). Spirulina platensis has been studied extensively for its health benefits, including its potential for lowering blood pressure. A previous study reported that phycocyanin, the abundance pigment in S. platensis, improved endothelial nitric oxide synthase (eNOS) expression levels (Ichimura et al., 2013). Antihypertensive activity of S. platensis is assumed from antioxidants, anti-inflammatory, or its angiostatic effect (Ali et al., 2015; Brito et al., 2020). Interestingly, different geographical locations of harvest are influenced by the total phenolics, antioxidants, or chlorophyll of S. platensis (Ramon-Mascarell et al., 2022). However, there is limited information on in vivo S. platensis hydromethanolic extract (SPE) studies on the local Spirulina, which has been harvested in Indonesian waters by sonication methods for enhancing its functional properties. This study aimed to examine the efficacy of SPE on controlling blood pressure, RAAS hormones, including renin, ACE, and Ang II, and pro-inflammatory cytokines in the spontaneously hypertensive rats (SHRs) model.

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Materials and Methods

Collection and extraction of S. platensis

Spirulina platensis powder was collected from PT Alga Bioteknologi, Indonesia. Briefly, 4.5 g of S. platensis powder was dissolved in 50% methanol (w/v), followed by continuous orbital agitation at 120 rpm at ambient temperature under low-light conditions. The mixture was then sonicated in a bath (Branson 1800) at 50 kHz of frequency in the dark, at room temperature for 30 minutes. The result was then centrifuged at 8,000 rpm for 15 minutes. The supernatant was collected and filtered using Whatman paper no. 1. The filtered supernatant was then evaporated using a rotary evaporator (Buchi Rotavapor^® R-100) at 60°C to remove the solvent. SPE was then collected and stored at 4°C for further analysis.

Animal experimental design

Twenty-five male Wistar (Rattus norvegicus) with 200 ± 10 g body weight (BW) were divided into five groups (n=5). Twenty rats were induced into SHR using deoxycorticosterone acetate (DOCA)-salt. DOCA salt was dissolved in corn oil and administered twice a week orally for 5 weeks. In the first five injections, rats were injected with a dosage of 20 mg/kg BW and then 10 mg/kg BW for the rest of the five times (Riyadi et al., 2020). Rats were measured for systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the tail-cuff method (Blood Pressure Analyzer, Kent Scientific, USA) (Riyadi et al., 2020) before injection, second week of treatment, and fourth week of treatment. Rats were then separated into five groups: normal rats, SHR, SHR treated with Captopril 5 mg/kgBW (SHR + C5), SHR treated with SPE 150 mg/kg BW (SHR + SPE150), and SHR treated with SPE 300 mg/kg BW (SHR + SPE300). The treatment was given orally for 28 days (Riyadi et al., 2020).

After 28 days, the rats were then sacrificed using a combination of ketamine and xylazine. The blood was drawn from the cardiac puncture and collected in a gel clot activator tube. The blood was then centrifuged at 3,000 rpm at 10°C for 10 minutes to obtain the serum. The collected serum was then stored at 4°C for further analysis.

Hypertension marker analysis

Hypertension marker analysis, including renin, ACE, and Ang II, was performed in the serum using enzyme-linked immunosorbent assay (ELISA). Sandwich ELISA was done by using an ELISA kit and following the procedure according to the manufacturer. The ELISA kit used was purchased from Bioassay Technology Laboratory, Shanghai, China, such as rat renin with catalogue number E0548Ra, rat angiotensin 2 with catalogue number E0655Ra, and rat ACE2 with catalogue number E0968Ra.

Level of pro-inflammatory cytokine measurement

Pro-inflammatory cytokines, including TNF-α and IL-6, were evaluated using ELISA. TNF-α ELISA kit used rat TNF-α with catalogue number ER1393 (FineTest, Wuhan, China), and the IL-6 ELISA kit used rat IL-6 with catalogue number ER0042 (FineTest, Wuhan, China). The ELISA procedure followed the manufacturer’s protocol.

Statistical analysis

The sample size of the present study was estimated by using Federer’s formula as follows:

(t – 1) (r – 1) ≥ 15 (1)

t=number of treatment groups, r=sample size per group

The data were assessed for normality using the Kolmogorov-Smirnov test. Differences between groups were analyzed with a one-way analysis of variance (ANOVA), followed by the Duncan’s multiple range test Duncans multiple range test (DMRT) as a post hoc analysis. A p-value of <0.05 was considered statistically significant.

Ethical approval

Bioethics Committee for Medical/Health Research of The Faculty of Medicine, Sultan Agung Islamic University, Semarang, approved the procedure and animal handling in this experiment with an ethical clearance number 203/V/2023/KomisiBioetik.

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Results

SPE lowers systolic and DBP

The results are summarized in Table 1. Our result demonstrated that the blood pressure of normal healthy rats’ groups was stable at 120–125 mmHg of SBP and 82–84 mmHg of DBP for 4 weeks. In comparison, the SHR groups exhibited a significant increase (0.00 < 0.05) in second and fourth weeks, ranging from 225 to 232 mmHg of SBP and 194 to 201 mmHg of diastole (Fig. 1). Our present results demonstrated that SPE administration for 2 weeks did not decrease blood pressure compared to the SHR groups. Interestingly, the lowering of blood pressure effect by SPE was observed at 4 weeks after treatment (Fig. 1). SPE at 300 mg/kg BW showed better results than SPE 150 mg/kg BW, and similar results with captopril 5 mg/kg BW to ameliorate both SBP and DBP in SHR (Fig. 1).

SPE decreases the hypertension marker

The hypertension markers, including renin, ACE, and Ang II, significantly increased in the SHR group compared with the normal group. After 28 days of treatment, there are decreased of renin (0.00 < 0.05), ACE (0.00 < 0.05), and Ang II (0.00 < 0.05) significantly compared to the SHR group and close to the result from the SHR treated with captopril group (Fig. 2).

SPE ameliorated the level of pro-inflammatory cytokine

The data analysis showed that the serum pro-inflammatory cytokines TNF-α and IL-6 in the SHR group are at the highest level between groups (Fig. 3). Administration of SPE decreased the level of TNF-α and IL-6 significantly compared with the SHR group (0.00 < 0.05). SPE 150 mg/kg BW also has results on decreasing TNF-α and IL-6.

Table 1. Results summary of the present study.

Fig. 1. Systolic and DBP in normal and SHR groups. NHR, normal healthy rats (non-SHR); SHR, spontaneously hypertensive rats; SHR + C5, SHR treated with Captopril 5 mg/kg BW; SHR + SPE150, SHR treated with S. platensis extract dosage 150 mg/kg BW; SHR + SPE300, SHR treated with S. platensis extract dosage 300 mg/kg BW. The different letters are considered different statistically at p < 0.05 (n=5) between groups and vice versa based on two-way ANOVA followed by DMRT as a post hoc test.

Fig. 2. The level of renin, ACE, and Ang II in the normal and SHR groups. NHR, normal healthy rats (non-SHR); SHR, spontaneously hypertensive rats; SHR + C5, SHR treated with Captopril 5 mg/kg BW; SHR + SPE150, SHR treated with S. platensis extract dosage 150 mg/kg BW; SHR + SPE300, SHR treated with S. platensis extract dosage 300 mg/kg BW. The different letters are considered different statistically at p < 0.05 (n=5) between groups and vice versa based on one-way ANOVA followed by DMRT as a post hoc test.

Fig. 3. The level of pro-inflammatory cytokines TNFα and IL6 in normal and SHR groups. NHR, normal healthy rats (non-SHR); SHR, spontaneously hypertensive rats; SHR + C5, SHR treated with Captopril 5 mg/kg BW; SHR + SPE150, SHR treated with S. platensis extract dosage 150 mg/kg BW; SHR + SPE300, SHR treated with S. platensis extract dosage 300 mg/kg BW. The different letters are considered different statistically at p < 0.05 (n=5) between groups and vice versa based on one-way ANOVA followed by DMRT as a post hoc test.

SPE decreased the stress oxidative status MDA

The MDA analysis resulted in the SHR group has higher level of MDA compared with the normal group (0.00 < 0.05). The MDA level decreased significantly after treatment in both Captopril and SPE groups (Fig. 4). The MDA levels in the SHR group treated with Captopril and SPE decreased significantly compared with the SHR group.

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Discussion

Spirulina platensis contains potassium that is assumed to have a lowering effect on blood pressure (Lee et al., 2008). The lipophilic components of Spirulina are assumed to activate the potassium channels and change the activity of K_ATP channels and modulate the vasodilator response during hypertension (Villalpando et al., 2020). The blue pigment, phycocyanin, is recognized to have antioxidant activity and might contribute to decreasing blood pressure through elevate the eNOS in the aorta (Bobescu et al., 2020; Moradi et al., 2021). Other studies reported that Spirulina maxima supplementation reduced the endothelial marker dysfunction, such as sVCAM-1, E-selectin, and endothelin-1, and improved the arterial stiffness index (Szulinska et al., 2017; Martínez-Sámano et al., 2018).

Spirulina platensis demonstrated a promising effect on blood pressure through enhancing the endothelial nitric oxide production and improving vascular function. Spirulina platensis-derived peptides induce direct endothelium-dependent vasodilatation in ex vivo vessels and have hemodynamic effects for reducing blood pressure through a PI3K/Akt signaling pathway (Carrizzo et al., 2019). A previous study reported that S. platensis peptides Ile-Gln-Pro (IQP), Val-Glu-Pro (VEP), or S. platensis hydrolysates (SH) could modulate the renin angiotensin system in SHR. IQP, VEP, and SH downregulate ACE, Ang II, and angiotensin type-1 receptor (Zheng et al., 2017). Spirulina platensis also contains phenolic acid, phycocyanin, and polysaccharides, which exhibited antihypertensive properties (Finamore et al., 2017). Moreover, S. platensis supplementation influences the gut microbiota abundance, which in turn regulates the ACE activity through the gut-heart axis (Hua et al., 2018).

Spirulina platensis supplementation can significantly reduce the production of pro-inflammatory cytokines, including TNF-α, in various experimental settings (Abu-Taweel et al., 2019; Bondar et al., 2023). Similar to the previous study, Spirulina extract decreased TNF-α, along with other inflammatory markers, such as IL-6 (Nasirian et al., 2018; Abouzed et al., 2022). Phycocyanins and phenolic compounds from S. platensis inhibited nuclear factor-kappa B activation, which in turn decreased the expression of inducible Nitric Oxide Synthase (iNOS) and reduced production of NO, contributing to vascular inflammation and dysfunction (Lee et al., 2017). In contrast, the decrease of pro-inflammatory markers is followed by the increase of anti-inflammatory markers, such as IL-10 (Santos et al., 2020). This dual action might contribute to the beneficial effects of Spirulina as an anti-hypertensive Click or tap here to enter text.Click or tap here to enter text.agent.

Fig. 4. The level of MDA in normal and SHR groups. NHR, normal healthy rats (non-SHR); SHR, spontaneously hypertensive rats; SHR + C5, SHR treated with Captopril 5 mg/kg BW; SHR + SPE150, SHR treated with S. platensis extract dosage 150 mg/kg BW; SHR + SPE300, SHR treated with S. platensis extract dosage 300 mg/kg BW. The different letters are considered different statistically at p < 0.05 (n=5) between groups and vice versa based on one-way ANOVA followed by DMRT as a post hoc test.

Our next result indicated that Spirulina administration significantly reduced MDA. MDA is a common marker of oxidative stress and lipid peroxidation, which is well-known to be elevated during hypertension (Riyadi et al., 2020). In line with our result, a previous work reported that S. platensis administration for 8 weeks could significantly reduce the MDA levels in plasma and tissues (Mazloomi et al., 2022). The antioxidant properties of Spirulina might contribute to modulating MDA levels. Spirulina could stimulate endogenous enzymatic and non-enzymatic antioxidants, such as glutathione peroxidase and superoxide dismutase (Mahmoud and Abd El-Ghffar, 2019). Further, the endogenous antioxidants neutralize ROS and prevent lipid peroxidation, thereby reducing MDA formation. Current research reported that C-phycocyanin in Spirulina displayed high scavenging activity, along with β-carotene, diadinoxanthin, and diatoxanthin to prevent cardiovascular diseases (Deng and Chow, 2010; Sommella et al., 2018; Grover et al., 2021). Spirulina extracts scavenge ROS and inhibit lipid peroxidation, leading to a reduction in oxidative stress-induced damage by neutralizing free radicals in a dose-dependent manner, restoring redox balance, and reducing vascular inflammation without cytotoxic effects (Gabr et al., 2020; Alves et al., 2025). Additionally, by lowering oxidative stress, Spirulina can improve vascular function and reduce hypertension-related complications (Abdel-Daim et al., 2013).

In conclusion, our results demonstrated that local S. platensis with sonication methods has beneficial effects on spontaneous hypertensive rats. The administration of SPE reduces the blood pressure, TNF-α, IL-6, and MDA. The limitations of the present study are that we did not examine the urinary sodium and potassium excretion amounts and ratios, blood potassium levels, and kidney function parameters. Additionally, the changes in the gene expression related to inflammatory cytokines are not observed in the present study. Further investigations are still required to explain more details of the SPE mechanism for improving hypertension. Spirulina platensis from Indonesian waters might have the potential to be considered as a nutraceutical supplement to mitigate hypertension and other diseases related to inflammation disruption. SPE could serve as a natural, well-tolerated supplement with relatively few side effects compared to conventional antihypertensive drugs, which might be particularly beneficial in populations with mild to moderate hypertension or where pharmacotherapy side effects are a concern. Further high-quality clinical trials are necessary to clarify optimal clinical protocols and confirm their efficacy and safety in diverse patient populations for future translational applications.

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Acknowledgments

The authors thank the Faculty of Marine and Fisheries Sciences, Diponegoro University, for facilitating this research.

Conflicts of interest

The authors declare no conflict of interest.

Funding

This research was funded by the Ministry of Education, Culture, Research, and Technology with grant number 047/ES/PG.02.00.PL/2024 and 601-35/UN7.D2/PP/VI/2024.

Authors' contributions

P.H.R. was responsible for conceptualization, funding acquisition, supervision, writing original draft, and writing-review and editing, E.S. contributed in conducted investigation, methodology, validation, writing original draft, and writing-review and editing, T.W.A. made contributions in formal analysis, validation, and writing original draft, A.D.A. was responsible for investigation, visualization, and writing original draft, and M.F.A. assisted in investigation, validation, and writing original draft. All these authors have substantial contributions to the final manuscript and have approved this submission.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request under the Project funding.

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