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3′,4′-Dihydroxyflavonol reduces vascular contraction through Ca2+ desensitization in permeabilized rat mesenteric artery

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Abstract

3′,4′-Dihydroxyflavonol (DiOHF) exerts endothelium-independent relaxation in rat aortic rings. In this study, we hypothesized that DiOHF reduces vascular contraction through Ca2+ desensitization in permeabilized third-order branches of rat mesenteric arteries. The third-order branches of rat mesenteric arteries were permeabilized with β-escin and subjected to tension measurement. Cumulative addition of phenylephrine (0.3–30 μM) produced concentration-dependent vascular contraction of endothelium-intact and endothelium-denuded arterial rings, which were inhibited by pretreatment with DiOHF (10, 30, or 100 μM). In addition, DiOHF dose-dependently decreased vascular contractions induced by 3.0 μM phenylephrine. β-Escin-permeabilized third-order branches of mesenteric arteries were contracted with Ca2+, NaF, or guanosine-5′-(γ-thio)triphosphate (GTPγS) 30 min after pretreatment with DiOHF or vehicle. Pretreatment with DiOHF for 30 min inhibited vascular contraction induced by cumulative additions of Ca2+ (pCa 9.0–6.0) or NaF (4.0–16.0 mM) in permeabilized arterial rings. Cumulative addition of DiOHF also reduced vascular contraction induced by Ca2+-controlled solution of pCa 6.0, 16.0 mM NaF, or 100 μM GTPγS in permeabilized arterial rings. DiOHF inhibited the increase in vascular tension provoked by calyculin A, even though it did not affect vascular tension already produced by calyculin A. DiOHF accelerated the relaxation induced by rapidly lowering Ca2+. DiOHF reduced vascular contraction through Ca2+ desensitization in permeabilized third-order branches of rat mesenteric arteries. These results suggest that DiOHF may have a therapeutic potential in the treatment of cardiovascular diseases.

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Abbreviations

AlF −4 :

Aluminum tetrafluoride

[Ca2+]i :

Intracellular free calcium concentration

CPI17:

PKC-potentiated inhibitory protein for heterotrimeric MLCP of 17 kDa

DiOHF:

3′,4′-Dihydroxyflavonol

EGTA:

Ethylene glycol bis(2-aminoethyl ether)-N,N,N′N′-tetraacetic acid

GPCRs:

G protein-coupled receptors

GTP:

Guanosine-5′-triphosphate

GTPγS:

Guanosine-5′-(γ-thio)triphosphate

MLC:

Myosin light chain

MLCK:

Myosin light chain kinase

MLCP:

Myosin light chain phosphatase

MYPT1:

Myosin phosphatase targeting subunit 1

NaF:

Sodium fluoride

pCa:

−log [Ca2+]

PDBu:

Phorbol 12,13-dibutyrate

PIPES:

Piperazine-1,4-bis(2-ethanesulfonic acid)

PKC:

Protein kinase C

SPC:

Sphingosylphosphorylcholine

SR:

Sarcoplasmic reticulum

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014066) and the Brain Korea 21 Project in 2011.

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Authors and Affiliations

  1. Department of Pharmacology, Kyungpook National University School of Medicine, 101 Dongin-2-Ga, Daegu, 700-422, Republic of Korea

    Hye Young Kim & In Kyeom Kim

  2. Cardiovascular Research Institute, Kyungpook National University School of Medicine, Daegu, 700-422, Republic of Korea

    Young Mi Seok & In Kyeom Kim

  3. School of Medical Sciences, RMIT University, Bundoora, Victoria, 3083, Australia

    Owen L. Woodman

  4. School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria, Australia

    Spencer J. Williams

  5. Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, 700-422, Republic of Korea

    In Kyeom Kim

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  1. Hye Young Kim
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Correspondence to In Kyeom Kim.

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Hye Young Kim and Young Mi Seok contributed equally to this paper.

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Kim, H.Y., Seok, Y.M., Woodman, O.L. et al. 3′,4′-Dihydroxyflavonol reduces vascular contraction through Ca2+ desensitization in permeabilized rat mesenteric artery. Naunyn-Schmiedeberg's Arch Pharmacol 385, 191–202 (2012). https://doi.org/10.1007/s00210-011-0697-8

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