Control of Cardiac Ca2+ Levels: Inhibitory Actions of Sphingosine on Ca2+ Transients and L-type Ca2+ Channel Conductance

• Published in: Circulation research 1994-12, Vol.75 (6), p.981-989
• Main Authors: McDonough, Patrick M, Yasui, Kenji, Betto, Romeo, Salviati, Giovanni, Glembotski, Christopher C, Palade, Philip T, Sabbadini, Roger A
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Biological and medical sciences; Calcium - metabolism; Calcium - physiology; Calcium Channels - drug effects; Calcium Channels - metabolism; Calcium Channels - physiology; Ceramides - pharmacology; Fundamental and applied biological sciences. Psychology; Heart; Heart - drug effects; Heart - physiology; Muscle Proteins - metabolism; Myocardial Contraction; Myocardium - cytology; Myocardium - metabolism; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Sphingosine - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.75.6.981

The naturally occurring second messenger sphingosine (SPH) was examined for its ability to influence cardiac myocyte Ca regulation. SPH inhibited intracellular Ca transients in adult and neonatal rat ventricular myocytes. The inhibition was steeply dose dependent, with complete blockage of the Ca transients occurring in the 20-to 25-μmol/L range. Whole-cell patch clamping revealed substantial inhibition of the L-type Ca channel current (ICa) by SPH. The ability of SPH to block both the Ca transients and I was not dependent on protein kinases, since the general protein kinase inhibitor H7 failed to prevent the actions of SPH. The specificity of the effect of SPH was determined in experiments showing that SPH analogues did not produce comparable effects. Neither the naturally occurring ceramide, N-stearoyl SPH, nor the cell-permeant ceramide, N-acetyl SPH, had SPH-like actions on the Ca transients or L-type channel conductances. Caffeine-induced Ca transients were also inhibited by the actions of SPH on cardiac sarcoplasmic reticulum Ca release, and the threshold for caffeine-induced Ca release was raised. We conclude that SPH inhibits excitation-contraction coupling in cardiac myocytes by reducing the amount of entering “trigger Ca” for Ca-induced Ca release and by simultaneously raising the threshold of the ryanodine receptor for Ca-induced Ca release. Consequently, we propose that sphingolipids produced by the sphingomyelin signal transduction pathway could be physiologically relevant regulators of cardiac [Ca]i and therefore cardiac contractility.