Chronic and acute effects of kefir: the role of angiotensin converting enzyme inhibition instead of nitric oxide balance

Abstract

Probiotic consumption promotes numerous health benefits. The aim of this study is 1) to evaluate the antihypertensive effect of kefir in a hypertension rat model caused by the administration of the nitric oxide synthesis inhibitor, L-NAME, and 2) to evaluate the acute angiotensin converting enzyme (ACE) inhibitory activity of the soluble nonbacterial fraction (SNBF) of kefir. To develop the first aim, male rats were separated into three groups: control group (C) treated with 0.3 mL/100 g of milk; L-NAME group (LN) received 10 mg/kg of said inhibitor; and Kefir group (K) treated with 0.3 mL/100 g of kefir plus L-NAME (10 mg/kg of said inhibitor). The treatments were given by oral gavage twice a day for four weeks. For the second aim”instead additionally, male rats received angiotensin I (in bolus) in three doses (Ang I: 0.03, 3 and 300 µg/kg) and were separated into two groups: a) received captopril (30 mg/kg i.v.) and b)received SNBF of kefir (5 mL/kg i.v.). Blood pressure were evaluated before and after Ang I. After treatment, hemodynamic parameters were evaluated, heart weight was recorded, and body weight gain was calculated. SNBF of kefir did not decrease the blood pressure for L-NAMEtreated animals, and no changes were observed in the cardiac parameters. However, the SNBF of kefir demonstrated acute inhibition of ACE in vivo similar to that of captopril. Thus, our results suggest that kefir may improve human cardiovascular systems by using mechanisms independent of nitric oxide syntheses. Additionally, the renin angiotensin system is probably the most important system involved in kefir effect regarding hypertension.

Keywords:
Nitric oxide; Blood pressure; Probiotic; ACE inhibition; Soluble nonbacterial fraction

INTRODUCTION

Probiotics are live microorganisms that, when consumed, promote valuable health benefits, and they are also found in medicines as well as naturally in some foods (Sanders 2015). Kefir is a fermented milk that supports gut regulation, reduces inflammation and regulates baroreflex, as demonstrated in previous works (Klippel et al. 2016; Rosa et al. 2016; Kim et al. 2017). Improving the gut microbiome offers many health advantages (Sirisinha 2016). Further, it is well established that dysbiosis is involved in the development of many diseases, including hypertension (Richards et al., 2016; Yang, Zubcevic, 2017).

In addition to modulating the gut microbiota, kefir also uses its bioactive peptides to benefit physiological systems, including the cardiovascular system, and to produce immunomodulatory, antioxidant and antithrombotic effects as well as angiotensin converting enzyme (ACE) inhibitory activities (Ebner et al. 2015).

In recent studies, our group demonstrated the importance and influence of kefir treatment for hypertension (Friques et al. 2015; Klippel et al. 2016; Brasil et al. 2018) in an animal model of essential hypertension using Spontaneously Hypertensive Rats (SHR) which indicated that kefir caused a decrease in blood pressure using both its probiotic action and its bioactive peptides. However, the effects of kefir in other animal models for hypertension with shorter treatment time and other mechanisms independent of the ACE inhibitory action have not yet been evaluated.

Furthermore, secondary hypertension is caused by endothelial dysfunction, kidney dysfunction, a decrease in nitric oxide production and other factors (Puar et al., 2016; Rimoldi, Scherrer, Messerli, 2018). The synthesis of nitric oxide (NO), a potent vasodilator agent, has an important effect on blood pressure control and impacts the development of hypertension (Kružliak, Novák, Novák, 2014; Tain, Huang, 2014).

Decreased NO synthesis or bioavailability advances an increase in vascular resistance and the development of hypertension. This is supported by the chronic intake of NO synthase from N(ω)-nitro-L-arginine methyl ester (L-NAME) (Dornas, Silva, 2011), which provides an important model for studying the mechanisms of action of new drugs (Yang et al. 2012; Zhu et al. 2018), ultimately indicating that the kefir treatment acts as donor of NO and promotes acute vasorelaxation.

Therefore, the aim of the present study was to evaluate the effects of a four-week kefir treatment on the blood pressure and cardiac alterations induced in rats by the chronic inhibition of NO synthesis with L-NAME. Additionally, we analyzed the acute ACE inhibitory activity of the soluble, nonbacterial fraction of kefir. Thus, our hypothesis was that treatment with kefir would increase vasorelaxation and subsequently reduce high blood pressure, describing a new mechanism of kefir regarding hypertension.

MATERIAL AND METHODS

Kefir preparation

Kefir was prepared from grains kindly given by Dr. Célia L.L.F. Ferreira of Federal University of Viçosa (UFV). The grains were added to pasteurized milk at a concentration of 4% (m/v) and were kept at room temperature for 24 hours (Santanna et al. 2016). The grains were then separated by filtration and the fermented milk obtained was stored in a refrigerator (8 ºC) for an additional 24 hours. Lastly, the fermented milk was maintained at-80 ºC until its usage.

Separation of the soluble, nonbacterial fraction of kefir

After the production of milk the soluble, nonbacterial fraction of kefir (SNBF) was separated according to Tsai et al. (2008). Briefly, the milk was heated to 98 ºC for four minutes, followed by centrifugation at 10000 rpm (4 ºC) for 30 minutes and it is noteworthy that the supernatant was filtered. The supernatant was collected and frozen (-80 ºC) until the analysis. The control was prepared with milk constituting a pH adjusted to 4 using acetic acid.

Experimental animals

For the experiments, 2-3-month-old male Wistar rats weighing between 200-300 g were used. The animals were grouped in cages with controlled temperature and humidity, a dark-light cycle of 12 hours and food and water ad libitum. The animals were provided by the animal care facility from the University of Vila Velha (UVV), Vila Velha, Brazil. All procedures were approved by the Institutional Committee on Animal Care (CEUA, Protocol# 040/2014)and were performed in agreement with the guidelines for the care and use of laboratory animals as recommended by the National Institutes of Health (NIH) (Garber et al. 2010).

Chronic evaluations

To determine whether kefir treatment plays a beneficial role in the hypertension that develops due to insufficient nitric oxide formation, the animals received a chronic administration of N(ω)-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) and were separated into three groups (n=7 each) as follows: the control group (C) received milk (0.3 mL/100 g) by gavage as the vehicle for kefir; the L-NAME group (LN) received milk as the vehicle for kefir and L-NAME at 10 mg/kg; and the kefir group (K) received kefir (0.3 mL/kg; Friques et al., 2015) and the same dosage of L-NAME. All treatments were given twice a day for four weeks. After that period, the animals were subjected to hemodynamic evaluations. It is important to note that L-NAME was administered through the drinking water.

Acute evaluations

Indeed, kefir is a source of bacteria and yeast, and thus the acute evaluations were performed with the SNBF of kefir. This process was accomplished by anesthetizing the animals with a mixture of ketamine and xylazine (100/10 mg/kg), and their femoral artery and vein were catheterized. The animals were then separated into two groups (n=6 each) for evaluation as follows: the captopril group received captopril (30 mg/kg; i.v.); and the kefir group received the soluble fraction of kefir (5 mL/kg; i.v.). None of the animals in these groups received pre-treatment with L-NAME. Lastly, the infusion was performed using an infusion pump (Insight^®, Ribeirão Preto, São Paulo, Brazil) at a rate of 0.5 mL/min (Mangiapane et al. 1994).

To determine the acute capacity of ACE inhibition, three doses of Angiotensin I (Ang I: 0.03; 3 and 300 μg/kg, i.v.) were injected to the animals before and after the administration of either SNBF or captopril. The difference in blood pressure increased after the inhibition (∆MAP mmHg) and this change was used to determine the ACE inhibition.

Blood pressure measurements

The animals with the chronic treatment were anesthetized with a mixture of ketamine and xylazine (100/10 mg/kg, i.p.). After the anesthesia was complete, the femoral artery and vein were separated and catheterized (Brasil et al. 2014). At least 24 hours after the surgical procedure, the blood pressure (Mean Arterial Pressure (MAP), Diastolic Blood Pressure (DBP), Systolic Blood Pressure (SBP)) and heart rate (HR) were determined as previously described (Andrade et al. 2011).

Ponderal data

The animals with the chronic treatment were weighed to determine the difference between the initial and final body weights (∆BW). After treatment, the animals were euthanized with an anesthetic overdose, and their hearts were excised, washed, cleaned and weighed to determine cardiac hypertrophy. The ratio of the heart weight (HW) to the body weight (BW) was used as an index of cardiac hypertrophy.

Statistical analysis

The data are presented as the mean ± standard error mean (S.E.M.). All the results were subjected to a one-way variance analysis (ANOVA) followed by Tukey’s post hoc test. The differences were significant when p<0.05.

RESULTS

The principal result from the present study was that kefir was unable to prevent the hypertension caused by L-NAME. Nonetheless, kefir promoted acute ACE inhibition, which was probably the main mechanism of action for decreasing the blood pressure in the hypertensive animals.

Kefir did not promote a decrease in the MAP and cardiac hypertrophy by using a model of hypertension caused by L-NAME

FIGURE 1
Effect of chronic treatment with kefir and L-NAME on the Mean Arterial Pressure (MAP). * p<0.05 compared to the C group. C: control animals that received milk (0.3 mL/100 g twice a day) as a vehicle for kefir; LN: L-NAME-treated animals that received milk (0.3 mL/100 g twice a day) and L-NAME (10 mg/kg); K: kefir-treated animals that received kefir 0.3 mL/100 g twice a day and L-NAME. L-NAME was provided in the drinking water, and the milk and kefir were administered by gavage.

As expected, the ingestion of L-NAME at a dose of 10 mg/kg by the Wistar rats, promoted an increased mean MAP and, consequently, cardiac hypertrophy (Figure 1). In addition, chronic treatment with kefir did not cause a decrease in this parameter for the kefirtreated group.

Hemodynamic parameters were not changed after chronic treatment with kefir in the L-NAME model of hypertension

All the other parameters were evaluated after the chronic treatment of L-NAME in hypertensive animals and neither changed after the kefir treatment (Table I).

Hemodynamic parameters were not changed after chronic treatment with kefir in the L-NAME model of hypertension.

Kefir prevented the increase in blood pressure promoted by Ang I

With the aim of determining the potential of the kefir treatment to decrease the blood pressure by other mechanisms, we evaluated acute ACE inhibition in vivo. Kefir prevented an increase in blood pressure assisted by Ang I (p<0.01) in which the first dose (0.03 μg/ kg) exhibited a similar prevention to that of captopril (Figure 2).

TABLE I
Values of the parameters evaluated after a chronic treatment with kefir in the L-NAME model of hypertension

Groups				Parameters
	MAP	SBP	DBP	HR	HW/BW	ΔBW
C	127±3	154±3	100±4	395±15	2.63±0.03	34±5
LN	160±4*	192±3*	121±3*	381±9	2.80±0.04*	39±4
K	158±2*	187±3*	123±4*	391±4	2.75±0.03*	27±6

• The values are presented as the mean± standard error of mean (SEM).
• ^*
  p<0.05 compared to the C group.

FIGURE 2
Acute effect of Captopril or kefir on ACE. Both promoted a decrease in the Ang I effect on blood pressure. For the first dose, the effect of kefir was the same as captopril. Captopril and kefir (Before), effect promoted by Ang I before a bolus application of the substances. Captopril and kefir (After), effect promoted by Ang I after a bolus application of the substances.** p<0.01 compared to the kefir before group;⁺⁺ p<0.01 compared to the captopril before group;^## p<0.01 compared to the captopril after group.

Kefir prevented the increase in blood pressure promoted by Ang I.

DISCUSSION

Our results demonstrated that, for the first time, kefir was incapable of decreasing blood pressure in L-NAME-induced hypertension after four weeks of treatment. The results suggested that the period of treatment may not have been sufficient to demonstrate the effect of kefir on vascular relaxation nor on NO bioavailability in this animal model. Furthermore, the chief mechanism of action of kefir in hypertension may be the inhibition of the angiotensin converting enzyme.

Hypertension is classified as either essential or secondary, according to the main pathophysiology mechanisms (PK et al. 2017), however the former is multifactorial and more prevalent. In 2010, approximately 34 million people were diagnosed with essential hypertension in the United States (Mozaffarian et al. 2016), which significantly impacted health system costs (Elliott 2003). On the other hand, secondary hypertension is less prevalent and yet it is responsible for 10% of hypertension in adults (PK et al. 2017). Secondary hypertension differs from essential hypertension because it is caused by a known event or pathophysiological condition such as primary aldosteronism, renal stenosis and others (Rimoldi, Scherrer, Messerli, 2018).

Additionally, the hypertension induced by the intake of L-NAME mimics a situation where the endothelium is not capable of synthetizing NO, a potent vasodilator agent (Dornas, Silva, 2011). This kind of model evaluates the capacity of the treatment to donate NO to further treat hypertension promoted by the decreased NO bioavailability.

In this present study, the short treatment with kefir did not cause a decrease in blood pressure in the animals treated with L-NAME. Also, none of the parameters measured (SBP; DBP; HR; HW/BW; ∆BW;) were changed with the kefir treatment. Previously, our group showed that kefir decreased blood pressure after a long treatment period using a spontaneously hypertensive rats model of hypertension (Friques et al. 2015; Klippel et al. 2016; Brasil et al. 2018), which is an animal model that mimics essential hypertension in humans and that includes multiple mechanisms involved in the rise of blood pressure (Dornas, Silva, 2011).

Additionally, there are different systems involved regarding the positive effects of kefir. For example, Klippel et al., (2016) demonstrated that treatment with kefir for eight weeks lowered blood pressure and heart rate in SHR animals. This decrease was followed by an ameliorated autonomic control of pressure, indicating the possibility of kefir to act on the neural control of pressure. Friques et al., (2015) evaluated the effects of kefir treatment on endothelial function during eight weeks and observed an improvement in said function associated with a restoration of the ROS/NO imbalance. Here, the difference between the results demonstrated the effect of time on the treatment with kefir and the models used.

Recently, studies have focused on showing the potential role of probiotics against hypertension. However, it is also necessary to evaluate the different parameters and mechanisms that influence this activity (Chen et al. 2014; Yap et al. 2016; Robles-Vera et al. 2017). Some other authors demonstrated that, for probiotic action, time is an important factor for reaching beneficial effects (Ahrén et al., 2015; Yap et al., 2016). Previous study demonstrated that the probiotic effect for Lactobacillus paracasei, was time-dependent and the resulting positive effects on the immune stimulation started after nine weeks of administration (Tsai et al. 2008). In animal models, Chen et al., (2014) evaluated the effect of Lactobacillus helveticus strains on hypertension and found that seven weeks of treatment was sufficient to reveal a significant antihypertensive effect for both systolic and diastolic blood pressure, which was accompanied by a reduction in the extent of left ventricular hypertrophy. Yap et al., (2016) discovered that administrating Lactobacillus casei strain promotes a decrease on systolic and diastolic blood pressure, reverted aorta remodeling and promoted NO production, which improved vasodilation after eight weeks of treatment in hypertensive animals. All the treatments were experimented for longer periods in the SHR models of hypertension.

In contrast, the effect of probiotics on the L-NAME model of hypertension, in a shorter period of time, is also reported in literature (Xu et al. 2013; Ahrén et al. 2015; Yang et al. 2015; Robles-Vera et al. 2018). Our results are consistent with data from other authors, showing no effect on systolic and diastolic blood pressure after a four week treatment with a dietary supplement of Lactobacillus plantarum together with fermented blueberry (Xu et al. 2013; Ahrén et al. 2015). Robles-Vera et al., (2018) proved that Lactobacillus fermentum CECT5716 (LC40) treatment did not prevent the hypertension induced by L-NAME, despite being capable of preventing gut dysbiosis and reducing vascular oxidative stress and pro-inflammatory status.

The health benefits of the ingestion of probiotics is extensively explored (Leite et al., 2013; Nielsen, Gürakan, Ünlü, 2014; Sanders, 2015; Beilharz et al., 2018) of which the probiotic kefir contributes to the reported positive effects (Quirós et al. 2005; Kim et al. 2017). These effects are attributed to kefir’s ability to modulate the gut microbiome, and it is also observed that dysbiosis negatively affects other systems including the cardiovascular system (Yang et al. 2015). Additionally, studies indicate that gut dysbiosis in hypertension varies, according to the model of hypertension, through the modulation of bacteria, which is considered important in the regulation of the immune system, thus influencing both the gut microbiota and blood pressure (Yang, Zubcevic, 2017; Robles-Vera et al., 2018).

A microbiological analysis of the grains used in our study was previously conducted and demonstrated the presence of a great source of bacteria (Acetobacter aceti, Acetobacter sp., Lactobacillus delbrueckii delbrueckii, Lactobacillus fermentum, Lactobacillus fructivorans, Enterococcus faecium, Leuconostoc spp.), as well as Lactobacillus kefiranofaciens and yeasts (Candida famata, Candida krusei) (Friques et al. 2015). In addition to its effect on the gut microbiome, the fermentation of milk induces the release of many peptides, which are absorbed by the intestinal mucosa and offers health benefits (Quirós et al. 2005; Ebner et al. 2015; Santanna et al. 2016; Brasil et al. 2018). Ebner et al., (2015) demonstrated that the fermentation of milk kefir lead to the release of 236 different peptides from which sixteen had previously indicated beneficial properties such as antimicrobial, antioxidant, ACE inhibitor and others. This finding indicates that these peptides, rather than microbiome activity, had positive effects on the organism.

In this study, the acute effect of SNBF of kefir on ACE was evaluated and demonstrated the advancement of an acute ACE inhibition, which was observed by a reduction in the increase in blood pressure promoted by Ang I. This result corroborated with others from our group (Brasil et al. 2018), which showed that kefir established ACE inhibition and that other mechanisms of action attributed to the cardiovascular effects of kefir.

With respect to the effects of kefir on other parameters, no effect from the kefir treatment on cardiac hypertrophy and on body weight gain was observed. Additionally, it was expected that the animals treated with L-NAME presented cardiac hypertrophy (Adamcova, Ruzickova, Simko, 2013), as demonstrated by an increased HW/BW ratio, and no changes on body weight gain. (Buckley, Johns, 2011). However, as previously observed, kefir has the capacity to decrease cardiac hypertrophy in an SHR hypertension model (Klippel et al. 2016), and the differences in the results observed when compared to our study can be attributed, at least in part, to the divergence in the time of treatment and to the animal model used.

This study was limited by the lack of evaluation on analyzing the bacterial population present in the gut and fecal samples from the animals, bioactive compounds from the soluble and nonbacterial fraction of kefir. Although literature indicates that changes in the gut microbiota after kefir treatment promote a reduction in blood pressure, the presence of peptides and others active compounds in this fraction could bring more reliability to our findings. Therefore, further studies are necessary to identify the bacterial population and the bioactive compounds in the soluble fractions of kefir that explain the unchanged pressure in this model of hypertension.

CONCLUSION

In conclusion our results demonstrated that kefir did not diminish blood pressure in the L-NAME model of hypertension after four weeks of treatment. Additionally, none of the other parameters evaluated were ameliorated from the treatment. Lastly, kefir promoted acute angiotensin-converting enzyme inhibition, proving that the effect on the renin angiotensin system was probably the major mechanism of action for the probiotic.

ACKNOLEDGMENTS

We would like to give acknowledgement and gratitude to FAPES for their financial support. TUA receives fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq: grant number 311925/2018-9).

DECLARETION OF INTEREST

None

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Publication Dates

• Publication in this collection
  26 Nov 2021
• Date of issue
  2021

History

• Received
  19 Feb 2019
• Accepted
  12 July 2019