Full-text resources of PSJD and other databases are now available in the new Library of Science.
Visit https://bibliotekanauki.pl


Preferences help
enabled [disable] Abstract
Number of results


2013 | 8 | 6 | 766-775

Article title

The influence of pemirolast on autonomic imbalance in rat cystitis model


Title variants

Languages of publication



Cyclophosphamide (CP) treatment is associated with the risk of haemorrhagic cystitis (HC). Moreover, CP-induced HC is complicated by autonomic nervous system (ANS) dysfunction. Pemirolast is thought to be a mast cell stabiliser that inhibits the release of many inflammatory mediators and sensory neuropeptides, and thus, it may be considered a potential chemoprotective HC agent. The aim of the study was to indirectly estimate the effect of pemirolast in experimental HC by measuring ANS activity with the heart rate variability (HRV) method. In CP-treated rats, we found a decreasing trend of overall autonomic activity, together with an imbalance between the main components, and a dominant very low frequency (VLF) power component. Pemirolast treatment did not improve the total HRV power value or the main non-normalized HRV components. Moreover, CP-HC animals treated with pemirolast displayed a different disproportion of normalized spectral components as compared to both control and CP-HC animals without pemirolast treatment, with the balance between normalized low frequency (nLF) and normalized high frequency (nHF) shifted towards nLF. This finding, together with a relatively high VLF tension, indicates that the pemirolast treatment resulted in high sympathetic activity that may contribute to HC exacerbation; thus, this agent seems to be ineffective in CP-induced HC.










Physical description


1 - 12 - 2013
6 - 12 - 2013


  • Department of Pathophysiology, Jagiellonian University Medical College, Poland, Kraków, 31-121, Czysta 18
  • Department of Pathophysiology, Jagiellonian University Medical College, Poland, Kraków, 31-121, Czysta 18
  • Department of Pathophysiology, Jagiellonian University Medical College, Poland, Kraków, 31-121, Czysta 18


  • [1] Brock N., Oxazaphosphorine cytostatics: pastpresent-future: seventh cain memorial award lecture, Cancer Res. J., 1989, 49, 1–7
  • [2] Brock N., The history of the oxazaphosphorine cytostatics, Cancer, 1996, 78, 542–547 http://dx.doi.org/10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y[Crossref]
  • [3] Ross W.C., The chemistry of cytotoxic alkylating agents, Adv. Cancer Res., 1953, 1, 397–449 http://dx.doi.org/10.1016/S0065-230X(08)60008-1[Crossref]
  • [4] Brock N., Ideas and reality in the development of cancer chemiotherapeutic agents, with particular reference to oxazaphosphorine cytostatics, J. Cancer Res. Clin. Oncol., 1986, 111, 1–12 http://dx.doi.org/10.1007/BF00402768[Crossref]
  • [5] Kerbush T., de Kraker J., Keizer J., van Putten J.W.G., Groen H.J.M., Jansen R.L.H., et al., Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolits, Clin. Pharmacokinet., 2001, 40, 41–62 http://dx.doi.org/10.2165/00003088-200140010-00004[Crossref]
  • [6] Friedman O.M., Seligman A.M., Preparation of N-phosphorylated derivatives of bis-β-chloroethylamine, J. Am. Chem. Soc., 1954, 76, 655–658 http://dx.doi.org/10.1021/ja01632a006[Crossref]
  • [7] Lawson M., Vasilaras A., De Vries A., Mactaggart P., Nicol D., Urological implications of cyclophosphamide and ifosfamide, Scand. J. Urol. Nephrol., 2008, 42, 309–317 http://dx.doi.org/10.1080/00365590701570953[Crossref]
  • [8] Levine L.A., Richie J.P., Urological complications of cyclophosphamide, J. Urol., 1989, 141, 1063–1069
  • [9] Korkmaz A., Topal T., Oter S., Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation, Cell Biol. Toxicol., 2007, 23, 303–312 http://dx.doi.org/10.1007/s10565-006-0078-0[Crossref][WoS]
  • [10] Dobrek Ł., Thor P.J., Bladder urotoxicity pathophysiology induced by the oxazaphosphorine alkylating agents and its chemoprevention, Post. Hig. Med. Dosw., 2012, 66, 592–602 http://dx.doi.org/10.5604/17322693.1009703[Crossref]
  • [11] Holzer P., Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides, Neuroscience, 1988, 24, 739–768 http://dx.doi.org/10.1016/0306-4522(88)90064-4[Crossref]
  • [12] Dobrek Ł., Thor P., Heart rate variability in overactive bladder experimental model, Arch. Med. Sci., (in press, in English), DOI: 10.5114/aoms.2012.30946 [Crossref][WoS]
  • [13] Gyorfi A., Fazekas A., Posch E., Irmes F., Rosivall L., Role of histamine in the development of neurogenic inflammation of rat oral mucosa, Agents Action, 1991, 32, 229–236 http://dx.doi.org/10.1007/BF01980879[Crossref]
  • [14] Steinhoff M., Stander S., Seeliger S., Ansel J.C., Schmelz M., Luger T., Modern aspects of cutaneous inflammation, Arch. Dermatol., 2003, 139, 1479–1488 http://dx.doi.org/10.1001/archderm.139.11.1479[Crossref]
  • [15] Kemp J.P., Bernstein I.L., Bierman C.W., Li J.T., Siegel S.C., Spangenberg R.D., et al., Pemirolast, a new oral nonbronchodilator drug for chronic asthma, Ann. Allegry, 1992, 68, 488–491
  • [16] Kawashima T., Iwamoto I., Nakagawa N., Tomioka H., Yoshida S., Inhibitory effect of pemirolast, a novel antiallergic drug, on leukotriene C4 and granule protein release from human eosinophils, Int. Arch. Allergy Immunol., 1994, 103, 405–409 http://dx.doi.org/10.1159/000236662[Crossref]
  • [17] Fujimiya H., Nakagawa S., Miyata H., Nozawa Y., Effect of a novel antiallergic drug, pemirolast, on activation of rat peritoneal mast cells: inhibition of exocytotic response and membrane phospholipid turnover, Int. Arch. Allergy Immunol., 1991, 96, 62–67 http://dx.doi.org/10.1159/000235536[Crossref]
  • [18] Itoh Y., Sendo T., Hirakawa T., Takasaki S., Goromaru T., Nakano H., et al., Pemirolast potently attenuates paclitaxel hypersensitivity reactions through inhibition of the release of sensory neuropeptides in rats, Neuropharmacology, 2004, 46, 888–894 http://dx.doi.org/10.1016/j.neuropharm.2003.11.018[Crossref]
  • [19] Yahata H., Saito M., Sendo T., Itoh Y., Uchida M., Hirakawa T., et al., Prophylactic effect of pemirolast, an antiallergic agent, against hypersensitivity reactions to paclitaxel in patients with ovarian cancer, Int. J. Cancer, 2006, 118, 2626–2638
  • [20] Chopra B., Barrick S.R., Meyers S., Beckel J.M., Zeidel M.L., Ford A.P.D.W., et al., Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium, J. Physiol., 2005, 562(Pt 3), 859–871 http://dx.doi.org/10.1113/jphysiol.2004.071159[Crossref]
  • [21] Dinis P., Churrua A., Avelino A., Yaqoob M., Bevan S., Nagy I., et al., Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis, J. Neurosci., 2004, 24, 11253–11263 http://dx.doi.org/10.1523/JNEUROSCI.2657-04.2004[Crossref]
  • [22] Tatsushima Y., Egashira N., Kawashiri T., Mihara Y., Yano T., Mishima K., et al., Involvement of substance P in peripheral neuropathy induced by paclitaxel but not oxaliplatin, J. Pharmacol. Exp. Therap., 2011, 337, 226–235 http://dx.doi.org/10.1124/jpet.110.175976[Crossref]
  • [23] Tatsushima Y., Egashira N., Matsushita N., Kurobe K., Kawashiri T., Yano T., et al., Pemirolast reduces cisplatin-induced kaolin intake in rats, Eur. J. Pharmacol., 2011, 661, 57–62 http://dx.doi.org/10.1016/j.ejphar.2011.04.026[Crossref]
  • [24] Gohda T., Ra C., Hamada C., Tsuge T., Kawachi H., Tomino Y., Suppressive activity of pemirolast potassium, an antiallergic drug, on glomerulonephritis. Studies in glomerulonephritis model rats and in patients with chronic glomerulonephritis concerrently affected by allergic rhinitis, Arzneimittelforschung, 2008, 58, 18–23 (in German)
  • [25] Malik M., Bigger J.T., Camm A.J., Guidelines. Heart rate variability. Standards of measurements, physiological interpretations and clinical use. Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology, Eur. Heart J., 1996, 17, 354–381 http://dx.doi.org/10.1093/oxfordjournals.eurheartj.a014868[Crossref]
  • [26] Maggi C.A., Meli A., Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 1: general considerations, Experientia, 1986, 42, 109–114 http://dx.doi.org/10.1007/BF01952426[Crossref]
  • [27] Maggi C.A., Meli A., Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 2: cardiovascular system, Experientia, 1986, 42, 292–297 http://dx.doi.org/10.1007/BF01942510[Crossref]
  • [28] Morais M.M., Belarmino-Filho J.N., Brito G.A.C., Ribeiro R.A., Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna. Braz. J. Med. Biol. Res., 1999, 32, 1211–1215 http://dx.doi.org/10.1590/S0100-879X1999001000006[Crossref]
  • [29] Schroder A., Newgreen D., Andersson K.E., Detrusor responses to prostaglandin e2 and bladder outlet obstruction in wild-type and ep1 receptor knockout mice, J. Urol., 2004, 172, 1166–1170 http://dx.doi.org/10.1097/01.ju.0000134186.58854.2c[Crossref]
  • [30] Zeng J., Pan C., Jiang C., Lindström S., Cause of residual urine in bladder outlet obstruction: an experimental study in the rat, J. Urol., 2012, 188, 1027–1032 http://dx.doi.org/10.1016/j.juro.2012.04.101[Crossref]
  • [31] Bilchick K.C., Berger R.D., Heart rate variability, J. Cardiovasc. Electrophysiol., 2006, 17, 693–694
  • [32] Thayer J.F., Ahs F., Fredrikson M., Sollers J.J., Wager T.D., A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health, Neurosci. Biobehav. Rev., 2012, 36, 747–756 http://dx.doi.org/10.1016/j.neubiorev.2011.11.009[WoS][Crossref]
  • [33] Stauss H.M., Heart rate variability, Am. J. Physiol. Regul. Integr. Comp. Physiol., 2003, 285, R927–R931
  • [34] Pumprla J., Howorka K., Groves D., Chester M., Nolan J., Functional assessment of heart rate variability: physiological basis and practical applications, Int. J. Cardiol., 2002, 84, 1–14 http://dx.doi.org/10.1016/S0167-5273(02)00057-8[Crossref]
  • [35] Taylor J.A, Carr D.L., Myers C.W., Eckberg D.L., Mechanisms underlying very low frequency RRinterval oscillations in humans, Circulation, 1998, 98, 547–555 http://dx.doi.org/10.1161/01.CIR.98.6.547[Crossref]
  • [36] Silva Soares P., da Nobrega A.C.L., Ushizima M.R., Irigoyen M.C.C., Cholinergic stimulation with piridostigmine increases heart rate variability and baroreflex sensivity in rats, Auton. Neurosci., 2004, 113, 24–31 http://dx.doi.org/10.1016/j.autneu.2004.05.002[Crossref]
  • [37] Thayer J.F., Fischer J.E., Heart rate variability, overnight urinary norepinephrine and C-reactive protein: evidence for the cholinergic anti-inflammatory pathway in healthy human adults, J. Int. Med., 2009, 265, 439–447 http://dx.doi.org/10.1111/j.1365-2796.2008.02023.x[Crossref][WoS]
  • [38] Tracey K.J., The inflammatory reflex, Nature, 2002, 420, 853–859 http://dx.doi.org/10.1038/nature01321[Crossref]
  • [39] Thayer J.F., Vagal tone and the inflammatory re- flex, Cleve. Clin. J. Med., 2009, 76, S23–S26 http://dx.doi.org/10.3949/ccjm.76.s2.05[Crossref]
  • [40] Flierl M.A., Rittirsch D., Nadeau B.A., Chen A.J., Sarma J.V., Zetoune F.S., et al., Phagocyte-derived catecholamines enhance acute inflammatory injury, Nature, 2007, 449, 721–725 http://dx.doi.org/10.1038/nature06185[WoS][Crossref]
  • [41] Flierl M.A., Rittirsch D., Nadeau B.A., Sarma J.V., Day D.E., Lentsch A.B., et al., Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response, PLos One, 2009, 4, e4414 http://dx.doi.org/10.1371/journal.pone.0004414[Crossref]
  • [42] Johnson J.D., Campisi J., Sharkey C.M., Kennedy S.L., Nickerson M., Greenwood B.N., Fleshner M., Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines, Neuroscience, 2005, 135, 1295–1307 http://dx.doi.org/10.1016/j.neuroscience.2005.06.090[Crossref]
  • [43] Elenkov I.J., Papanicolaou D.A., Wilder R.L., Chrousos G.P., Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications, Proc. Assoc. Am. Physicians, 1996, 108, 374–381
  • [44] Maestroni G.J.M., Mazzola P., Langerhans cells β2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity, J. Neuroimmunol., 2003, 144, 91–99 http://dx.doi.org/10.1016/j.jneuroim.2003.08.039
  • [45] Connor T.J., Brewer C., Kelly J.P., Harkin A., Acute stress suppresses pro-inflammatory cytokines TNF-α and Il-1β independent of a catecholamine- driven increase in Il-10 production, J. Neuroimmunol., 2005, 159, 119–128 http://dx.doi.org/10.1016/j.jneuroim.2004.10.016

Document Type

Publication order reference


YADDA identifier

JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.