Perindopril augments ecto-ATP diphosphohydrolase activity and enhances endothelial anti-platelet function in human umbilical vein endothelial cells.
OBJECTIVE
Recent clinical trials have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs) reduce thrombotic events by unknown mechanisms in patients with atherosclerotic cardiovascular diseases.


METHODS
We studied the in-vitro effects of perindopril, an ACEI, on the ability of human umbilical vein endothelial cells (HUVEC) to inhibit platelet aggregation.


METHODS
Platelet aggregation in the presence of HUVEC and endothelial surface expression and activities of ecto-ATP diphosphohydrolase (ecto-ADPase), CD39, were determined. The capability of HUVEC to release prostacyclin and nitric oxide (NO) was also investigated.


RESULTS
Perindoprilat (an active metabolite of perindopril) significantly enhanced the surface expression and activities of ecto-ADPase and prostacyclin release, resulting in enhancement of ability to inhibit platelet aggregation by HUVEC. These effects of perindoprilat were also observed in HUVEC activated by tumour necrosis factor (TNF)-alpha, which increased the expression of intracellular adhesion molecule-1 (ICAM-1), CD54, and, despite up-regulation of prostacyclin release, attenuated endothelial anti-platelet properties by decreasing ecto-ADPase activity. Perindoprilat partially restored this capability, but failed to reduce enhanced expression of ICAM-1. By contrast, the role of NO as a platelet inhibitor appeared minimal in HUVEC. Candesartan, an angiotensin II receptor (AT(1)) blocker, did not affect endothelial anti-platelet property.


CONCLUSIONS
Perindoprilat was found to augment endothelial capability to inhibit platelet aggregation by increasing ecto-ADPase activity and prostacyclin release in HUVEC. This beneficial effect of perindoprilat appeared to be preserved in the activated cells exposed to TNF-alpha, although no evidence was found to support that it could reverse the inflammation process induced by cytokines.
Kishi
Yukio
Y
Center for Preventive Medicine, Tokyo Kyosai Hospital, Tokyo, Japan. kishi.hsc@tkh.meguro.tokyo.jp
Ohta
Seiko
S
Kasuya
Natsuko
N
Sakita
Sin-Ya
SY
Ashikaga
Takashi
T
Isobe
Mitsuaki
M
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001081:Apyrase / Q000378:metabolism*; D001792:Blood Platelets / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D000806:Angiotensin-Converting Enzyme Inhibitors; D015703:Antigens, CD; D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D011464:Epoprostenol; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen; D020913:Perindopril