Human platelet Ca2+ mobilization, glycoprotein IIb/IIIa activation, and experimental coronary thrombosis in vivo in dogs are all inhibited by the inotropic agent amrinone.
BACKGROUND
Inotropic drugs are often used to treat acute, severe heart failure resulting from acute myocardial infarction and other unstable coronary artery syndromes. However, catecholamine inotropic agents may potentiate coronary thrombosis via a platelet alpha2-adrenergic mechanism, thus exacerbating the original problem. The present studies were designed to determine whether the nonadrenergic inotropic and vasodilator drug amrinone, which elevates platelet cAMP levels, would both inhibit human platelet Ca2+ mobilization and adhesion molecule expression ex vivo and protect against experimental coronary thrombosis in vivo in dogs.


RESULTS
Human platelets in suspension were preincubated with amrinone 2.5 to 15 microg/mL; stimulated with the agonists thrombin 0.1 U/mL, ADP 10(-6) mol/L, or arginine vasopressin 10(7) mol/L; and studied for Ca2+ mobilization, glycoprotein IIb/IIIa activation, and P-selectin expression by fluorescent flow cytometry methods. Experimental coronary thrombosis in vivo was studied in an open-chest dog model with critical coronary artery stenosis and deep vessel wall injury. Results showed that at the cellular level, amrinone inhibited agonist-induced Ca2+ mobilization and had modest inhibitory effects on adhesion molecule expression. In vivo in dogs, intravenous amrinone 2 mg/kg plus infusion at 20 microg x kg(1) x min(-1) completely abolished coronary thrombosis.


CONCLUSIONS
The fact that amrinone inhibited human platelet activation at the cellular level and protected against experimental coronary thrombosis in vivo in dogs suggests a potentially advantageous antithrombotic action for this inotropic and vasodilator drug.
Sill
J C
JC
Department of Anesthesiology, Mayo Clinic, Rochester, Minn 55905, USA. sill.john@mayo.edu
Bertha
B
B
Berger
I
I
Uhl
C
C
Nugent
M
M
Folts
J
J
D000676:Amrinone / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000097:blood*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation; D003328:Coronary Thrombosis / Q000139:chemically induced / Q000517:prevention & control*; D004285:Dogs; D004837:Epinephrine; D006801:Humans; D019007:P-Selectin / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; D014665:Vasodilator Agents; D000676:Amrinone; D002118:Calcium; D004837:Epinephrine