The data obtained in this study demonstrate that the concentration of serotonin is markedly elevated (18-to 27-fold) at the site of a coronary arterial stenosis in open-chest, anesthetized dogs with cyclic flow variations. Cyclic flow variations in this experimental preparation were abolished by ketanserin, a 5-hydroxytryptamine antagonist, but serotonin concentration at the site of the coronary stenosis remained elevated. The intra-atrial administration of serotonin (0.16 to 1 mg/min) restored cyclic flow variations after they had been abolished by ketanserin. Taken together, these data suggest that serotonin may be one of the important mediators of cyclic flow variations in this experimental preparation.Circulation 73, No. 3, 572-578, 1986. PREVIOUS STUDIES from our laboratory and others have suggested that platelet aggregation is an important factor in some occlusive coronary disease states.'4 Platelets possess both a2-adrenergic and serotonergic receptors, which are thought to be responsible for the platelet aggregatory effects of catecholamines and serotonin (5-hydroxytryptamine). Separate receptors responsible for regulating the uptake of serotonin into platelets also have been identified.5 6 In concentrically narrowed canine coronary arteries, spontaneous transient coronary thrombosis results in cyclic flow variations (CFVs). This preparation was described by Folts et al.7 and has been used in subsequent studies by our laboratory3'4 and by others2 to examine the mechanism(s) contributing to the development of CFVs in stenotic canine coronary arteries. CFVs are characterized by gradual decreases in blood flow over a period of minutes followed by either spontaneous or induced abrupt increases in flow. CFVs are thought to be produced by platelet aggregation at the stenotic site alternating with thrombus dislodgement and embolization.We have shown that ketanserin In the present study, we tested the hypothesis that serotonin may be one of the important mediators of CFVs in stenotic canine coronary arteries. The tissue concentration of serotonin was determined in both normal canine coronary arterial segments and in stenotic canine coronary arterial segments in which CFVs had occurred. The concentration of serotonin was determined in the same coronary arteries in a separate group of dogs in which CFVs were abolished by ketanserin. Furthermore, the role of serotonin in mediating CFVs was determined by establishing CFVs in another group of dogs, eliminating them with ketanserin, and subsequently infusing serotonin directly into the left atrium to determine whether CFVs could be restored by displacing ketanserin from its receptor site with excess of the agonist.

We tested the hypothesis that thromboxane A 2 and thromboxane AJ/PGH2 receptor occupation are important in mediating cyclical reductions in coronary blood flow (CFVs) in concentrically narrowed canine coronary arteries. Two potent and selective thromboxane A2/PGH 2 receptor antagonists, SQ29,548 and SQ28,668 eliminated CFVs and restored a normal pattern of blood flow through the severely narrowed vessels in 77 and 75% of the dogs, respectively. CFVs were eliminated within several minutes of an intravenous bolus injection of SQ29,548 or SQ28,688. A continuous infusion of SQ29,548 (0.2 mg/kgmin) prevented the recurrence of CFVs throughout the duration of its infusion. Left atrial infusion of the thromboxane A 2 mimetic, U46619, restored CFVs in 5 of 8 SQ29,548-treated and in 5 of 7 SQ28,668-treated dogs. Circulating concentrations of the stable metabolites of TxA 2 and PGIj, TxBj and 6-keto-PGF la , respectively, were unaffected by administration of SQ29,548. However, stenosed vascular segments of the left anterior descending coronary artery (LAD) of SQ29,548-treated dogs produced significantly less thromboxane A 2 than comparable segments from untreated dogs. Morphologic studies showed that stenosed coronary arteries in which CFVs had been abolished by either SQ29,548 or SQ28.668 had relatively few adherent platelets, whereas comparable coronary segments removed from untreated animals had relatively large, platelet-rich mural thrombi. SQ29,548 did not alter the synthesis of Txfi 2 by platelets. 6-keto-PGF la concentrations in the stenosed LAD and nonstenosed circumflex coronary arteries were not altered by SQ29,548 administration. These data suggest that the thromboxane Aj/PGI^ receptor antagonists, SQ29,548 and SQ28,688, inhibit cyclic reductions in coronary blood flow in this model by preventing the accumulation of platelets at the site of a critical coronary arterial stenosis. The data also suggest that TxA 2 is important in mediating the interaction between platelets and the constricted coronary artery that is responsible for the development and maintenance of CFVs in this experimental model. (Circulation Research 1986;59:568-578) E VIDENCE from recent studies suggests that an important relation exists between the release of platelet-derived vasoactive substances during platelet aggregation and the development of acute coronary heart disease syndromes, such as unstable angina pectoris. Thromboxane A 2 (TxA 2 ), synthesized and released from platelets during aggregation, is a potent vasoconstrictor and platelet aggregating substance. 12 The transcardiac concentrations of thromboxane B 2 (TxB 2 ), the inactive metabolite of TxA 2 , are elevated in patients with active unstable angina pectoris. 3 An in vivo canine model of transient coronary flow

THE BRITISH MEDICAL JOURNAL. 723 a specimen of the same kind, which is very interesting. The patient was in this hospital, and you will find all the particulars in the Museum Catalogue, Series xi, No. 4. This man had, it was evident, extensive laceration of the kidney, from which he quite recovered ; but two or three months afterwards he died of typhoid fever, and the healed laceration of the kidney was fogad. There can be no doubt about this case. I have given you already the plan of treatment which you should adopt when peritonitis ensues in these cases. But when the laceration is at the back of the kidney, and diffuse cellular inflammation occurs in the loin, you must make a free incision to prevent burrowing. The treatment of lacerated kidney is, for the most part, as I have told you, very simple; but much to my surprise, a new plan of treatment was given to me some years ago when I was examiner at the Army Board. It was to " to cut out the injured organ-an operation which has not unfrequently been performed with success"! This answer was given to me in writing by a gentleman who possessed two diplomas! I need not tell you that this treatment I would not advise you to follow. This patient, as I have said, is going out tomorrow ; but he has been warned to be very careful in everything, but especially as to walking and going about much, owing to the injury which I suspect he met with about the pelvis.

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