Demonstration of antithrombotic activity of glomerular adenosine diphosphatase.
We have demonstrated that reduced glomerular adenosine diphosphatase (ADPase) activity within the rat kidney is associated with an increased thrombotic tendency. To establish a possible causal relationship between these intraglomerular events, experiments were conducted to inhibit adenosine diphosphate (ADP) degradation without influencing other glomerular prothrombotic or antithrombotic mechanisms. Concurrently, we studied intraglomerular platelet aggregation. Two ways of selective inhibition of glomerular ADPase activity were applied: (1) by competitive substrates (ie, uridine diphosphate [UDP]), and (2) by the nondegradable ADP analogue ADP-beta-S. Both strategies were used during ex vivo alternate perfusion of kidneys with platelets and ADP (to test intraglomerular thrombotic tendency). Each group (n = 6) received different substrates or a combination of substrates. A significant increase in platelet aggregation was observed in kidneys after perfusion with platelets and ADP together with the competitive substrate UDP as compared to perfusions with platelets and ADP alone (78.5% +/- 9.8% v 27.9% +/- 11.4% glomeruli staining positive for platelets, P less than .005). In contrast, UDP alone had no effect on platelet aggregation. Other nucleoside polyphosphates (guanosine diphosphate and inosine triphosphate) were also effective as competitive substrates in the ex vivo perfusion model (n = 4). None of these substrates was capable of increasing ADP-induced aggregation when studied in vitro. In addition, ADP- beta-S also increased platelet aggregation in the perfusion model as compared with native ADP (P less than .005). These results show that selective reduction of ADP degradation in intact kidneys strongly promotes the intraglomerular proaggregatory condition. It can be concluded that glomerular ADPase exerts potent antithrombotic activity within the normal rat kidney.
Poelstra
K
K
Department of Pathology, University of Groningen, The Netherlands.
Baller
J F
JF
Hardonk
M J
MJ
Bakker
W W
WW
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001081:Apyrase / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005343:Fibrinolytic Agents; D006153:Guanosine Diphosphate / Q000378:metabolism; D006651:Histocytochemistry; D007293:Inosine Triphosphate / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D014530:Uridine Diphosphate / Q000378:metabolism
D005343:Fibrinolytic Agents; D007293:Inosine Triphosphate; D006153:Guanosine Diphosphate; D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; D001081:Apyrase