Laboratory Investigation Coronary Blood Flow

The phospholipid platelet-activating factor (PAF) stimulates platelet aggregation and coronary vasoconstriction. In this study we determined whether PAF alters coronary flow patterns in vivo in a canine preparation with concentric coronary artery stenosis. This preparation is characterized by cyclic flow variations in coronary blood flow associated with transient platelet aggregation at the site of the coronary constriction. Thirty-nine male mongrel dogs were used in three protocols. In protocol I, PAF (10-9 or 10-1 mol/min) was infused into the coronary artery proximal to the stenosis to determine (1) whether PAF induces cyclic flow variations and (2) whether PAF has an effect on systemic hemodynamics. Cyclic flow variations were induced in three of six dogs; in these animals, mean arterial pressure decreased by 5.5% and 42. 1I% 10 min after infusion of the lower and higher dose of PAF. In protocol 2, cyclic flow variations were abolished with either the thromboxane synthetase inhibitor UK38485 (mean dose 2.2 mg/kg iv), the serotonin antagonist ketanserin (0.5 mg/kg iv), or the ca,-adrenergic antagonist yohimbine (2 mg/kg iv). Subsequent administration of PAF restored the frequency of cyclic flow variations to the preantagonist levels. Thromboxane (Tx) B_ and 6-ketoPGFIr, the stable metabolites of TxA, and prostacyclin, respectively, were measured in blood obtained distal to the coronary stenosis. TxB, levels increased substantially during cyclic flow variations and were returned to control values with the thromboxane synthetase inhibitor UK38485. Infusion of PAF subsequently restored cyclic flow variations without altering coronary arterial TxB, levels. Furthermore, although PAF-induced platelet aggregation in vitro was associated with an increase in platelet thromboxane release, thromboxane synthetase inhibition did not alter PAF-induced platelet aggregation. Taken together, these data indicate that PAF may initiate and/or restore cyclic flow variations after their abolition with either a thromboxane synthetase inhibitor or a serotonin or a2-receptor antagonist. These data support previous studies in vitro demonstrating an action of PAF on platelet aggregation that is independent of thromboxane, serotonin. or a,-adrenergic agonists. Circulation 72, No. 2, 397-405, 1985. THE CLINICAL SYNDROME of unstable angina pectoris may occur in association with decreases in myocardial oxygen supply.' This may be caused by factors that reduce coronary blood flow. Some of these factors include (1 ) coronary arterial spasm, (2) hemorrhage into a nonocclusive plaque, (3) platelet aggregation over areas of plaque or endothelial denudation, From the Departments of Internal Medicine (Cardiology Division). Pharmacology, and Patholovy. University of Texas Health Science Center. Dallas. Supported in part by NIH Ischemic SCOR 17669. HL-2547 1, and the Moss Fund. Dallas. Dr. Campbell is the recipient of NIH Research Career Development Award K04-HL0080l. Address tor correspondence: James T. Willerson. M.D., Room L5.134, University of Texas Health Science Center. 5323 Harry Hines Blvd.. Dallas, TX 75235. Received Jan. 8. 1985; revision accepted May 2. 1985. Vol. 72, No. 2. August 1985 and (4) natural progression of coronary atherosclerosis. Platelet aggregates may mechanically obstruct an artery or may synthesize and release vasoactive agents such as thromboxane (Tx) A,, which has vasoconstrictor properties. Hirsh et al.' found elevated coronary sinus-to-aortic ratios of TxB1, the stable metabolite of TxA,, in patients with unstable angina pectoris. Folts et al.' developed an experimental preparation of a concentrically stenosed canine coronary artery. In this preparation there are episodic. spontaneous decreases in coronary blood flow interrupted by restorations of blood flow. These alterations in coronary blood flow have been called cyclic flow variations, which are associated with microscopic thrombi composed of platelets, erythrocytes, and leukocytes' 4 and 397 by gest on A ril 7, 2017 http://ciajournals.org/ D ow nladed from