Arzneimittelforschung 2011; 61(4): 229-233
DOI: 10.1055/s-0031-1296192
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Effects of agmatine on the survival rate in rats bled to hemorrhage

Fethi Gül
1   Anesthesiology Clinics, Haydarpa§a Numune Hastanesi (Haydarpaşa State Hospital), Istanbul, Turkey
,
Tuba Pelit
1   Anesthesiology Clinics, Haydarpa§a Numune Hastanesi (Haydarpaşa State Hospital), Istanbul, Turkey
,
Berna Terzioğlu
2   Clinical Biochemistry Laboratory, Haydarpaşa Numune Hastanesi (Haydarpaşa State Hospital), Istanbul, Turkey
,
Osman Ekinci
1   Anesthesiology Clinics, Haydarpa§a Numune Hastanesi (Haydarpaşa State Hospital), Istanbul, Turkey
,
M Zafer Gören
3   Department of Medical Pharmacology and Experimental Animal House and Laboratory (DEHAMER),Marmara University, School of Medicine, Haydarpaşa, Istanbul, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
27 November 2011 (online)

Abstract

Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like α2-adrenergic, imidazoline and N-methyl-D-aspartic acid (NMDA) receptors and besides it is involved in the nitric oxide mediated effects. It has also been proposed that it possesses vasodilator effects and increases glomerular filtration rate in rats. The aim of this study was to supply evidence for the effects of agmatine in a rat model of hemorrhagic shock and explain the possible mechanisms of action. The iliac arteries and veins of Sprague-Dawley rats were catheterized under ur-ethane anesthesia and around 2 ml/100 g blood was withdrawn within 20 min until the mean arterial blood pressure was stabilized around 25 mmHg. The rats were either pretreated with physiological saline, yohimbine (an α2-adrenergic receptor antagonist) or L-arginine (a nitric oxide donor) intravenously before administration of agmatine (300 >g/kg). Agmatine restored blood pressure in rats pretreated with physiological saline where all rats survived. Pretreatment with L-arginine abolished the increase in blood pressure produced by agmatine and the 1 h survival rate decreased to 67% (p < 0.01). Yohimbine pretreatment also suppressed agmatine induced restoration of blood pressure; however, the survival rate was found to be 17% for 3 min. No statistically significant effect was observed in the heart rate responses. These results may suggest that agmatine may increase survival through α2-adrenergic receptors and restores blood pressure through nitric oxide and adrenergic mechanisms in rats bled to hemorrhage.

 
  • References

  • 1 Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994; 263: 966-9
  • 2 Piletz JE, Chikkala DN, Ernsberger P. Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha-2 adrenergic receptors. J Pharmacol Exp Ther. 1995; 272: 581-7
  • 3 Pinthong D, Hussain JF, Kendall DA, Wilson VG. Comparison of the interaction of agmatine and crude methanolic extracts of bovine lung and brain with alpha 2-adrenoceptor binding sites. Br J Pharmacol. 1995; 115: 689-95
  • 4 Pinthong D, Wright IK, Hanmer C, Millns P, Mason R, Kendall DA et al. Agmatine recognizes alpha 2-adrenoceptor binding sites but neither activates nor inhibits alpha 2-adrenoceptors. Naunyn Schmiedeberg's Arch Pharmacol. 1995; Jan 351 (1) 10-6
  • 5 Auguet M, Viossat I, Marin JG, Chabrier PE. Selective inhibition of inducible nitric oxide synthase by agmatine. Jpn J Pharmacol. 1995; Nov 69 (3) 285-7
  • 6 Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J. 1996; 316: 247-9
  • 7 Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur J Pharmacol. 1996; 296: 17-22
  • 8 Fairbanks CA, Schreiber KL, Brewer KL, Yu CG, Stone LS, Kitto KF et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci USA. 2000; Sep 13 97 (19) 10584-9
  • 9 Yananli H, Gören MZ, Berkman K, Aricioglu F. Effect of agmatine on brain 1-citrulline production during morphine withdrawal in rats: A microdialysis study in nucleus accumbens. Brain Res. 2007; Feb 1132 (1) 51-8
  • 10 Lortie MJ, Novotny WF, Peterson OW, Vallon V, Malvey K, Mendonca M et al. Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat. J Clin Invest. 1996; Jan 15 97 (2) 413-20
  • 11 Gao Y, Gumusel B, Koves G, Prasad A, Hao Q, Hyman A et al. Agmatine: a novel endogenous vasodilator substance. Life Sci. 1995; 57 (8) 83-6
  • 12 Ishikawa T, Misonou T, Ikeno M, Sato K, Sakamaki TN. Omega-hydroxyagmatine: a novel substance causing endothelium-dependent vasorelaxation. Biochem Biophys Res Commun. 1995; Sep 214 (1) 145-51
  • 13 Stuehr DJ, Kwon NS, Nathan CF, Griffith OW, Feldman PL, Wiseman J. N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine. J Biol Chem. 1991; Apr 5 266 (10) 6259-63
  • 14 Yokoi I, Kabuto H, Habu H, Inada K, Toma J, Mori A. Structure-activity relationships of arginine analogues on nitric oxide synthase activity in the rat brain. Neuropharmacology. 1994; Nov 33 (11) 1261-5
  • 15 Komori Y, Wallace GC, Fukuto JM. Inhibition of purified nitric oxide synthase from rat cerebellum and macrophage by L-arginine analogs. Arch Biochem Biophys. 1994; Dec 315 (2) 213-8
  • 16 Senneguier N, Stuehr DJ. Analysis of substrate induced electronic, catalytic and structural changes in inducible NO synthase. Biochemistry. 1996; 35: 5883-92
  • 17 Hubbard JW, Pfister SL, Biediger AM, Herzig TM, Keeton KT. The pharmacokinetic properties of yohimbine in the conscious rat. Naunyn Schmiedeberg' Arch Pharmacol. 1988; May 337 (5) 583-7
  • 18 Jun T, Wennmalm A. L-Arginine-induced hypotension in the rat: evidence that NO synthesis is not involved. Acta Physiol Scand. 1994; Dec 152 (4) 385-90
  • 19 Collins JA, Braitberg A, Margraff HW, Butcher HR. Hemorrhagic shock in rats. Arch Surg. 1969; Oct 99 (4) 484-8
  • 20 Jurkiewicz NH, Garcez do CarmoL, Hirata H, da Costa SantosW, Jurkiewicz A. Functional properties of agmatine in rat vas deferens. Eur J Pharmacol. 1996; Jul 4 307 (3) 299-304
  • 21 Sun MK, Regunathan S, Reis DJ. Cardiovascular responses to agmatine, a clonidine-displacing substance, in anesthetized rat. Clin Exp Hypertens. 1995; 17: 115-28
  • 22 Szabo B, Urban R, Limberger N, Starke K. Cardiovascular effects of agmatine, a “clonidine-displacing substance”, in conscious rabbits. Naunyn Schmiedeberg' Arch Pharmacol. 1995; Mar 351 (3) 268-73
  • 23 Raasch W, Schafer U, Qadri F, Dominiak P. Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction. Br J Pharmacol. 2002; Feb 135 (3) 663-72
  • 24 Brian BH, Adrenoceptor-activating and other sympathomimetic drugs, Adrenoceptor antagonist drugs 10th ed. In: Katzung BR. editor. Basic and Clinical Pharmacology. Singapore: McGraw-Hill Education. 2007; p. 121-58
  • 25 Jackson EK, Gillespie DG, Zhu C, Ren J, Zacharia LC, Mi Z. Alpha2-adrenoceptors enhance angiotensin II-induced renal vasoconstriction: role for NADPH oxidase and RhoA. Hypertension. 2008; Mar 51 (3) 719-26
  • 26 Morrisey JJ, Klahr S. Agmatine activation of nitric oxide synthase in endothelial cells. Proc Assoc Am Physicians. 1997; Jan 109 (1) 51-7
  • 27 Regunathan S. Agmatine: biological role and therapeutic potentials in morphine analgesia and dependence. AAPS J. 2006; Jul 21 8 (3) E479-84
  • 28 Yesilyurt O, Uzbay IT. Agmatine potentiates the analgesic effect of morphine by an α2-adrenoceptor-mediated mechanism in mice. Neuropsychopharmacology. 2001; Jul 25 (1) 98-103
  • 29 Uzbay IT, Yesilyurt O, Celik T, Ergün H, Isimer A. Effects of agmatine on ethanol withdrawal syndrome in rats. Behav Brain Res. 2000; Jan 107 (1–2) 153-9
  • 30 Dogrul A, Coskun I, Uzbay T. The contribution of alpha-1 and alpha-2 adrenoceptors in peripheral imidazoline and adrenoceptor agonist-induced nociception. Anesth Analg. 2006; Aug 103 (2) 471-7