Rhinosinusitis is characterized by inflammation of the sinus and nasal mucosa. It is one of the most common health problems and accounts for more outpatient antibiotic prescriptions than any other diagnosis.1 Both host and environmental factors play a role in the development of rhinosinusitis. The pathophysiology causing acute rhinosinusitis involves a series of changes that lead to obstruction of the sinus ostia, swelling and inflammation of the mucosa, mucous stasis, impaired mucociliary clearance, and microbial infection. The goals of treatment are to reduce inflammation, eradicate infection, improve drainage and aeration of nasal and sinus mucosa, and restore mucociliary function.2 Common medical therapies for acute rhinosinusitis include antibiotics, nasal saline irrigation, decongestants, antihistamines, mucolytics, topical or systemic corticosteroids, and anti-inflammatory drugs. Little evidence supports the use of decongestants and antihistamines, although they may help to reduce rhinorrhoea and nasal congestion. Nasal irrigation with saline is usually used in acute rhinosinusitis and may improve mucociliary clearance but evidence is limited to support its use.3,4

Antibiotics are commonly prescribed for treatment and their use has been suggested to shorten the time to cure acute bacterial rhinosinusitis; however, concerns have been raised regarding the adverse effects of antibiotics, including resistance. A meta-analysis of randomized controlled trials showed that use of antibiotics for acute rhinosinusitis offers a small therapeutic benefit over placebo, with a corresponding rise in the risk for adverse events.5

Reactive Oxygen Species (ROS) are produced under physiological conditions and their production and antioxidant activity are balanced. Excessive accumulation of ROS causes lipid and protein peroxidation and can lead to cell damage and death. Cells overcome this oxidative stress via anti-oxidant defence mechanisms that include Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx), Catalase (CAT), Glutathione (GSH), and peroxiredoxins. Malondialdehyde (MDA), a product of lipid peroxidation, is therefore a good indicator of cellular damage. Recent studies showed that ROS acts as second messengers for inflammation activation and play a role in inflammation.6,7

Amlodipine (AML) is a dihydropyridine L-type calcium channel blocker with significant antibacterial activity against several gram-positive and gram-negative strains. It is reportedly the most powerful of the cardiovascular drugs with antibacterial activity.8,9 AML also has been reported to have anti-inflammatory activity. AML has been shown to decrease ischemia-reperfusion injury by improving the oxidative status in ileum ischemia-reperfusion induced rabbits.10

The growth of antibiotic resistance and the lack of discovery of new antibiotic compounds have increased the necessity for exploration of non-antibiotic compounds like AML that have antibacterial activity. In both acute and chronic sinusitis, inflammation and edema leads to obstruction of sinus ostia that further exacerbates the disease. We suppose that anti-inflammatory and antibacterial effects of AML can be beneficial in the treatment of rhinosinusitis.

The aim of the present study was to investigate possible effects of AML on oxidative status, inflammation, and tissue integrity in an animal model of experimentally induced acute rhinosinusitis.

The most commonly reported pathogens in acute bacterial rhinosinusitis are streptococcus pneumonia, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pyogenes, and Staphylococcus aureus. The Infectious Diseases Society of America recommends amoxicillin-clavulanate rather than amoxicillin as first line treatment and doxycycline, levofloxacin, and moxifloxacin in patients allergic to penicillin.17 The emergence of bacteria resistant to current antibiotic therapies is a worldwide clinical threat. It is essential to develop novel antibacterials to modulate the drug stress response of bacteria and host defence mechanisms. Although our study is representative of acute rhinosinusitis, tissue protective and anti-inflammatory effects of AML may have a role in preventing the prolongation of the disease and progression to chronic state.

Medicinal compounds used for the therapy of non-infectious pathology and that have antimicrobial properties are called non-antibiotics. These compounds are divided into two classes: those with direct antibacterial activity are called “antimicrobial non-antibiotics”, while the second group consists of “helper compounds” and “macrophage modulators”.18–20 The most well-known non-antibiotic compounds are phenothiazines,21 chlorpromazine, thioridazine,22,23 the anti-inflammatory drug diclofenac,24 antihistamines such as promethazine and diphenhydramine, and cardiovascular drugs such as amlodipine, dobutamine, lacidipine, nifedipine, and oxyfedrine.25–27 The exact mechanism of non-antibiotic action has not been determined but they have been proposed to modify cell permeability and affect potassium and calcium efflux pumps in susceptible bacteria. Drug resistance also has been reversed by addition of non-antibiotics such as phenothiazines and chlorpromazine to an antibiotic to which the bacteria are initially resistant.19

Amlodipine has been reported to have the most powerful antibacterial activity among cardiovascular non-antibiotics.11In vitro studies also suggested that dihydropyridine calcium antagonists act as antioxidants and reduce leukocyte-induced oxidation of low density lipoproteins.28 AML also has been suggested to improve endothelial dysfunction in diabetes through antioxidant and anti-inflammatory mechanisms.29 It has been shown to act synergistically with antibiotics and to have in vivo and in vitro antimicrobial activity against several bacteria.25

In our study, histopathological examination showed that AML improved lamina propria edema, collagen deposition, decreased ciliary loss compared to saline treated and cefazolin treated groups. Amlodipine group showed reduced PMNL infiltration and goblet cell number compared to saline treated group. However in cefazolin treated group, goblet cell number and PMNL infiltration was significantly lower than other treatment groups. Amlodipine also caused increased vasodilatation compared to all groups that may be attributed to the direct vasodilatatory effect of the compound. SOD and GSH are major components of the antioxidant mechanisms in tissue for combating ROS. In the present study, SOD and GSH levels were highest in the healthy control group followed by the SA, SC, and S groups. Levels of MDA, which indicate tissue damage by lipid peroxidation, were lowest in the control group and followed by the SA, SC, and S groups, in increasing order. In our study AML better improved the oxidative status than cefazolin sodium. These findings suggest that AML improved antioxidant defence mechanisms and reduced MDA levels, thereby preventing the tissue damage caused by ROS.

Although host defence mechanisms are basic ways to clear pathogenic microorganisms, the severity of infectious disease needs to be further controlled by additional protective mechanisms that limit the extent of tissue damage. This is referred to as disease tolerance, which is a biologic phenomenon mainly based on protection of self-tissues from immune attack. Tissue damage control is a very important component of host defence mechanisms against infection as this enforces the barrier function of epithelial cells to prevent pathogen access to host tissues and limits the disease severity without interfering with pathogen load.30

The pathophysiology of chronic sinusitis has been proposed to involve a dysfunctional immune response that occurs between the host and environment, locally at the level of mucosa. Defects in the mechanical barrier and increased microbial colonization lead to increased stimulation of the immune system and increased inflammation. Some reports indicate an altered oxidative status in chronic sinusitis. Kassim et al. reported that reduced glutathione level was significantly lower in severe cases of chronic sinusitis, but were similar in mild cases and controls.31 They found also significantly decreased level of SOD both in mild and severe cases compared to control subjects, with a greater decrease in severe cases. A study conducted by Westerveld et al. reported a significant reduction in reduced glutathione levels in mucosal samples taken from patients with chronic sinusitis compared to healthy controls, but no information was provided regarding the severity of disease in their study.32 Improvement in oxidative status of sinonasal mucosa and decrease in inflammation and tissue damage may potentially help to treat acute rhinosinusitis and may prevent further progression of the disease to chronic state.

The exact mechanism of antimicrobial action of AML remains to be fully established. However, a reduction in the minimum inhibitory concentrations of antibiotics by its use could make it a beneficial auxiliary compound for treatment of severe or recalcitrant bacterial infections of the upper respiratory tract. AML can improve antioxidant status and tissue integrity and decrease inflammation associated with bacterial rhinosinusitis. This drug may therefore have a potential role in the treatment of rhinosinusitis by controlling tissue damage and limiting the severity of disease.

The results of the present study indicated that AML improved SOD and GSH activities while decreasing MDA level, thereby enhancing the oxidative status and decreasing lipid peroxidation in the sinonasal mucosa.

This study evaluated the effect of AML on inflammation and oxidative status of sinonasal mucosa as a single agent. The combination of AML and antibiotic may produce a more dramatic decrease in oxidative stress and inflammation by acting synergistically with the antibiotic. We believe that future studies with different microorganisms and studies that investigate the effect of AML co-administered with an antibiotic both in acute and chronic rhinosinusitis models would be beneficial.

The animal experiments and procedures were performed in accordance with national guidelines for the use and care of laboratory animals, and the study was approved by Ataturk University's local animal care committee (approval number: 2014-1/12).

The authors declare no conflicts of interest.