The Na+/H+ exchange inhibitor cariporide is washed out of the myocardium by crystalloid cardioplegia.
BACKGROUND
Inhibition of the Na (+)/H (+) exchanger (NHE) is cardioprotective, but dosage and timing of NHE-inhibitors are critical for their efficacy. We studied the effect of a new dosing regime of the NHE-inhibitor cariporide on myocardial function and damage after cardioplegic arrest (CPA) and determined its myocardial and serum concentrations.


METHODS
3 pigs received a bolus of 180 mg cariporide intravenously (i. v.) and were sacrificed shortly thereafter to allow measurement of the myocardial concentrations of cariporide. Subsequently, 10 pigs were randomized to receive either i. v. cariporide (bolus followed by an infusion of 40 mg/h) or placebo. Cardiopulmonary bypass was initiated, and the heart was arrested for 60 minutes by infusion of St. Thomas Hospital solution. Left ventricular (LV) function was studied using microsonometry. Myocardial damage was assessed by troponin T. Serum concentrations of cariporide were measured throughout the study, and myocardial concentrations were measured before the end of CPA and 180 minutes thereafter.


RESULTS
Cariporide was present in all myocardial specimens (median: 1.4 ng/mg) studied previously. In the main study, LV function or myocardial damage did not differ significantly between the groups at any time point. Stable serum cariporide concentrations were achieved (3.4 +/- 0.5 microg/ml). Cariporide was detectable in only one of the myocardial biopsies obtained before the end of CPA, but 180 minutes thereafter, the myocardial cariporide concentration was 2.5 +/- 0.3 ng/mg.


CONCLUSIONS
We observed no effect of i. v. cariporide on LV function or myocardial damage after cardioplegic arrest. Our data suggest that cariporide is washed out of the myocardium by repeated application of crystalloid cardioplegia. Thus, the mode of delivery also appears to be critical for cardioprotection with NHE-inhibitors.
Bechtel
J F M
JF
Department of Cardiac Surgery, University of Lübeck, Lübeck, Germany. bechtel@medinf.mu-luebeck.de
Eichler
W
W
Toerber
K
K
Weidtmann
B
B
Hernandez
M
M
Klotz
K F
KF
Sievers
H H
HH
Bartels
C
C
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood*; D001794:Blood Pressure / Q000187:drug effects; D002315:Cardiopulmonary Bypass; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000097:blood*; D006324:Heart Arrest, Induced; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D011183:Postoperative Complications / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D017680:Potassium Compounds / Q000008:administration & dosage*; D012107:Research Design; D017923:Sodium-Hydrogen Exchangers / Q000097:blood* / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood*; D013552:Swine; D020107:Troponin T / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017680:Potassium Compounds; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D020107:Troponin T; C018369:potassium cardioplegic solution; C093373:cariporide