J H Ashton

Thrombin is an important mediator of platelet aggregation in stenosed canine coronary arteries with endothelial injury.

Cyclic variations in coronary blood flow (CFVs) in dogs with experimental coronary artery stenosis and endothelial injury appear to result primarily from the aggregation of platelets at the site of stenosis followed by dislodgement and distal embolization. Using this canine model, we tested the hypotheses: (a) that thrombin is an important mediator of CFVs in dogs with coronary stenoses and endothelial injury; (b) that inhibition of thrombin with heparin, or MCI-9038, a selective thrombin inhibitor, abolishes CFVs in this model; and (c) that abolition of CFVs by thrombin inhibition is time dependent. CFVs, produced in open-chest dogs by placing a flow-reducing plastic constrictor around the left anterior coronary artery, were monitored for either 30 min (group I) or 3 h (group II) before treatment with either heparin or 4-methyl-1-(N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl (MCI-9038). In group I, cyclic flow variations were abolished by heparin in 12 of 18 dogs and by MCI-9038 in 5 of 7 dogs. In group II, cyclic flow variations were not abolished by heparin in any of seven dogs and were abolished by MCI-9038 in only one of seven dogs. Thus, (a) thrombin appears to be an important mediator of cyclic flow variations in dogs with coronary artery stenosis and endothelial injury and (b) inhibition of thrombin abolishes CFVs after short but not prolonged periods of CFVs.

Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo. Thromboxane A2 and serotonin are possible mediators.

The goal of the present study was to demonstrate that intracoronary platelet deposition may trigger intense vasoconstriction of large epicardial coronary arteries in vivo and that this is largely mediated by thromboxane A2 and serotonin released by activated platelets. Cyclic flow variations (progressive declines in blood flow followed by sudden restorations of flow) due to recurrent intracoronary platelet activation and thrombus formation were induced by damaging the endothelium and placing a cylindrical constrictor on the left anterior descending coronary artery (LAD) in open-chest, anesthetized dogs. Coronary diameters were measured in vivo by means of ultrasonic crystals sutured on the LAD immediately distal to the constrictor (LAD1) and 1 cm below (LAD2) and on the circumflex coronary artery (Cx). Coronary artery diastolic diameters were measured continuously before and during cyclic flow variations and after they were abolished by administration of LY53857, a serotonin-receptor antagonist (group 1, n = 7), or SQ29548, a thromboxane-receptor antagonist (group 2, n = 7). During cyclic flow variations, at the nadir of coronary flow, LAD1 (a site of maximal platelet accumulation) cross-sectional area decreased by 52 +/- 10% and 38 +/- 6% in group 1 and 2 animals, respectively (p less than 0.001 compared with values recorded during a brief LAD occlusion obtained by a suture snare), whereas LAD2 (a site of minimal or no platelet accumulation) cross-sectional area did not differ from that recorded during the brief LAD occlusion. SQ29548 abolished cyclic flow variations in seven of seven dogs and LY53857 in six of seven, but they affected the increased coronary vasoconstriction differently: LAD1 cross-sectional area increased by 32 +/- 6% of the control value in SQ29548-treated animals, whereas it returned to baseline dimension values in the LY53857-treated group as these interventions also abolished the cyclic flow variations. We conclude that a marked coronary vasoconstriction may be triggered by local platelet deposition and that thromboxane A2 and serotonin are mediators of this vasoconstriction.

Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries.

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.

Conversion from chronic to acute coronary artery disease: Speculation regarding mechanisms

The factors that are primarily responsible for the conversion from chronic to acute coronary artery disease (CAD), including the development of unstable angina pectoris and acute myocardial infarction, remain uncertain. Some patients with angiographic evidence of extensive and severe coronary arterial stenoses anatomically do well with appropriate medical therapy, whereas others with similar or even anatomically less impressive coronary arterial stenoses have clinical manifestations of acute CAD. Improved insight into mechanisms responsible for the conversion of chronic CAD to acute CAD is essential for efforts directed at preventing acute myocardial infarction and sudden cardiac death. The purpose of this editorial is to emphasize recent developments in knowledge relating to alterations in prostaglandin production that may play a role in the development or perpetuation of acute CAD.

The effects of alpha 2-adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries.

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cyclic flow alterations importantly in this model.

Effect of thromboxane and serotonin receptor antagonists on intracoronary platelet deposition in dogs with experimentally stenosed coronary arteries.

We have reported previously that thromboxane A2 (TXA2) and serotonin (5-HT, 5-hydroxytryptamine) are important mediators of cyclic flow variations (CFVs) in a canine model of coronary artery stenosis and endothelial injury. The present study tested the hypothesis that a TXA2 receptor antagonist is more effective in reducing intracoronary platelet deposition at sites of endothelial injury and severe stenosis than a 5-HT2 receptor antagonist. CFVs developed after placing a plastic constrictor around the left anterior descending coronary artery (LAD) in 51 of 56 dogs. Autologous platelets labeled with 111In were injected in 48 animals. Ten control dogs (group 1A) were killed after CFVs were observed for 1 hour at the nadir of coronary blood flow. Five dogs (group 1B) did not develop CFVs after placement of the constrictor. CFVs were abolished with SQ 28668 (2.75 +/- 0.36 mg/kg, group 2) and SQ 29548 (0.45 +/- 0.1 mg/kg, group 3), two different TXA2 and PGH2 receptor antagonists, in eight of 10 and six of seven dogs, respectively. In eight of 10 dogs (group 4), CFVs were abolished with ketanserin (0.66 +/- 0.12 mg/kg), a 5-HT2 receptor antagonist. In group 2, 3, and 4 dogs, the respective drugs were given so that the minimal dose required to abolished CFVs was administered. In six of six dogs (group 5), a higher dose of ketanserin (i.e., 1.5 mg/kg) was used to abolish CFVs. At death, intracoronary platelet deposition was evaluated by calculating the LAD platelet accumulation ratio (111In activity in the LAD/111In activity in the circumflex coronary artery) in 43 dogs and, in 22 dogs, by microscopic examination of the LAD. A marked LAD platelet accumulation ratio was found in group 1A dogs at the stenotic site and in segments immediately distal to it. The LAD platelet accumulation ratio was significantly reduced by both the low and the high doses of ketanserin compared with group 1A dogs (p less than 0.001). However, the two TXA2 receptor antagonists further reduced the LAD platelet accumulation ratio compared with ketanserin-treated animals (p less than 0.01). Microscopic examination confirmed these findings. We conclude that SQ 28668 and SQ 29548, two different TXA2 receptor antagonists, reduce residual intracoronary platelet deposition associated with CFVs in this canine model more effectively than ketanserin, a 5-HT2 receptor antagonist.

Inhibition of cyclic flow variations in stenosed canine coronary arteries by thromboxane A2/prostaglandin H2 receptor antagonists.

We tested the hypothesis that thromboxane A2 and thromboxane A2/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/PGH2 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 A2 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 TxA2 and PGIj, TxB2 and 6-keto-PGF1α, 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 A2 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 Txfi2 by platelets. 6-keto-PGF1α concentrations in the stenosed LAD and nonstenosed circumflex coronary arteries were not altered by SQ29,548 administration. These data suggest that the thromboxane A2/PGH2 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 TxA2 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.

Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis.

Dynamic changes of the thrombus after its formation due to platelet activation may affect the speed of thrombolysis. In the present study, we wanted to evaluate the role played by thromboxane A2 (TXA2) and serotonin (5HT) in mediating platelet activation during lysis of intracoronary thrombi with human recombinant tissue-type plasminogen activator (t-PA). Coronary thrombi were induced in 26 anesthetized, open-chest dogs by inserting a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Presence of the thrombus was documented for 30 minutes. The dogs were then assigned to one of four groups as follows: group 1 dogs (n = 8), serving as controls, received a bolus of heparin (200 units/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg/min) for up to 90 minutes or until reperfusion was achieved; group 2 dogs (n = 10) received, immediately before heparin and t-PA, an intravenous bolus of SQ29548 (SQ) (0.4 mg/kg, a selective TXA2-receptor antagonist) and LY53857 (LY) (0.2 mg/kg, a selective serotonin S2-receptor antagonist); group 3 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of SQ alone (0.4 mg/kg); and group 4 dogs (n = 7) received, before heparin and t-PA, an intravenous bolus of LY alone (0.2 mg/kg). After thrombolysis, all dogs were monitored for 90 minutes or until a persistent reocclusion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular reflexes resulting from capsaicin-stimulated gastric receptors in anesthetized dogs.

To determine whether significant cardiovascular reflexes can be generated from gastric receptor stimulation, we developed an autoperfused canine stomach preparation from a dog anesthetized with a-chloralose so that capsaicin, a C fiber agonist, could be injected into the left gastroepiploic artery (ia) supplying the greater curvature of the stomach. Control injections were made into the inferior vena cava (IVC) to determine capsaicins effects on areas downstream from the stomach. Significant cardiovascular reflexes were obtained in 37 of 42 dogs after ia injection and in 26 of 26 dogs after IVC injection. Capsaicin (25-500 jig) caused significant increases in systolic blood pressure (SBP) (15%), heart rate (HR) (4%), contractility (maximal dP/dt) (19%), and systemic vascular resistance (SVR) (18%), whereas there were no changes in left ventricular end-diastolic pressure (LVEDP) or aortic flow (AF). On the other hand, downstream IVC capsaicin injections caused significant decreases in SBP (28%), HR (34%), dP/dt (33%), and AF (41%), but no change in SVR or LVEDP. The dP/dt response to ia injection continued to occur after overdrive right atrial pacing. However, the responses of pressure, rate, and dP/dt were diminished to a large extent by diaphragmatic celiac nerve section and to a smaller extent by diaphragmatic vagus nerve section. We conclude that these results demonstrate that capsaicin, a potent C-fiber agonist, can stimulate gastric or perigastric receptors to induce a significant activation of the cardiovascular system. Thus, the potential of the stomach to function as a reflexogenic organ which regulates the cardiovascular system has been demonstrated. Circ Res 46: 780-788, 1980

Serotonin S2and thromboxane A2-prostaglandin H2receptor blockade provide protection against epinephrine-induced cyclic flow variations in severely narrowed canine coronary arteries☆☆☆

The object of this study was to test the hypothesis that administration of both serotonin S2 and thromboxane A2-prostaglandin H2 (PGH2) receptor antagonists provides significant protection against epinephrine-induced cyclic coronary artery flow variations in open chest, anesthetized dogs with severe proximal coronary artery stenosis and endothelial injury. Three groups of dogs were studied. In Group 1 (n = 7) and Group 2 (n = 6), cyclic coronary flow variations were initiated after placement of a concentric constrictor around the left anterior descending coronary artery and were abolished by administration of either a thromboxane A2-prostaglandin H2 receptor antagonist, SQ29,548 (SQ) (Group 1), or a serotonin S2 receptor antagonist, LY53,857 (LY) (Group 2). Cyclic flow variations were restored with an epinephrine infusion and the second antagonist (LY for Group 1; SQ for Group 2) was administered to abolish epinephrine-induced cyclic flow variations. The rate of epinephrine infusion was increased until cyclic coronary flow variations returned (n = 8) or significant hemodynamic changes occurred. Plasma epinephrine concentrations were determined during a control period of cyclic coronary flow variations, after epinephrine restored cyclic flow variations in the presence of either SQ or LY, and again after epinephrine restored cyclic flow variations in the presence of both SQ and LY. A third group of dogs (Group 3, n = 9) required both SQ and LY to eliminate the initial cyclic coronary flow variations and infused epinephrine restored cyclic flow variations (n = 8). Plasma epinephrine concentrations were determined during a control period and after cyclic coronary flow variation restoration with epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)