Ivermectina como um inibidor das Ca2*-ATPases de membrana plasmática e de retículo sarco/endoplasmático no ducto deferente de rato
DOI:
https://doi.org/10.24220/2318-0897v23n2a2526Palavras-chave:
Cálcio, Ivermectina , RatosResumo
Objetivo
O presente trabalho investigou o efeito da ivermecüna no conteúdo de Ca2* e na atividade Ca2*-ATPásica (representada pela Ca2*-ATPase de membrana plasmática e pela Ca2*-ATPase de retículo sarco/endoplasmático presente no ducto deferente de rato
Métodos
Os ensaios foram realizados por meio de preparações de homogeneizado ultracentrifugado de duto deferente de rato na presença ou ausência do complexo proteína de ligação ao FK506 de 12 kDa-canal liberador de Ca2*. Após esse procedimento, avaliações do conteúdo de Ca2* e da atividade Ca2*-ATPásica foram realizadas em função de diferentes concentrações de ivermectina.
Resultados
Os dados mostram que a ivermecüna (10 pM) reduz o conteúdo de cálcio no retículo sarcopíasmático de frações FK506-binding protein (+) e FK506-binding protein (-) de homogeneizado ultracentrifugado de duto deferente de rato (50'’/, e 40c)/, de inibição, respectivamente. p<0.05) e inibe as atividades das enzimas Ca2*-ATPase de retículo sarco/endoplasmático e Ca2*-ATPase de membrana plasmática (33c’/, e 76%, respectivamente. p<0,05)
Conclusão
Os dados sugerem que a ivermecüna afeta a mobilização de cálcio no duto deferente de rato. o que indica que esse fármaco pode alterar a contratilidade desse músculo liso. Dessa forma, ivermectina pode ser ferramenta farmacológica interessante para alterar a função fisiológica do duto deferente e manipular o estado de fertilidade de ratos machos.
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Referências
Sanbe A, Tanaka Y, Fujiwara Y, Tsumura H, Yamauchi J, Cotecchia S, et al. -Adrenoceptors are required for normal male sexual fuction. Br J Pharmacol. 2007; 152(3):332-40.
Lepor H. The emerging role of alpha antagonists in the therapy of benign prostatic hyperplasia. J Androl. 1991; 12(6):389-94.
Tambaro S, Ruiu S, Dessi C, Mongeau R, Marchese G, Pani L. Evaluation of tamsulosin and alfuzosin activity in the rat vas deferens: Relevance to ejaculation delays.
J Pharmacol Exp Ther. 2005; 312(2):710-17.
van Dijk MM, de la Rosette JJMCH, Michel MC. Effects of -adrenoceptor antagonists on male sexual function. Drugs. 2006; 66(3):287-301.
Mulryan K, Gitterman DP, Lewis, CJ, Vial C, Leckle BJ, Cobb AL, et al. Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature. 2000; 403(6765):86-9.
Muzi-Filho H, Bezerra CGP, Souza AM, Boldrini LC, Takiya CM, Oliveira FL, et al. Undernutrition affects cell survival, oxidative stress, Ca2+ handling and signaling pathways in vas deferens, crippling reproductive capacity. PLOS ONE. 2013; 26(8):e69682.
Marín J. Mechanisms involved in the increased vascular resistance hypertension. J Auton Pharmacol. 1993; 13(2):127-76.
Kuriyama H, Kitamura K, Nabata H. Pharmacological and physiological significance of ion channels and factors that modulate them in vascular tissues. Pharmacol Rev. 1995; 47(3):387-573.
Orallo F. Regulation of cytosolic calcium levels in vascular smooth muscle. Pharmacol Ther. 1996; 69(3):153-71.
Iino M. Dynamic regulation of intracellular calcium signal through calcium release channels. Mol Cell Biochem. 1999; 190(1-2):185-90.
Rodriguez JB, Muzi-Filho H, Valverde RH, Quintas LE, Noel F, Einicker-Lamas M, et al. Rat vas deferens SERCA2 is modulated by Ca2+/calmodulin protein kinase II-mediated phosphorylation. Braz J Med Biol Res. 2013; 46(3):227-34.
Scaramello CBV, Muzi-Filho H, Zapata-Sudo G, Sudo RT, Cunha VMN. FKBP12 depletion leads to loss of sarcoplasmic reticulum Ca2+ stores in rat vas deferens. J Pharmacol Sci. 2009; 109(2):185-92.
Cameron AM, Steiner JP, Sabatini DM, Kaplin AI, Walensky LD, Snyder SH. Immunophilin FK506 binding protein associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux. Proc Natl Acad Sci. 1995; 92(5):1784-788.
Campbell WC. Ivermectin as an antiparasitic agent for use in humans. Annu Rev Microbiol. 1991; 45:445-74.
Liu LX, Weller PF. Antiparasitic drugs. N Engl J Med. 1996; 334(18):1178-84.
Ahern GP, Junankar PR, Pace SM, Curtis S, Mould JA, Dulhunty A. Effects of ivermectin and midecamycin on ryanodine receptors and the Ca2+-ATPase in sarcoplasmic reticulum of rabbit and rat skeletal muscle. J Physiol. 1999; 514(Pt 2):313-26.
Bilmen JG, Wootton LL, Michelangeli F. The inhibition of the sarcoplasmic/endoplasmic reticulum Ca2+- ATPase by macrocyclic lactones and cyclosporin A. Biochem J. 2002; 366(Pt 1):255-63.
Scaramello CBV, Cunha VMN, Rodriguez JBR, Noel F. Characterization of subcellular fractions and distribution profiles of transport components involved in Ca2+ homeostasis in rat vas deferens. J Pharmacol Toxicol Methods. 2002; 47(2):93-8.
Spencer GG, Yu X, Khan I, Grover AK. Expression of isoforms of internal Ca2+ pump in cardiac, smooth muscle and non-muscle tissues. Biochim Biophys Acta. 1991; 1063(1):15-20.
Carmody M, Mackrill JJ, Sorrentino V, O’Neill C. FKBP12 associates tightly with the skeletal muscle type 1 ryanodine receptor, but not with other intracellular calcium release channels. FEBS Lett. 2001; 505(1):97-102.
Mackrill JJ, O’Driscoll S, Lai FA, McCarthy TV. Analysis of type 1 ryanodine receptor-12 kDa FK506-binding protein interaction. Biochem Biophys Res Commun. 2001; 285(1):52-7.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Follin phenol reagent. J Biol Chem. 1951; 193(1):265-75.
Fabiato A, Fabiato F. Calculator programs for computing the composition of the solutions containing multiple metal and ligands used for experiments in skinned muscle cells. J Physiol. 1979; 75(5):463-505.
Christensen SB, Larsen IK, Rasmussen U. Thapsigargin and thapsigargicin, two histamine liberating sesquiterpene lactones from Thapsia garganica. Xray analysis of the 7,11-epoxide of thapsigargin. J Org Chem. 1982; 47(4):649-52.
Thastrup O, Cullen PJ, Drobak BK, Hanley MR, Dawson AP. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proc Natl Acad Sci. 1990; 87(7):2466-70.
Inesi G, Sagara Y. Specific inhibitors of intracellular Ca2+ transport ATPases. J Membr Biol. 1994; 141(1):1-6.
Grubmeyer C, Penefsky MS. The presence of two hydrolytic sites on beef heart mitochondrial adenosine triphosphatase. J Biol Chem. 1981; 256(8):3718-27.
Marín J, Encabo A, Briones A, García-Cohen EC, Alonso MJ. Mechanisms involved in the cellular calcium homeostasis in vascular smooth muscle: Calcium pumps. Life Sci. 1999; 64(5):279-303.
Wootton LL, Argent CCH, Wheatley M, Michelangeli F. The expression, activity and localisation of the secretory pathway Ca2+-ATPase (SPCA1) in different mammalian tissues. Biochim Biophys Acta. 2004; 1664(2):189-97.
