Inhibition of acute stent thrombosis under high-shear flow conditions by a nitric oxide donor, DMHD/NO. An ex vivo porcine arteriovenous shunt study.
BACKGROUND
Coronary stenting is limited by subacute thrombosis, especially in smaller-diameter vessels, in which shear rates are high. The objective of the present study was to determine whether local delivery of a new type of NO donor, the NO adduct of N,N'-dimethylhexanediamine (DMHD/NO), inhibits acute stent thrombosis (ST) at high-shear flow.


RESULTS
Effects of local infusion of DMHD/NO; intravenous aspirin, and heparin on ST were evaluated in an ex vivo porcine AV shunt model. Nitinol stents (2 mum in diameter, n = 120) were placed in a tubular chamber and perfused with blood from pigs (n = 13) at a shear rate of 2100s-1 for 20 minutes. ST was quantified by measurement of dry thrombus weight(TW). Effects on platelet aggregation (PA), blood pressure, bleeding time, and activated clotting time (ACT) were also examined. There was a dose-dependent inhibition of ST and PA by DMHD/NO. TW was reduced by 95% (1 +/- 2 versus 16 +/- 4 mg control, mean +/- SD, P < .001), and PA was reduced by 75% (4 +/- 3 versus 14 +/- 9 omega/min control, P < .05) at the highest dose of 10 mumol/L. DMHD/NO had no effects on bleeding time, ACT, or blood pressure. In contrast, aspirin (10 mg/kg), despite inhibiting PA, had no effects on TW (12 +/- 5 versus 16 +/- 8 mg control, P = .3). Heparin (200 U/kg) reduced TW by 33% (14 +/- 4 versus 21 +/- 3 mg control, P < .05) and prolonged ACT.


CONCLUSIONS
Local delivery of DMHD/NO produced a 15-fold inhibition of acute ST at high-shear flow without producing adverse systemic hemostatic or hemodynamic effects. Thus, treatment with DMHD/NO may be an effective strategy for prevention of stent thrombosis.
Kaul
S
S
Division of Cardiology, Cedars-Sinai Medical Center Research Institute, Los Angeles, CA, USA. kaut@csmc.edu
Makkar
R R
RR
Nakamura
M
M
Litvack
F I
FI
Shah
P K
PK
Forrester
J S
JS
Hutsell
T C
TC
Eigler
N L
NL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D001166:Arteriovenous Shunt, Surgical; D001241:Aspirin / Q000494:pharmacology; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006588:Hexanones / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D015607:Stents; D013552:Swine; D013927:Thrombosis / Q000517:prevention & control*; D014914:Whole Blood Coagulation Time
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D006588:Hexanones; C039195:3,4-dimethyl-2,5-hexanedione; D009569:Nitric Oxide; D006493:Heparin; D006152:Cyclic GMP; D001241:Aspirin