Reperfusion Causes Cytosolic Calcium Overload Due to Rapid Calcium Release from the Sarcoplasmic Reticulum

VALVERDE CA; KORNYEYEV D; VILA-PETROFF M; MATTIAZZI A; ESCOBAR AL

New London, NH, USA

Congreso; Gordon Research Conference 2008; 2008

Gordon Research Conferences

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-1610611985 1073750139 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; text-align:justify; text-indent:35.45pt; line-height:24.0pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-fareast-font-family:Calibri; mso-bidi-font-family:"Times New Roman"; mso-fareast-language:EN-US;} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Calibri; mso-fareast-font-family:Calibri; mso-hansi-font-family:Calibri;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> After a brief ischemic insult, a sustained contractile dysfunction occurs manifested as a sluggish recovery of pump function after revascularization, commonly defined as myocardial stunning. Substantial evidence supports that myocardial dysfunction is triggered by Ca2+ overload during reperfusion (R). Previous results from different laboratories including our own, describe a cascade of events triggered by R that involves the activation of Na+/H+ and Na+/Ca2+ (NCX) exchangers, with enhanced Ca2+ influx. Whether this Ca2+ influx directly produces the increase in cytosolic Ca2+ or this increase occurs as a consequence of sarcoplasmic reticulum (SR) Ca2+ release triggered in turn by the Ca2+ influx, is not known. To address this issue, we performed 12 min of global no-flow ischemia followed by R in the isovolumic Langendorff perfused mouse heart, positioned on a Pulsed Local Field Fluorescence microscope and loaded with either the calcium indicator Rhod-2 or Mag-Fluo-4 to assess cytosolic Ca2+ or intraluminal SR Ca2+ respectively. The results indicated an initial increase in diastolic Ca2+ during early R that gradually returned to pre-ischemic levels after 10 min of reperfusion. This increase was associated with a decrease in SR Ca2+ content that recovered within 10 min, as a mirror image of the diastolic Ca2+ profile. Additional experiments in which caffeine pulses (20 mM) were applied during preischemia, and 5 min and 10 min after R, confirmed that SR Ca2+ content was greatly diminished at the onset of R and gradually recovered after 5 min of R. The present findings indicate that the increase in diastolic Ca2+ that occurs upon R is due to a SR Ca2+ release -which might be at least partially caused by Ca2+ influx through the reverse NCX mode- and not just because of the Ca2+ entry through this exchanger, as has been previously thought