Dronedarone administration prevents body weight gain and increases tolerance of the heart to ischemic stress: a possible involvement of thyroid hormone receptor alpha1.
Hypothyroid heart displays a phenotype of cardioprotection against ischemia and this study investigated whether administration of dronedarone, an amiodarone-like compound that has been shown to preferentially antagonize thyroid hormone binding to thyroid hormone receptor alpha1 (TRalpha1), results in a similar effect. Dronedarone was given in Wistar rats (90 mg/kg, once daily (od) for 2 weeks) (DRON), while untreated animals served as controls (CONT). Hypothyroidism (HYPO) was induced by propylthiouracil administration. Isolated rat hearts were perfused in Langendorff mode and subjected to 20 minutes of zero-flow global ischemia (I) followed by 45 minutes of reperfusion (R). 3,5,3' Triiodothyronine remained unchanged while body weight and food intake were reduced. alpha-Myosin heavy chain (alpha-MHC) decreased in DRON while beta-myosin heavy chain (beta-MHC) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) expression (SERCA) was similar to CONT. In HYPO, alpha-MHC and SERCA were decreased while beta-MHC was increased. Myocardial glycogen content was increased in both DRON and HYPO. In DRON, resting heart rate and contractility were reduced and ischemic contracture was significantly suppressed while postischemic left ventricular end-diastolic pressure and lactate dehydrogenase release (IU/L min) after I/R were significantly decreased. In conclusion, dronedarone treatment results in cardioprotection by selectively mimicking hypothyroidism. This is accompanied by a reduction in body weight because of the suppression of food intake. TRs might prove novel pharmacologic targets for the treatment of cardiovascular illnesses.
Pantos
Constantinos
C
Department of Pharmacology, University of Athens, Athens, Greece. cpantos@cc.uoa.gr
Mourouzis
Iordanis
I
Malliopoulou
Vassiliki
V
Paizis
Ioannis
I
Tzeis
Stylianos
S
Moraitis
Panagiotis
P
Sfakianoudis
Konstantinos
K
Varonos
Dennis D
DD
Cokkinos
Dennis V
DV
D000222:Adaptation, Physiological; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D000077764:Dronedarone; D004435:Eating / Q000187:drug effects; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D007037:Hypothyroidism / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007536:Isomerism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D006003:Glycogen; D007770:L-Lactate Dehydrogenase; D009218:Myosins; D000252:Calcium-Transporting ATPases; D000077764:Dronedarone; D000638:Amiodarone