|Year : 2022 | Volume
| Issue : 4 | Page : 275-281
Actions of Caffeic Acid Loaded-Silver Nanoparticles on Blood Pressure, Oxidative Stress, and Antioxidants in Nitric Oxide Deficient Hypertensive Rats
Kanagaraj Kalaiarasi, Boobalan Raja, Dhanasekaran Saranya, Ravi Dhakshinamoorthi
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India
|Date of Submission||16-Jun-2022|
|Date of Decision||03-Jul-2022|
|Date of Acceptance||18-Aug-2022|
|Date of Web Publication||30-Nov-2022|
MSc, PhD Boobalan Raja
Associate Professor, Department of Biochemistry & Biotechnology, Annamalai University, Annnamalainagar-608 002, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objectives: This study aimed to evaluate the antihypertensive and antioxidant potential of caffeic acid-loaded silver nanoparticles (CA-AgNPs) in Nω −Nitro-L-arginine methyl ester hydrochloride (L-NAME) induced hypertension in male albino Wistar rats. Materials and methods: The rats have randomly divided into four groups, that is, Group I Control rats, Group II rats injected with CA-AgNPs, Group III L-NAME rats, and Group IV −L-NAME+ CA-AgNPs. Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg body weight) dissolved in drinking water daily for 4 weeks. Rats were given intraperitoneal injection of CA-AgNPs (0.5 mg/kg/ml). Results: The results showed that L-NAME administration caused a sustained increase in blood pressure, levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), and a significant decrease in the activities of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx), and levels of non-enzymatic antioxidants such as vitamin C and vitamin E in the tissues such as heart, aorta, liver, and kidney. Above pathological changes were considerably restored with the treatment of CA-AgNPs. Conclusions: The result confirms CA-AgNPs have enough potential to narrow down hypertension and oxidative stress in L-NAME hypertensive rats.
Keywords: Caffeic acid, hypertension, oxidative stress, antioxidants, silver nanoparticles
|How to cite this article:|
Kalaiarasi K, Raja B, Saranya D, Dhakshinamoorthi R. Actions of Caffeic Acid Loaded-Silver Nanoparticles on Blood Pressure, Oxidative Stress, and Antioxidants in Nitric Oxide Deficient Hypertensive Rats. Int J Nutr Pharmacol Neurol Dis 2022;12:275-81
|How to cite this URL:|
Kalaiarasi K, Raja B, Saranya D, Dhakshinamoorthi R. Actions of Caffeic Acid Loaded-Silver Nanoparticles on Blood Pressure, Oxidative Stress, and Antioxidants in Nitric Oxide Deficient Hypertensive Rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2022 [cited 2023 Jan 26];12:275-81. Available from: https://www.ijnpnd.com/text.asp?2022/12/4/275/362413
| Introduction|| |
Cardiovascular diseases (CVDs) are the major cause of morbidity and mortality in developed and developing countries. Hypertension is a crucial risk factor for CVDs and contributes to one-third of global mortality., Hypertension, a worldwide epidemic at present, is not a disease in itself rather it is an important risk factor for serious cardiovascular disorders including myocardial infarction, stroke, heart failure, and peripheral artery disease.
It is well-established that oxidative stress contributes to the development of hypertension through nitric oxide (NO) deficiency.,, The vascular endothelial cells product NO is a potent vasodilator with important role in the growth and resistance of blood vessels.,, NO synthase inhibitors induce endothelial dysfunction and oxidative stress by decreasing NO activity. Subchronic administration of laboratory rodents with NO synthase inhibitors, such as N-nitro-L-arginine methyl ester (L-NAME), results in chronic hypertension,, hence the common use of this chemical for developing hypertension in experimental models.
Phenolic acids are predominantly spread-out in food sources like nuts, grains, and beverages. Caffeic acid (CA) is a hydroxycinnamic acid that belongs to the phenolic acid family of polyphenols. It is the main hydroxycinnamic acid present in the human diet, with the highest content being found in blueberries, kiwis, plums, cherries, and apples, although also present in cereals, carrots, salad, eggplants, cabbage, artichoke, and coffee.,, CA shows promising antihypertensive and antioxidant activities, and might possess favorable effects both in in vitro and in vivo model.,,, Its antioxidant ability is a major mechanism via which it functions ([Figure 1]). The molecular structure of caffeic acid possesses a cathecol group with an α,β-unsaturated carboxylic acid chain. It can be expressed in duo ways; as a primary antioxidant which prevents the production of free radicals and as a secondary antioxidant by forming complexes with metals thus inhibiting peroxides decomposition, thus decreasing the production of free radicals and their attack on lipids, double bonding affinity of polyunsaturated fatty acids, bases of DNA, and amino acids of proteins.
Though numerous drugs acting via different mechanism of action are available in the market as conventional formulations for the treatment of hypertension but they face substantial challenges regarding their bioavailability, dosing, and associated adverse effects which greatly limit their therapeutic efficacies. Various studies have demonstrated that nanocarriers can significantly increase the drug bioavailability thereby reducing the frequency of dosing in addition to minimizing toxicity associated with a high dose of the drug. Nanoparticles seem to be the better approach to removing the constraints related to oral delivery of antihypertensive. Different nanoparticulate systems like polymeric nanoparticles and lipid-based nanoparticles (nanoemulsion, SLN, NLC, lipotomes) have been studied to overcome limitations associated with the oral delivery of antihypertensive. In this background this study was designed to determine the antihypertensive and antioxidant potential of caffeic acid-loaded silver nanoparticle (CA-AgNPs) in L-NAME-induced hypertension in male Albino Wistar rats.
| Materials and methods|| |
Adult male albino Wistar rats of 8 weeks old (150–220 g) were purchased from Nandha College of Pharmacy, Erode, Tamil Nadu, India. Animals were kept in a polypropylene cage by given a standard pellet diet and water in ad libitum. They were maintained in an air-conditioned room with a 12 h light/12 h dark cycle. The experimental process was carried out with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals, New Delhi, India and approved by the Animal Ethical Committee of Nandha College of pharmacy (Reg No.688/PO/Re/S/02/CPCSEA, Pro. No.NCP/IAEC/2021-22/26).
Drugs and chemicals
Caffeic acid, silver nitrate, and Nω −Nitro-L-arginine methyl ester hydrochloride (L-NAME) were purchased from Sigma-Aldrich Company (St. Louis, Missouri, USA). All other chemicals used for studies were of analytical grade obtained from E. Merck, Mumbai and HIMEDIA, Mumbai, India.
Synthesis of caffeic acid-loaded silver nanoparticles (CA-AgNPs)
About 5 mL of caffeic acid (20 mM) was added to a 5 mL of 2 × 10−3 M of AgNO3 and the reaction mixture was stirred for about 20 min at room temperature conditions. The change in the color of the solution from colorless to brown indicated the formation of silver nanoparticles.
L-NAME-induced hypertensive animal model and CA-AgNPs treatment
To induce hypertension, rats were given L-NAME in drinking water at a dosage of 40 mg/kg b.w. for 4 weeks.,. CA-AgNPs (0.5 mg/kg/ml) was given intraperitoneal injection every day for a period of consecutive 4 weeks.,,
Each of the following groups consisted of six animals. Group I: Control; Group II: rats were treated with CA-AgNPs (0.5 mg/kg b.w.); Group III: rats were given
L-NAME (40 mg/kg b.w.); Group IV: rats were co-administered with L-NAME (40 mg/kg b.w.) and CA-AgNPs (0.5 mg/kg/ml). After the completion of the experimental period, the rats were anesthetized and sacrificed by cervical dislocation. Tissues such as heart, aorta, kidney, and liver were surgically removed, washed with cold physiological saline, cleared off adherent lipids, and immediately transferred to ice-cold containers.
Blood pressure measurement
Before the commencement of the experiment, animals were trained with the instrument for measuring blood pressure. In all groups of animals, mean arterial pressure was measured every week during the entire period of the study noninvasively using a tail-cuff method (IITC, model 31, USA) according to standard procedures. Values reported are the average of three readings. All the recordings and data analyses were done using a computerized data acquisition system and software.
Lipid peroxidation products and antioxidants
The levels of thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LOOH) in tissues (liver, heart, aorta, and kidney) were estimated by the methods of Niehaus and Samuelsson and Jiang et al. respectively. The activities of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in tissues were estimated by the methods,,, respectively. The levels of non-enzymatic antioxidants such as vitamin C and vitamin E in tissues were estimated by the methods,,, respectively.
Data were analyzed by one-way analysis of variance followed by Duncan’s multiple range tests using a statistical package for the social science software version 20.0. “IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, New York, USA).” Values are represented as mean ± S.D. for six rats in each group. Values were considered significant when P < 0.05.
| Results|| |
[Figure 2] and [Figure 3] show the effect of CA-AgNPs on systolic and diastolic blood pressure in control and L-NAME-induced hypertensive rats for 4 weeks. The systolic and diastolic blood pressures were found to be significantly higher (P < 0.05) in L-NAME-induced hypertensive rats (group III). Treatment with CA-AgNPs significantly (P < 0.05) reduced the systolic and diastolic blood pressure in L-NAME-induced hypertensive group (group IV). There is no significant variation between groups I and II.
|Figure 2 Effect of CA-AgNPs on systolic blood pressure (SBP) in control and L-NAME-induced hypertensive rats. Columns are mean ± S.D. for six rats in each group. Data were analyzed by one-way ANOVA followed by Duncan’s multiple range test (DMRT). **Correspondence to P < 0.05 compared with the control. #P < 0.05 compared with the L-NAME.|
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|Figure 3 Effect of CA-AgNPs on diastolic blood pressure (DBP) in control and L-NAME-induced hypertensive rats. Columns are mean ± S.D. for six rats in each group. Data were analyzed by one-way ANOVA followed by Duncan’s multiple range test (DMRT).***Correspondence to P < 0.05 compared with the control. #P < 0.05 compared with the L-NAME.|
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The values of TBARS, LOOH in tissues are given in [Table 1]. TBARS, LOOH values in liver, heart, kidney, and aorta of L-NAME-induced hypertensive rats (group III) were significantly higher when compared with those of control rats (group I) (P < 0.05). Treatment with CA-AgNPs to rats with L-NAME-induced hypertension (group IV) reduced the TBARS, LOOH values significantly compared with L-NAME-induced hypertension (group III) ([Table 1]).
The activities of SOD, CAT, and GPx in tissues (liver, kidney, heart, and aorta) of control and L-NAME hypertensive rats are presented in [Table 2]. The activities of these enzymatic antioxidants were significantly (P < 0.05) decreased in L-NAME-induced hypertensive rats (group III). Treatment with CA-AgNPs significantly (P < 0.0.5) restored the activity of these enzymatic antioxidants in tissues (group IV). SOD, CAT, and GPx values have no alteration in treatment with CA-AgNPs in control rats (group II) compared with the control rats (group I).
[Table 3] illustrates the levels of non-enzymatic antioxidants such as vitamin C and vitamin E in tissues. Their levels were significantly decreased in L-NAME-induced hypertensive rats (group III) compared with the control rats (group I). Administration of CA-AgNPs to L-NAME-induced hypertensive rats (group IV) significantly improved the levels of vitamin C and E compared with untreated rats (group III). Vitamin C and E levels did not alter significantly on treatment with CA-AgNPs of rats (group II) compared with normal control rats (group I).
| Discussion|| |
Chronic blockade of nitric oxide (NO) synthesis by L-NAME-mediated nitric oxide synthase (NOS) inhibition is a well-known model of hypertension. Although this model cannot be easily extrapolated to human hypertension conditions, it provides the possibility of reducing the causes of increased blood pressure to a single factor, which is a decrease in NO bioavailability. Sufficient NO is associated with normal vasodilation and, consequently, normal blood pressure. Thus, a failure to generate NO or an enhanced NO consumption can lead to hypertension. We confirmed that chronic administration of L-NAME leads to a marked elevation in blood pressure as well as a CA-AgNPs preventing effect in animals.
Though numerous drugs acting via different mechanisms of action are available in the market as conventional formulations for the treatment of hypertension but they face substantial challenges regarding their bioavailability, dosing, and associated adverse effects which greatly limit their therapeutic efficacies. Various studies have demonstrated that nanocarriers can significantly increase the drug bioavailability thereby reducing the frequency of dosing in addition to minimizing toxicity associated with a high dose of the drug. Caffeic acid (CA) is a naturally occurring hydroxycinnamic acid with an interesting array of biological activities; for example, antioxidant, anti-inflammatory, antimicrobial, and cytostatic. More recently, several synthetic analogs have also shown similar properties, and some with the advantage of added stability. The significant reduction in blood pressure in our study is correlated with previous studies that show that CA, exhibit vasorelaxant activity by acting on the endothelial and vascular smooth muscle cells. Vasorelaxant mechanisms include the increased endothelial NO secretion, modulation of calcium and potassium channels, and modulation of adrenergic receptors. Together with a negative chronotropic effect, vasorelaxant activity contributes to lower blood pressure, as several preclinical studies show. Their antioxidant, anti-inflammatory, and anti-angiogenic properties contribute to an important anti-atherosclerotic effect, and protect tissues against ischemia/reperfusion injuries and the cellular dysfunction caused by different physico-chemical agents.
Oxidative stress performs a critical function in the progression of hypertension, which in turn, promotes the generation of free radicals and oxidative damages to multiple organs especially the heart, which results in a decrease cell membrane fluidity., Oxidative stress damage biological molecules by increasing the large amount of ROS. Bioavailability of ROS has a major impact on cardiovascular disease associated with hypertension. The ROS production, superoxide anion, hydrogen peroxide, and lipid peroxides levels were reported to increase in L-NAME-induced hypertensive rats, due to a decrease in enzymatic and non-enzymatic antioxidants.,,
Our findings also confirmed that CA-AgNO3 loaded nanoparticles significantly reduced the lipid peroxidation markers such as TBARS, LOOH, and increased the activity and levels of enzymatic and non-enzymatic antioxidants. The antioxidant activity of CA, at least in cellular systems in vitro, the closest to in vivo conditions, is dependent not only on the molecular structure, but also on the solubility, hydrophobicity, and stability of the compounds. CA is able to scavenge both reactive oxygen and nitrogen species, in acellular and in cellular systems., CA prevents the chain initiation of lipid peroxidation by scavenging peroxyl radical (LOO⋅). CA has also been shown to maintain proteins against oxidation by scavenging ROS and by assisting in their repair through transfer of electrons to amino acid radicals. Finally, antioxidant and free radical scavenging activities are attributed to several functional groups in the CA molecular structure, with the ortho-dihydroxyl functionality in the catechol ring being probably the best studied so far.,,,
| Conclusion|| |
New generation antihypertensive drugs, new novel molecular targets, and nanotechnology-based delivery systems are currently in the pivotal stage of preclinical trial and clinical trial and are showing positive results. Nanotechnology is a promising approach to resolving several constraints of antihypertensive. The targeted nanoparticles can effectively take antihypertensive to its site of action whether it is the kidney, heart, or smooth muscle. The result from our study confirms CA-AgNPs have enough potential to narrow down hypertension and oxidative stress in L-NAME-induced hypertensive rats. However, further studies will be necessary to deepen the unique properties of this new formulation, thus providing the basis for new therapeutic strategies in this type of hypertension.
The authors acknowledge the support from Dr S.K. Siva Kumar, Associate Professor, Department of Physics, Faculty of Science, Annamalai University for his support in the synthesis and characterization of CA-AgNO3 nanoparticles.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]