Pharmacological manipulation of canine cyclooxygenase and thromboxane synthetase in vivo: differential renal and platelet recovery rates.
Aspirin (acetylsalicylic acid) was chronically infused i.v. into dogs at a low dose (0.1 mg/kg/hr) using a surgically implanted Alzet osmotic pump. The time course for inhibition of cyclooxygenase and for its recovery after removal of the pump were followed in washed platelet preparations and in kidney medulla microsomes using [14C]arachidonic acid metabolism. Chronic acetylsalicylic acid infusion inhibited platelet cyclooxygenase 60% after 1 day of treatment and 95% after 3 days. Recovery of platelet arachidonate metabolism after removal of the osmotic pump was very rapid (T 1/2 = 0.9 days). Renal cyclooxygenase was also completely inhibited after 3 days but showed a slower recovery rate (T 1/2 = 2.8 days). Therefore, canine platelets, unlike human platelets, recover more rapidly from acetylsalicylic acid inhibition than do the kidneys. We have also established a whole blood method to study the effective time course of thromboxane synthetase inhibitors. The relative potencies for inhibiting platelet thromboxane synthetase after i.v. bolus administration of the agents studied was OKY-1581 greater than OKY-046 = dazoxiben much greater than Ro 22-7878. The effective half-life of OKY-1581, OKY-046 and dazoxiben was 2 hr while the half-life of Ro 22-7878 was 0.5 hr.
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology*; D016861:Cyclooxygenase Inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000201:enzymology*; D008689:Methacrylates / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D008689:Methacrylates; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase; C034364:ozagrel; D001241:Aspirin