Ivermectin as an inhibitor of the plasma membrane and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPases in rat vas deferens

Humberto Muzi-Filho, Dominick Rodrigues Alves de Souza, Christianne Bretas Vieira Scaramello, Valeria do Monti Nascimento Cunha

Resumo


Objective

The present work investigated the effect of ivermectin on Ca2+ content and on the Ca2+-ATPase activity (represented by the plasma membrane Ca2+-ATPase and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase present in rat vas deferens.

Methods

The assays were carried out using ultracentrifuged homogenate preparations from rat vas deferens in the presence or absence of the 12-kDa FK506-binding protein-Ca2+ release channel complex. Measures of Ca2+ content and Ca2+ ATPase activity were then carried out in function of different concentrations of ivermectin.

Results

The data show that ivermectin (10 μM) reduces the sarcoplasmic reticulum Ca2+ content in FK506-binding protein (+) and FK506-binding protein (-) fractions of ultracentrifuged homogenate from rat vas deferens (inhibition of 50% and 40%, respectively, p<0.05) and inhibits both the activities of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase and plasma membrane Ca2+-ATPases pumps (33% and 16%, respectively, p<0.05).

Conclusion

These data suggest that ivermectin effects Ca2+ handling in the rat vas deferens, indicating that this drug could alter the contractility of this smooth muscle. Therefore, ivermectin could be an interesting pharmacological tool to alter the physiological function of vas deferens and to manipulate the fertility status of male rats.

Indexing terms: Calcium. Ivermectin. Rats.


Palavras-chave


Calcium. Ivermectin. Rats.

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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.

; 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.

; 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.

; 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;

(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;

:445-74.

Liu LX, Weller PF. Antiparasitic drugs. N Engl J Med.

; 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.

; 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-

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.

; 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;

(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-

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;

(2):189-97.




DOI: https://doi.org/10.24220/2318-0897v23n2a2526

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Revista de Ciências Médicas

ISSNe 2318-0897 (eletrônico)
ISSN 1415-5796 (impresso)

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