Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes: Impact on swelling-induced negative inotropic effect

Luis Alberto Gonano, Malena Morell, Juan Ignacio Burgos, Raul Ariel Dulce, Verónica Celeste De Giusti, Ernesto Alejandro Aiello, Joshua Hare, Martin Vila Petroff

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Aims Cardiomyocyte swelling occurs in multiple pathological situations and has been associated with contractile dysfunction, cell death, and enhanced propensity to arrhythmias.We investigate whether hypotonic swelling promotes nitric oxide (NO) release in cardiomyocytes, and whether it impacts on swelling-induced contractile dysfunction. Methods and results Superfusing rat cardiomyocytes with a hypotonic solution (HS; 217 mOsm), increased cell volume, reduced myocyte contraction and Ca<sup>2+</sup> transient, and increased NO-sensitive 4-amino-5-methylamino-2', 7'-difluorofluorescein diacetate (DAF-FM) fluorescence. When cells were exposed to HS + 2.5 mMof theNOsynthase inhibitor L-NAME, cell swelling occurred in the absence of NOrelease. Swelling-induced NO release was also prevented by the nitric oxide synthase 1 (NOS1) inhibitor, nitroguanidine, and significantly reduced in NOS1 knockout mice. Additionally, colchicine (inhibitor of microtubule polymerization) prevented the increase in DAF-FM fluorescence induced by HS, indicating that microtubule integrity is necessary for swelling-inducedNOrelease. The swelling-induced negative inotropic effectwas exacerbated in the presence of either L-NAME, nitroguandine, the guanylate cyclase inhibitor, ODQ, or the PKG inhibitor, KT5823, suggesting that NOS1-derived NO provides contractile support via a cGMP/PKG-dependent mechanism. Indeed, ODQ reduced Ca<sup>2+</sup> wave velocity and both ODQ and KT5823 reduced the HS-induced increment in ryanodine receptor (RyR2, Ser2808) phosphorylation, suggesting that in this context, cGMP/PKG may contribute to preserve contractile function by enhancing sarcoplasmic reticulum Ca<sup>2+</sup> release. Conclusions Our findings suggest a novel mechanism for NO release in cardiomyocytes with putative pathophysiological relevance determined, at least in part, by its capability to reduce the extent of contractile dysfunction associated with hypotonic swelling.

Original languageEnglish (US)
Pages (from-to)456-466
Number of pages11
JournalCardiovascular Research
Volume104
Issue number3
DOIs
StatePublished - Dec 1 2014

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Cardiac Myocytes
Nitric Oxide
Nitric Oxide Synthase
Ryanodine Receptor Calcium Release Channel
NG-Nitroarginine Methyl Ester
Microtubules
Fluorescence
Hypotonic Solutions
Guanylate Cyclase
Colchicine
Sarcoplasmic Reticulum
Cell Size
Knockout Mice
Polymerization
Muscle Cells
Cardiac Arrhythmias
Cell Death
Phosphorylation
KT 5823

Keywords

  • Contractile dysfunction
  • Hypotonic swelling
  • Ischaemia reperfusion
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Gonano, L. A., Morell, M., Burgos, J. I., Dulce, R. A., De Giusti, V. C., Aiello, E. A., ... Petroff, M. V. (2014). Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes: Impact on swelling-induced negative inotropic effect. Cardiovascular Research, 104(3), 456-466. https://doi.org/10.1093/cvr/cvu230

Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes : Impact on swelling-induced negative inotropic effect. / Gonano, Luis Alberto; Morell, Malena; Burgos, Juan Ignacio; Dulce, Raul Ariel; De Giusti, Verónica Celeste; Aiello, Ernesto Alejandro; Hare, Joshua; Petroff, Martin Vila.

In: Cardiovascular Research, Vol. 104, No. 3, 01.12.2014, p. 456-466.

Research output: Contribution to journalArticle

Gonano, Luis Alberto ; Morell, Malena ; Burgos, Juan Ignacio ; Dulce, Raul Ariel ; De Giusti, Verónica Celeste ; Aiello, Ernesto Alejandro ; Hare, Joshua ; Petroff, Martin Vila. / Hypotonic swelling promotes nitric oxide release in cardiac ventricular myocytes : Impact on swelling-induced negative inotropic effect. In: Cardiovascular Research. 2014 ; Vol. 104, No. 3. pp. 456-466.
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T2 - Impact on swelling-induced negative inotropic effect

AU - Gonano, Luis Alberto

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AU - Burgos, Juan Ignacio

AU - Dulce, Raul Ariel

AU - De Giusti, Verónica Celeste

AU - Aiello, Ernesto Alejandro

AU - Hare, Joshua

AU - Petroff, Martin Vila

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N2 - Aims Cardiomyocyte swelling occurs in multiple pathological situations and has been associated with contractile dysfunction, cell death, and enhanced propensity to arrhythmias.We investigate whether hypotonic swelling promotes nitric oxide (NO) release in cardiomyocytes, and whether it impacts on swelling-induced contractile dysfunction. Methods and results Superfusing rat cardiomyocytes with a hypotonic solution (HS; 217 mOsm), increased cell volume, reduced myocyte contraction and Ca2+ transient, and increased NO-sensitive 4-amino-5-methylamino-2', 7'-difluorofluorescein diacetate (DAF-FM) fluorescence. When cells were exposed to HS + 2.5 mMof theNOsynthase inhibitor L-NAME, cell swelling occurred in the absence of NOrelease. Swelling-induced NO release was also prevented by the nitric oxide synthase 1 (NOS1) inhibitor, nitroguanidine, and significantly reduced in NOS1 knockout mice. Additionally, colchicine (inhibitor of microtubule polymerization) prevented the increase in DAF-FM fluorescence induced by HS, indicating that microtubule integrity is necessary for swelling-inducedNOrelease. The swelling-induced negative inotropic effectwas exacerbated in the presence of either L-NAME, nitroguandine, the guanylate cyclase inhibitor, ODQ, or the PKG inhibitor, KT5823, suggesting that NOS1-derived NO provides contractile support via a cGMP/PKG-dependent mechanism. Indeed, ODQ reduced Ca2+ wave velocity and both ODQ and KT5823 reduced the HS-induced increment in ryanodine receptor (RyR2, Ser2808) phosphorylation, suggesting that in this context, cGMP/PKG may contribute to preserve contractile function by enhancing sarcoplasmic reticulum Ca2+ release. Conclusions Our findings suggest a novel mechanism for NO release in cardiomyocytes with putative pathophysiological relevance determined, at least in part, by its capability to reduce the extent of contractile dysfunction associated with hypotonic swelling.

AB - Aims Cardiomyocyte swelling occurs in multiple pathological situations and has been associated with contractile dysfunction, cell death, and enhanced propensity to arrhythmias.We investigate whether hypotonic swelling promotes nitric oxide (NO) release in cardiomyocytes, and whether it impacts on swelling-induced contractile dysfunction. Methods and results Superfusing rat cardiomyocytes with a hypotonic solution (HS; 217 mOsm), increased cell volume, reduced myocyte contraction and Ca2+ transient, and increased NO-sensitive 4-amino-5-methylamino-2', 7'-difluorofluorescein diacetate (DAF-FM) fluorescence. When cells were exposed to HS + 2.5 mMof theNOsynthase inhibitor L-NAME, cell swelling occurred in the absence of NOrelease. Swelling-induced NO release was also prevented by the nitric oxide synthase 1 (NOS1) inhibitor, nitroguanidine, and significantly reduced in NOS1 knockout mice. Additionally, colchicine (inhibitor of microtubule polymerization) prevented the increase in DAF-FM fluorescence induced by HS, indicating that microtubule integrity is necessary for swelling-inducedNOrelease. The swelling-induced negative inotropic effectwas exacerbated in the presence of either L-NAME, nitroguandine, the guanylate cyclase inhibitor, ODQ, or the PKG inhibitor, KT5823, suggesting that NOS1-derived NO provides contractile support via a cGMP/PKG-dependent mechanism. Indeed, ODQ reduced Ca2+ wave velocity and both ODQ and KT5823 reduced the HS-induced increment in ryanodine receptor (RyR2, Ser2808) phosphorylation, suggesting that in this context, cGMP/PKG may contribute to preserve contractile function by enhancing sarcoplasmic reticulum Ca2+ release. Conclusions Our findings suggest a novel mechanism for NO release in cardiomyocytes with putative pathophysiological relevance determined, at least in part, by its capability to reduce the extent of contractile dysfunction associated with hypotonic swelling.

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KW - Hypotonic swelling

KW - Ischaemia reperfusion

KW - Nitric oxide

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