Malate reduced blood pressure and exerted differential effects on renal hemodynamics; role of the nitric oxide system and renal epithelial sodium channels (ENaC)

ElsevierVolume 938, 5 January 2023, 175441European Journal of PharmacologyAuthor links open overlay panelAbstract

Malate regulates blood pressure via nitric oxide production in salt-sensitive rats, a genetic model of hypertension. This study investigated the possible contributions of malate to blood pressure regulation and renal haemodynamics in normotensive rats. Malate (0.1, 0.3 and 1 μg/kg, iv) was injected into rats or L-nitro-arginine methyl ester (L-NAME)-treated rats and mean arterial blood pressure (MABP), cortical blood flow (CBF), and medullary blood flow (MBF), was measured. The clearance study involved infusion of malate at 0.1 μg/kg/h into rats, and MABP, CBF, MBF, glomerular filtration rate (GFR), urine volume (UV) and sodium output (UNaV) were determined. Mechanistic studies to evaluate the role of renal sodium channels involved the treatment with malate (600 mg/kg, po), amiloride (2.5 mg/kg, po) or hydrochlorothiazide (HCTZ) (10 mg/kg, po), and UV and UNaV were determined. Malate elicited significant peak reductions in MABP (124 ± 6.5 vs 105 ± 3.1 mmHg) at 0.1 μg/kg), CBF (231 ± 18.5 vs 205 ± 10.9 PU). L-NAME did not reverse the effect of malate on MABP but tended to blunt the effect on CBF (40%) and MBF (87%) at 0.3 μg/kg. Infusion of malate reduced MABP, CBF, and MBF in a time-dependent manner (p<0.05). Malate exerted a three-fold decrease in GFR in a time-related fashion (p<0.05) as well as increased UV. UNaV increased by 86% in malate-treated-amiloride rats (p<0.05). These data indicate that malate modulates blood pressure and exerts vascular and tubular effects on renal function that may involve epithelial sodium channels (ENaC).

Introduction

The novel biochemical pathway linking the intermediary, malate, and nitric oxide (NO) production in salt-sensitive rats (SS) included intermediary metabolic products of mitochondrial metabolism as possible causative factors in genetic hypertension (Hou et al., 2017). Malate, the product of the hydrolytic breakdown of fumarate by the enzyme fumarase (Jan et al., 2017), was deficient in salt-sensitive (SS)-rats due to a genetic alteration in fumarase that reduced its catalytic action (Tian et al., 2009; Zheng and Tian, 2022). Therefore, the reduction in malate led to pathological alterations in the kidneys of SS rats that manifested as increased production of reactive oxygen species and reduced NO production (Hou et al., 2016). This crosstalk between malate and NO is related to the novel biochemical pathway: the malate–aspartate–NO hypothesis. This hypothesis showed that malate supplementation increased NO production in the renal medulla of salt-sensitive rats and reduced blood pressure in these animals (Hou et al., 2017). Therefore, the hypothesis of malate–L-arginine–NO mechanistically linked malate and its upstream products, fumarase and fumarate, to the regulation of blood pressure in salt-sensitive rats. NO is a known vasodilator that regulates endothelial homeostasis and renal haemodynamics and it is vital in the regulation of pressure natriuresis in the renal medulla (Ahmeda, 2018; Majid and Navar, 1997). Considering the intricate role of the kidney in the long-term regulation of blood pressure, NO is therefore a potent antihypertensive and ligands that increase NO production directly impact the regulation of blood pressure (Edosuyi et al., 2021; Seriki et al., 2018). These links to NO underlined the blood pressure-lowering activity of malate in SS rats, a genetic model of hypertension (Tian and Liang, 2021). This present study investigated the role of malate in the regulation of blood pressure and renal haemodynamics in normotensive rats and assessed for any contribution of the nitric oxide system and renal ion channels.

Section snippetsExperimental animals

Eighty-eight (88) male Sprague Dawley rats (6–10 weeks; 180–300 g) were housed in standard cages under 12-h lighting conditions at the Texas Southern University Animal Facility, Houston, Texas. Animals were placed on standard rat food (Purina Chow; Purina, St Louis, MO, USA) and water ad libitum. All experiments were approved by the Institutional Animal Care and Use Committee (IACUC) (Protocol number: #9004/Rats/1034). Animals were handled under the Care and Use of Laboratory Animals guidelines

Effect of bolus administration of malate on blood pressure, cortical blood flow, and medullary blood flow

As shown in Fig. 1, malate reduced blood pressure in a non-dose dependent manner and a peak reduction (Δ −19.0 ± 3.1 mmHg, p<0.05) occurred at 0.1 μg/kg when compared to baseline (124 ± 6.5 mmHg, n = 6). There was a simultaneous decrease in cortical blood flow (CBF) at all doses with significant reductions at 0.1 (Δ −26.0 ± 10.9 PU, p<0.05) and 0.3 μg/kg (Δ −40.0 ± 15.9 PU, p<0.05) from baseline (n = 6). However, medullary blood flow tended to increase at all doses and the peak increase from

Discussion

This study has demonstrated that aside from its role in salt-sensitive hypertension (Tian and Liang, 2021), malate could also contribute to the physiological regulation of renal and systemic haemodynamics in the normotensive state. Malate acted like a vasodilator, decreased mean arterial blood pressure (MABP) and cortical blood flow (CBF) but tended to increase medullary blood flow (MBF). The malate-induced reduction in MABP possibly led to a direct decrease in CBF. Interestingly, malate

Conclusions

Our study has shown that malate reduces blood pressure and exerts vascular effects that impact renal function. These effects also involve natriuresis through tubular actions on ENaC that enhance sodium excretion. Effects of malate seem renally mediated and are not specifically dependent on nitric oxide production or the activity of the fumarase enzyme. It is thus probable that malate may act as a vasodilator and thus contribute to the physiological regulation of renal and systemic haemodynamics.

Funding

This work was supported by the National Institutes of Health (NIH) (5 G12 MD007605).

CRediT authorship contribution statement

Osaze Edosuyi: Methodology, Software, Data curation, Writing – original draft, preparation, Visualization, Investigation, Software, Validation, Writing – review & editing. Ayobami Adesuyi: Methodology, Software, Writing – review & editing. Myung Choi: Methodology, Software, Visualization, Investigation. Ighodaro Igbe: Conceptualization, Supervision, Writing – review & editing. Adebayo Oyekan: Conceptualization, Data curation, Writing – original draft, preparation, Visualization, Investigation,

Declaration of competing Interest

The authors have declared that there are no conflicts of interest.

Acknowledgements

None.

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