Nifedipine represses ion channels, transporters and Ca(2+)-binding proteins in hearts of spontaneously hypertensive rats.
The Ca(2+) antagonists nifedipine has been used for more than three decades to treat hypertension, but its effects on the transcriptional regulation of cardiac genes are basically unknown. We therefore studied expression of genes coding for ion channels, ion transporters and associated partners as well as Ca(2+)-binding proteins in ventricular tissue of normotensive and spontaneously hypertensive (SH) rats after repeated intraperitoneally (i.p.) dosing of nifedipine. Notably, we observed significant (P < 0.05) repression in transcript levels of most of the genes investigated, including cardiac Na(+), K(+), Ca(2+)-channels (L-type Ca(2+)-channel, K(ir)3.4, K(ir)6.1, Na(v)1.5), ATP-driven ion exchangers (Na(+)-K(+)-ATPase, NCX-1, PMCA 2 and 4, SERCA 2a and 2b) and their associated partners (phospholamban, RyR-2) as well as cytoskeletal proteins (alpha and beta-MHC, alpha cardiac and alpha skeletal actin, troponin T and I). Repression in transcript levels was, however, only seen in ventricular tissue of hypertensive animals. This points to fundamental differences in the mode of action of nifedipine in diseased and healthy animals. Indeed, this preponderance of repressed genes will promote disturbed ion homeostasis to result in contractile dysfunction. It is of considerable importance that repressed gene expression was also seen in end-stage human heart failure. We propose repression of cardiac-specific gene expression as a hallmark of nifedipine treatment in hypertrophic hearts.
Zwadlo
Carolin
C
Fraunhofer Institute of Toxicology and Experimental Medicine, Drug Research and Clinical Inhalation, Nicolai-Fuchs-Str. 1, D-30625 Hannover, Germany.
Borlak
Jürgen
J
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006973:Hypertension / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D016623:Ion Pumps / Q000235:genetics / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D002147:Calmodulin; D037282:Calreticulin; D003598:Cytoskeletal Proteins; D007473:Ion Channels; D016623:Ion Pumps; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D009543:Nifedipine