Gdula-Argasińska, Joanna

Librowski, Tadeusz

Moniczewski, Andrzej

Pytka, Karolina

Rapacz, Anna

Sałat, Kinga

Tyszka-Czochara, Małgorzata

Jagiellonian Univeristy Repository

PL ISSN 0001-530X © Polish Academy of Sciences, Cracow 2012AntihistAminic Activity of LidocAine derivAtives  in the isoLAted GuineA PiG iLeumTadeusz Librowski*1, Karolina PytKa**, Kinga Sałat**, anna raPacz**,  andrzej MoniczewSKi***, joanna gdula-argaSińSKa*  and Małgorzata tySzKa-czochara** Department of Radioligands, ** Department of Pharmacodynamics,  *** Department of Toxicology, Jagiellonian University, Medical College,  Faculty of Pharmacy, Medyczna 9, 30-688 Cracow, PolandAccepted October 17, 2012Local anesthetics (LAs) are drugs that inhibit membrane depolarization by reducing sodium conductance. In addi-tion to the most prominent and well-defined function of LAs described above, numerous studies have shown that LAs possess many other properties, such as anti-inflammatory, anti-arrhythmic or analgesic activities. Furthermore, LAs are structurally similar to histamine H-receptor antagonists. Thus, LAs can be considered antihistaminic drugs. The aim of the present study was to determine and compare the antihistaminic effects of lidocaine derivatives - JCB-1, JCB-2 and JCB-3 - on the isolated guinea pig ileum. Only JCB-1 and JCB-2 at the highest concentration (10-4M) showed the antihistaminic effect. The studied compounds showed a dose-dependent effect. Interestingly, lower con-centrations of the studied compounds (10-8M and 10-10M) caused the opposite effect – increased the contraction of the ileum induced by histamine. These effects necessitate further studies. Nevertheless, this is the first time that JCB compounds have been demonstrated to possess antihistaminic properties.Key words: lidocaine derivatives, guinea pig ileum, antihistaminic activity, hista- mine ACTA BIOLOGICA CRACOVIENSIA Series Zoologia 54: 25–28, 20121 mflibrow@cyf-kr.edu.plINTRODUCTIONLocal anaesthetic agents (LAs) can be defined as drugs which are used to produce reversible in-terruption of pain impulses in a specific region of the body by direct interaction with voltage-gated Na channels, without loss of consciousness in pa-tients. Most of the LAs consist of an aromatic ring linked by a carbonyl containing moiety through a carbon chain to a substituted amino group. As mentioned previously, LAs cause reversible inter-ruption of the conduction of impulses in periphe-ral nerves. The primary electrophysiological effect of these drugs is a local decrease in the rate and degree of depolarisation of the nerve membrane, so the threshold potential for transmission is not 26 Librowski et al.reached and the electrical impulse is not propaga-ted down the nerve. This effect is due to blockade of sodium channels, thereby impairing sodium ion flux across the membrane. In addition to the most prominent and well-defined function of LAs de-scribed above, numerous studies have shown that LAs possess many other properties, such as anti-inflammatory, anti-arrhythmic, analgesic, anti-convulsant, antifungal and antibacterial activities (aydin et al., 2001; caSutto et al., 2006; de iuLis et al., 2001; Frey, 2001; Goodman et al., 2002; hel-LsTröm et al., 1988; hollMann and durieux, 2000; Pina-Vaz et al., 2000).The structure of LAs resembles the structure of histamine H-receptor antagonists, suggesting that LAs may influence histamine release. Seve-ral studies have shown that lidocaine (LID) used at a concentration lower than that used in infil-tration anesthesia inhibits histamine release from mast cells (KaziMierczaK et al., 1976). Moreover, some studies had shown that low concentrations of LID or mepivacaine inhibited histamine relea-se from activated mast cells. The effect was more intense when pH was more alkaline (suzuki et al., 2000). Recent studies suggest that both inhaled and intravenous LID inhibit bronchial contraction caused by histamine (Groben et al., 2007). On the other hand, a few studies have demonstrated that LID may cause bronchial contraction induced by histamine (hirota et al., 1999). Even though there are many available LAs, their activity time is not satisfactorily long and they often produce untoward side effects. Hence, the search for a long-lasting, safer LA is the goal of many research studies. The aim of the present study was to determine and compare the antihi-staminic effects of LID derivatives - JCB-1, JCB-2 and JCB-3 - on the isolated guinea pig ileum. LID was used as the reference drug.MATERIALS AND METHODSAnimalsMale and female guinea pigs (300–450 g) were used in the experiment. The animals were housed and fed in a laboratory maintained at constant tempe-rature of 22°C under standard conditions (12:12 h light-dark cycle, standard pellet diet, water ad libitum). The treatment of laboratory animals in the present study was in accordance with the re-spective Polish and European regulations and was approved by the Local Ethics Committee.DrugsJCB-1, JCB-2 and JCB-3, LID (lignocainum hydro-chloricum, Polfa, Poland) were dissolved in distil-led water.Isolated guinea pig ileumMale and female guinea pigs were sacrificed by cer-vical dislocation. The ileum was immediately remo-ved and cut into approximately 2.5-cm segments. The segments were placed in a carbogen-aerated organ bath (37oC) containing buffer (120 µM NaCl, 5.6 µM KCl, 2.2 M MgCl, 2.4 M CaCl, 19 µM NaHCO3 and 10 µM glucose). One end of the ileal segment was attached to the transducer (FDT10-A), and the resting tension was adjusted to a load of 0.5 g. All the samples were allowed to equilibrate for at least 30 min before contractions were measured. After 30-minute incubation, 10-7 M histamine was ad-ded to the buffer and the contraction of the ileum was recorded. Next, the ileum was washed twice with buffer and the compound under investigation was added to the buffer for 15 min. Finally, another concentration of 10-7M histamine was added and the change in ileum contraction strength was re-corded. The contractions were recorded using com-puter software (MP35 Data Acquisition Unit).Statistical analysisThe data are expressed as mean ± SEM. Differen-ces between treatments and controls were exami-ned for statistical significance using a paired t-test, where the p-value of less than 0.05 indicated a statistically significant difference.RESULTSJCB-1 used at 10-6M, 10-8M and 10-10M concentra-tions increased the strength of ileum contraction by 7.36%, 23.67% and 45.67%, respectively. In contrast, at a concentration of 10-4M the strength 27Influence of Lidocaine Derivatives on the Guinea-Pig Ileumof ileum contraction was significantly decreased by 18.16%.Similarly, JCB-2 at concentrations of 10-6M, 10-8M and 10-10M increased the strength of ileum contraction by 33.9%, 23.64% and 17.09%, re-spectively. However, when used at a concentration of 10-4M, it significantly decreased the strength of ileum contraction by 26.08%. The compound JCB-3 significantly increased the histamine-indu-ced contractions of the guinea pig ileum at con-centrations of 10-8M and 10-10M by 19.18% and 10.33%, respectively.LID at concentrations of 10-6M, 10-8M and 10-10M increased the strength of ileum contrac-tions induced by histamine by 6.66%, 13.47% and 8.55%, respectively. No statistically significant effect was observed at a concentration of 10-4M.DISCUSSIONThe guinea pig ileum is a very common model used to determine whether a potential drug has an anti- histaminic effect or not (Larsson et al., 2007). As mentioned previously, the structure of LAs resem-bles the structure of histamine H1-receptor anta-gonists. As the studied compounds are LID deri-vatives, we attempted to determine their effect on H1 receptor. Recent data indicate that LAs, except of their local-anaesthetic action, can also have an-tihistaminic properties (KaziMierczaK et al., 1976; Librowski, 2005). It has also been proved that an-tihistaminic agents exhibit analgesic and anti-in-flammatory activities (Panaszek et al., 2007; Tamad-donFard et al., 2008). Furthermore, studies in the guinea pig ileum demonstrate that LAs behave si-milarly to histamine H1-receptor antagonists (ho-rio et al., 1997; Librowski et al., 2009). The studied compounds showed a dose-dependent effect. Only JCB-1 and JCB-2 at the highest concentration (10-4M) showed antihistaminic effect. The effect was much more intense than the effect caused by LID at the same concentration. Considering all the stu-died compounds, JCB-2 was characterized by the greatest strength; it inhibited ileum contractions induced by histamine at a concentration of 10-4M by 26%. Interestingly, lower concentrations of the studied compounds (10-8M and 10-10M) caused the opposite effect. They increased the contractions of the guinea pig ileum induced by histamine. JCB-1 showed the strongest effect; at a concentration of -5005010-4 10-6 10-8 10-10LidocaineJCB-1**********% of changeFig. 1. The effect of JCB-1 and lidocaine on histamine-in-duced contraction in the guinea pig ileum. The results are expressed as mean ± SEM of 8 samples per group. * p < 0.05, ** p < 0.01, *** p < 0.001-5005010-4 10-6 10-8 10-10LidocaineJCB-2***********% of changeFig. 2. The effect of JCB-2 and lidocaine on histamine-in-duced contraction in the guinea pig ileum. The results are expressed as mean ± SEM of 8 samples per group. * p < 0.05, ** p < 0.01-5005010-4 10-6 10-8 10-10LidocaineJCB-3********% of changeFig. 3. The effect of JCB-3 and lidocaine on histamine-in-duced contraction in the guinea pig ileum. The results are expressed as mean ± SEM of 8 samples per group. * p < 0.05, ** p < 0.01, *** p < 0.00128 Librowski et al.10-10M it increased the ileum contraction by 45%. Moreover, the lower the concentration of JCB-1 was, the stronger the effect was observed. Both the increases and the decreases in ileum contrac-tions were much greater for the studied compoun-ds than for LID.Recent data indicate that LID can either en-hance (hirota et al., 1999; hirota et al., 2001) or decrease the strength of bronchi or trachea con-traction induced by histamine (downes and loeh-ninG, 1977; Groeben and PeTers, 2007). Our results are in agreement with these findings. Perhaps the fact that JCB-1, JCB-2 and JCB-3 are derivatives of LID is associated with their differential influen-ce on contractions of the guinea pig ileum induced by histamine.The mechanism by which JCBs exert their antihistaminic effects remains unknown. This issue, in addition to the observations that lower concentrations exert opposite effects, necessitates further studies. Nevertheless, this is the first time that JCB compounds have been demonstrated to possess antihistaminic properties.REFERENCESaydin, o.n., eyiGor, m. and n. aydin. 2001. 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Antihistaminic activity of lidocaine derivatives in the isolated guinea pig ileum

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Antihistaminic activity of lidocaine derivatives in the isolated guinea pig ileum

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