High-dose droperidol protects against experimental coronary thrombosis in dogs and pigs and attenuates aggregation of porcine platelets and Ca2+ mobilization in human platelets.
BACKGROUND
Activation of platelets after contact with thrombogenic substrates may be an early factor leading to coronary artery thrombosis and myocardial infarction. Haloperidol, a butyrophenone, possesses weak in vitro platelet inhibitory activity. Experiments were designed to determine whether droperidol, a butyrophenone adjunct to anesthesia, protected against experimental coronary thrombosis in intravenously anesthetized open-chest dogs and pigs, attenuated ex vivo porcine platelet aggregation, and inhibited agonist-induced increases in [Ca2+]i in human platelets.


METHODS
In dogs and pigs, a lesion consisting of deendothelialization, deep vessel wall injury, and critical stenosis was created in the proximal circumflex arteries, resulting in coronary thrombus formation accompanied by decreased circumflex artery blood flow. Embolization of the thrombus restored flow, but the cycle then repeated, resulting in repetitive cyclical flow reductions (CFRs). These were measured using an electromagnetic flow probe.


RESULTS
In dogs, droperidol 0.2 mg/kg intravenous rapidly abolished CFRs in all ten animals, with frequency decreasing from 0.22 +/- 0.01 cycles/min to 0. Droperidol 0.8 mg/kg intravenous rapidly abolished CFRs in seven of eight pigs, with frequency decreasing from 0.15 +/- 0.01 to 0.02 cycles/min (P < 0.005). In both species, additional doses of droperidol were effective against CFRs augmented with intravenous epinephrine, a catecholamine that stimulates thrombosis. Ex vivo platelet aggregation studies were performed in platelet-rich plasma obtained from pigs before and after droperidol 0.8 mg/kg intravenous. Pretreatment with the drug resulted in marked inhibition of aggregation evoked by collagen, modest attenuation of that elicited by adenosine diphosphate (ADP), but no effect on that evoked by arachidonic acid. In human platelets, apparent [Ca2+]i was estimated using the fluorescent indicator indo-1 and flow cytometry. Droperidol 10(-7), 10(-6), and 10(-5)M had a dose-dependent inhibitory effect on the amplitude of increases in [Ca2+]i evoked by 10(-5)M serotonin (plus 10(-7)M epinephrine). The higher droperidol concentration decreased the response to as much as 30% of control (P < 0.001). Droperidol lacked effect on Ca2+ mobilization elicited with 10(-6)M ADP.


CONCLUSIONS
The results from three experimental models indicate that droperidol attenuates experimental coronary thrombosis in animals and suggest that this inhibition may result, in part, from a direct droperidol depressant effect on platelet activation and aggregation.
Bertha
B G
BG
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905.
Sill
J C
JC
Berger
I
I
Folts
J D
JD
Milde
J H
JH
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000097:blood*; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000517:prevention & control*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004329:Droperidol / Q000008:administration & dosage*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles; D008297:Male; D008954:Models, Biological; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D013045:Species Specificity; D013552:Swine
D007211:Indoles; D012701:Serotonin; D000244:Adenosine Diphosphate; C048960:indo-1; D004329:Droperidol; D002118:Calcium