The inhibition of human platelet function by ganodermic acids.
Human gel-filtered platelets aggregate at greater than 20 microM-ganodermic acid S [lanosta-7,9(11),24-triene-3 beta, 15 alpha-diacetoxy-26-oic acid] [Wang, Chen, Shiao & Wang (1989) Biochim. Biophys. Acta 986, 151-160]. This study showed that platelets at less than 20 microM-ganodermic acid S displayed both concentration- and time-dependent inhibition of function, in which the agent potency in response to inducers was ADP-fibrinogen greater than collagen greater than thrombin. The agent caused a biphasic time-dependent effect on platelet phosphoinositide metabolism. The first phase involved the decrease in the pool size of phosphoinositide by 10-20%. The second phase, in which both the resynthesis of phosphatidylinositol 4,5-bisphosphate (PIP2) and the decrease of [32P]phosphatidic acid occurred, took place after 30 min. Scanning electron microscopy also revealed a time-dependent morphological change in platelets in the presence of the agent. The cells initially became spiculate discs, then swelled to a 'potato-like' morphology at 60 min. Further studies on the time-dependent inhibition of thrombin response revealed that: (1) the percentage inhibition of cell aggregation was comparable with that occurring with an increase of cytosolic free Ca2+ concentration [( Ca2+]i) or the phosphorylation of marker proteins; (2) [32P]Pi-labelled platelets showed the time-dependent inhibition of thrombin-stimulated PIP2 resynthesis as indicated by first-2-min time-course studies of phosphoinositide interconversion; (3) scanning electron microscopy revealed that the aged platelet population showed an increase in the percentage of non-responding cells on prolonged incubation. The results, taken together, enabled one to discuss a possible mechanism for the time-dependent inhibition by ganodermic acid S of platelet response to thrombin.
Wang
C N
CN
Institute of Life Science, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.
Chen
J C
JC
Shiao
M S
MS
Wang
C T
CT
D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002850:Chromatography, Gel; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D010710:Phosphates / Q000097:blood; D010716:Phosphatidylinositols / Q000097:blood / Q000302:isolation & purification; D010743:Phospholipids / Q000097:blood / Q000302:isolation & purification; D010974:Platelet Aggregation
D010710:Phosphates; D010716:Phosphatidylinositols; D010743:Phospholipids; C061905:ganodermic acid S; D007810:Lanosterol