Effects of cAMP modulators on long-chain fatty-acid uptake and utilization by electrically stimulated rat cardiac myocytes.
Recently, we established that cellular contractions increase long-chain fatty-acid (FA) uptake by cardiac myocytes. This increase is dependent on the transport function of an 88 kDa membrane FA transporter, FA translocase (FAT/CD36), and, in analogy to skeletal muscle, is likely to involve its translocation from an intracellular pool to the sarcolemma. In the present study, we investigated whether cAMP-dependent signalling is involved in this translocation process. Isoproterenol, dibutyryl-cAMP and the phosphodiesterase (PDE) inhibitor, amrinone, which markedly raised the intracellular cAMP level, did not affect cellular FA uptake, but influenced the fate of intracellular FAs by directing these to mitochondrial oxidation in electrostimulated cardiac myocytes. The PDE inhibitors 3-isobutyl-1-methylxanthine, milrinone and dipyridamole each significantly stimulated FA uptake as well as intracellular cAMP levels, but these effects were quantitatively unrelated. The stimulatory effects of these PDE inhibitors were antagonized by sulpho- N -succinimidylpalmitate, indicating the involvement of FAT/CD36, albeit that the different PDE inhibitors use different molecular mechanisms to stimulate FAT/CD36-mediated FA uptake. Notably, 3-isobutyl-1-methylxanthine and milrinone increased the intrinsic activity of FAT/CD36, possibly through its covalent modification, and dipyridamole induces translocation of FAT/CD36 to the sarcolemma. Elevation of intracellular cGMP, but not of cAMP, by the PDE inhibitor zaprinast did not have any effect on FA uptake and metabolism by cardiac myocytes. The stimulatory effects of PDE inhibitors on cardiac FA uptake should be considered when applying these agents in clinical medicine.
Luiken
J J F P
JJ
Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, NL-6200 MD Maastricht, The Netherlands. j.luiken@fys.unimaas.nl
Willems
J
J
Coort
S L M
SL
Coumans
W A
WA
Bonen
A
A
Van Der Vusse
G J
GJ
Glatz
J F C
JF
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D018955:CD36 Antigens; D000242:Cyclic AMP / Q000378:metabolism*; D004558:Electric Stimulation; D005227:Fatty Acids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013347:Subcellular Fractions / Q000378:metabolism
D018955:CD36 Antigens; D005227:Fatty Acids; D008562:Membrane Glycoproteins; D027361:Organic Anion Transporters; D003994:Bucladesine; D000242:Cyclic AMP; D007545:Isoproterenol