Gingerol, a novel cardiotonic agent, activates the Ca2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum.
Gingerol, isolated as a potent cardiotonic agent from the rhizome of ginger, stimulated the Ca2+-pumping activity of fragmented sarcoplasmic reticulum (SR) prepared from rabbit skeletal and dog cardiac muscles. The extravesicular Ca2+ concentrations of the heavy fraction of the fragmented SR (HSR) were measured directly with a Ca2+ electrode to examine the effect of gingerol on the SR. Gingerol (3-30 microM) accelerated the Ca2+-pumping rate of skeletal and cardiac SR in a concentration-dependent manner. The rate of 45Ca2+ uptake of HSR was also increased markedly by 30 microM gingerol without affecting the 45Ca2+ efflux from HSR. Furthermore, gingerol activated Ca2+-ATPase activities of skeletal and cardiac SR (EC50, 4 microM). The activation of SR Ca2+-ATPase activity by gingerol (30 microM) was completely reversed by 100-fold dilution with the fresh saline solution. Kinetic analysis of activating effects of gingerol suggests that the activation of SR Ca2+-ATPase is uncompetitive and competitive with respect to Mg . ATP at concentrations of 0.2-0.5 mM and above 1 mM, respectively. Kinetic analysis also suggests that the activation by gingerol is mixed-type with respect to free Ca2+ and this enzyme is activated probably due to the acceleration of enzyme-substrate complex breakdown. Gingerol had no significant effect on sarcolemmal Ca2+-ATPase, myosin Ca2+-ATPase, actin-activated myosin ATPase and cAMP-phosphodiesterase activities, indicating that the effect of gingerol is rather specific to SR Ca2+-ATPase activity. Gingerol may provide a valuable chemical tool for studies aimed at clarifying the regulatory mechanisms of SR Ca2+-pumping systems and the causal relationship between the Ca2+-pumping activity of SR and muscle contractility.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002396:Catechols; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005233:Fatty Alcohols / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*
D002132:Calcium Radioisotopes; D002396:Catechols; D005233:Fatty Alcohols; D007473:Ion Channels; D000255:Adenosine Triphosphate; C007845:gingerol; D000252:Calcium-Transporting ATPases; D002118:Calcium