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Research ArticleCARDIOVASCULAR

Inhibition of Ryanodine Receptors by 4-(2-Aminopropyl)-3,5-dichloro-N,N-dimethylaniline (FLA 365) in Canine Pulmonary Arterial Smooth Muscle Cells

Olga Ostrovskaya, Ravi Goyal, Noah Osman, Claire E. McAllister, Isaac N. Pessah, Joseph R. Hume and Sean M. Wilson
Journal of Pharmacology and Experimental Therapeutics October 2007, 323 (1) 381-390; DOI: https://doi.org/10.1124/jpet.107.122119
Olga Ostrovskaya
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Ravi Goyal
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Noah Osman
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Claire E. McAllister
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Isaac N. Pessah
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Joseph R. Hume
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Sean M. Wilson
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Abstract

Ryanodine is a selective ryanodine receptor (RyR) blocker, with binding dependent on RyR opening. In whole-cell studies, ryanodine binding can lock the RyR in an open-conductance state, short-circuiting the sarcoplasmic reticulum, which restricts studies of inositol-1,4,5-trisphosphate receptor (InsP3R) activity. Other RyR blockers have nonselective effects that also limit their utility. 4-(2-Aminopropyl)-3,5-dichloro-N,N-dimethylaniline (FLA 365) blocks RyR-elicited Ca2+ increases in skeletal and cardiac muscle; yet, its actions on smooth muscle are unknown. Canine pulmonary arterial smooth muscle cells (PASMCs) express both RyRs and InsP3Rs; thus, we tested the ability of FLA 365 to block RyR- and serotonin-mediated InsP3 R-elicited Ca2+ release by imaging fura-2-loaded PASMCs. Acute exposure to 10 mM caffeine, a selective RyR activator, induced Ca2+ increases that were reversibly reduced by FLA 365, with an estimated IC50 of ∼1 to 1.5 μM, and inhibited by 10 μM ryanodine or 10 μM cyclopiazonic acid. FLA 365 also blocked L-type Ca2+ channel activity, with 10 μM reducing Ba2+ current amplitude in patch voltage-clamp studies to 54 ± 6% of control and 100 μM FLA 365 reducing membrane current to 21 ± 6%. InsP3R-mediated Ca2+ responses elicited by 10 μM 5-hydroxytryptamine (serotonin) in canine PASMCs and 100 μM carbachol in human embryonic kidney (HEK)-293 cells were not reduced by 2 μM FLA 365, but they were reduced by 20 μM FLA 365 to 76 ± 9% of control in canine PASMCs and 52 ± 1% in HEK-293 cells. Thus, FLA 365 preferentially blocks RyRs with limited inhibition of L-type Ca2+ channels or InsP3R in canine PASMCs.

Footnotes

  • This work was supported by National Institutes of Health Grants HL49254 and P20RR15518 from National Center for Research Resources (to J.R.H.); Grants ES11269 and AR17605 (to I.N.P.); Grants HL10476 and AI55642; and a University of Mississippi faculty fellowship. A portion of this material is based upon work supported by the National Science Foundation under Grant MRI 0619774 (to S.M.W.), a University of Mississippi graduate student fellowship (to R.G.), and by the National Center for Natural Product Research.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.122119.

  • ABBREVIATIONS: RyR, ryanodine receptor; SR, sarcoplasmic reticulum; PASMC, pulmonary arterial smooth muscle cell; InsP3, inositol-1,4,5-trisphosphate; InsP3R, inositol-1,4,5-trisphosphate receptor; Cav, calcium channel; RuR, ruthenium red; FLA 365, 4-(2-aminopropyl)-3,5-dichloro-N,N-dimethylaniline; PSS, physiological saline solution; HEK, human embryonic kidney; AM, acetoxymethyl ester; IBa, Ba2+ current; 5-HT, 5-hydroxytryptamine (serotonin); CCh, carbachol; ANOVA, analysis of variance; SERCA, sarcoplasmic-endoplasmic reticulum Ca2+ ATPase; Rya, ryanodine; CPA, cyclopiazonic acid; CAF, caffeine.

  • ↵1 Current affiliation: Department of Pharmacology University of Tennessee, Memphis, Tennessee.

    • Received March 5, 2007.
    • Accepted July 18, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 368 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 3
1 Mar 2019
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Research ArticleCARDIOVASCULAR

Inhibition of Ryanodine Receptors by 4-(2-Aminopropyl)-3,5-dichloro-N,N-dimethylaniline (FLA 365) in Canine Pulmonary Arterial Smooth Muscle Cells

Olga Ostrovskaya, Ravi Goyal, Noah Osman, Claire E. McAllister, Isaac N. Pessah, Joseph R. Hume and Sean M. Wilson
Journal of Pharmacology and Experimental Therapeutics October 1, 2007, 323 (1) 381-390; DOI: https://doi.org/10.1124/jpet.107.122119

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Research ArticleCARDIOVASCULAR

Inhibition of Ryanodine Receptors by 4-(2-Aminopropyl)-3,5-dichloro-N,N-dimethylaniline (FLA 365) in Canine Pulmonary Arterial Smooth Muscle Cells

Olga Ostrovskaya, Ravi Goyal, Noah Osman, Claire E. McAllister, Isaac N. Pessah, Joseph R. Hume and Sean M. Wilson
Journal of Pharmacology and Experimental Therapeutics October 1, 2007, 323 (1) 381-390; DOI: https://doi.org/10.1124/jpet.107.122119
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