Coronary Endothelial Injury Research Articles

Time course of coronary endothelial healing after injury due to ischemia and reperfusion.

Although it has been demonstrated in short-term preparations that ischemia with early reperfusion results in coronary vascular injury manifested by abnormal endothelium-dependent relaxation and increased permeability to plasma proteins, it has not been clear whether these abnormalities are permanent or reversible. In a canine model, regional coronary ischemia was accomplished by 1 hour of left anterior descending coronary artery ligation, and follow-up studies were performed after reperfusion for 1 hour, 48 hours, 2 weeks, or 9 weeks. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilator ADP and the endothelium-independent vasodilator nitroprusside. At 1 and 48 hours of reperfusion, relaxation of rings from the ischemic reperfused artery to ADP was blunted, but relaxation to nitroprusside was normal. At 2 weeks there was a nonsignificant trend toward a blunted response to ADP in the ischemic/reperfused rings, and at 9 weeks a completely normal response to ADP was observed. Coronary microvascular permeability was assessed by measurement of protein leak index (PLI), by using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. At 1 and 48 hours of reperfusion there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. There was a small increase in PLI at 2 weeks but a completely normal measurement at 9 weeks. Electron microscopy of ischemic/reperfused vessels demonstrated endothelial cell swelling and other abnormalities in epicardial arteries and the microcirculation at 48 hours of reperfusion but normal endothelium at 2 weeks of reperfusion. After 1 hour of regional coronary ischemia, coronary endothelial injury occurs early in reperfusion with abnormalities in epicardial coronary artery endothelium-dependent relaxation, coronary microvascular permeability, and both epicardial coronary artery and microvascular histology. This pattern of injury persists for at least 48 hours, but there is partial functional and complete histological recovery within 2 weeks and complete functional recovery within 9 weeks.

Mechanisms of coronary vasomotor dysfunction in the transplanted heart

The transplanted heart sustains both cold ischemic and reperfusion injuries. These can produce coronary vascular endothelial or smooth muscle injury or both, which, in turn, can produce coronary vasomotor dysfunction. Using a canine model of autologous heart transplantation, we examined the following coronary vasomotor control mechanisms in isolated coronary artery rings: (1) endothelial-dependent cyclic guanosine monophosphate (cGMP)-mediated vasorelaxation (response to acetylcholine); (2) endothelial-independent cGMP-mediated vasorelaxation (response to sodium nitroprusside); and (3) β-adrenergic cyclic adenosine monophosphate (cAMP)-mediated vasorelaxation (response to isoproterenol hydrochloride). Further, these mechanisms were related to 3 hours of cold ischemia alone and to 3 hours of cold ischemia plus 1 hour of reperfusion. Autologous heart transplantation was performed in dogs, and isolated distal left anterior descending coronary artery rings were studied in individual organ chambers. Cold ischemia alone produced significant dysfunction of β-adrenergic cAMP-mediated vasorelaxation, which was exacerbated after reperfusion. Neither endothelial-dependent nor endothelial-independent cGMP-mediated vasorelaxation was dysfunctional after cold ischemia alone, but both were significantly impaired after reperfusion. We conclude that cold ischemia and reperfusion each produce coronary vasomotor dysfunction in the transplanted heart. Cumulatively, such coronary vasomotor dysfunction can acutely impair coronary vasodilatation and potentially jeopardize myocardial blood flow in the transplanted heart.

Release of von willebrand factor by cardiopulmonary bypass, but not by cardioplegia in open heart surgery

von Willebrand Factor (vWF) is released from endothelial cells. Increased vWF in the coronary circulation during cardiac surgery could be a potential indicator of coronary endothelial injury or stimulation, and thus a possible tool to evaluate regimens of myocardial protection. Release of vWF was investigated in 12 patients undergoing coronary artery bypass surgery with cardiopulmonary bypass (CPB). Concomitant samples of arterial and coronary sinus blood for measurement of vWF (antigen method) were drawn before start of CPB and 1, 4, 10 and 30 min after release of the aortic cross clamp. Additional arterial samples were drawn pre-, per-, and postoperatively. Preoperative arterial vWF was 1.58±0.59 IU/ml (mean ± SD), and increased during CPB (highest level 2.37±0.76 IU/ml, p<0.0026). No difference between arterial and coronary sinus vWF levels was found. Arterial vWF increased further the first postoperative day (3.96±0.92 IU/ml, p<0.0026). In conclusion, systemic vWF is increased during CPB, and may be a possible marker of endothelial injury/activation to evaluate deleterious effects of different equipment for CPB. Reperfusion of the ischaemic, cardioplegic heart did not release vWF in the coronary circulation.

Ischemie preconditioning and long-chain acyl carnitine in the canine heart

This study investigated the effects of ischemic preconditioning on myocardial carnitine-linked metabolism and high-energy phosphates in the canine model of ischemia and reperfusion. Anesthetized dogs underwent 1 hour of coronary artery occlusion and 4.5 hours of reperfusion. The dogs were randomly assigned to a control group (no intervention for 30 minutes), a preconditioned group (four repeated episodes of 3 minutes of mechanical coronary occlusion, each followed by 5 minutes of reperfusion), and a coronary cyclic flow variation (CFV) group (coronary artery stenosis and endothelial injury, resulting in an average of four episodes of platelet thrombosis and dislodgment). After completion of the protocol, ATP, creatine phosphate, and long-chain acyl carnitine concentrations were studied in both nonischemic and previously ischemic myocardium. In Part I of this study (Ovize et al., Circulation 1992, 85:779-789), it was reported that both mechanical occlusion and CFV before sustained occlusion resulted in a decrease in infarct size. In the present paper, we report changes in high-energy phosphates and long-chain acyl carnitine in these groups. Control, preconditioned, and CFV groups showed similar depletion in ATP content and "overshoot" in creatine phosphate stores. Control dogs exhibited a significant accumulation of long-chain acyl carnitine in the previously ischemic tissue (219 +/- 61 vs 131 +/- 38 nmoles/g wet weight in the nonischemic tissue; P < 0.05). No significant increase in long-chain acyl carnitine occurred in the mechanically preconditioned and CFV groups. These results indicate that brief episodes of transient ischemia before sustained coronary occlusion prevent long-chain acyl carnitine accumulation in the ischemic and reperfused canine myocardium.

Cyclic flow variations in a conscious dog model of coronary artery stenoses and endothelial injury correlate with acute ischemic heart disease syndromes in humans

Objectives. The purpose of this study was to test the hypothesis that episodes of cyclic flow variations (CFVs) in conscious dogs with coronary stenoses and endothelial injury correlate with acute ischemic heart disease syndromes in humans.Background. Although the canine model with CFVs has proved to be a useful model of coronary thrombosis, whether CFVs progress to these syndromes has not been clearly described.Methods. Cyclic flow variations were produced by an external constrictor placed at the site of the left anterior descending coronary artery with injured endothelium. Blood flow in this artery and 24-h Holter electrocardiogram (ECG) were recorded during the 1st 5 postoperative days.Results. Of 41 dogs that underwent the initial operative procedure successfully, 29 developed an episode of CFVs. In five dogs in which CFVs persisted throughout the monitoring period, the left anterior descending coronary artery flow decreased until day 3 and thereafter increased through day 5. Transient coronary occlusion during CFVs induced ST segment changes that returned to baseline after reflow. In 12 dogs, CFVs progressed to persistent coronary occlusion, and histologic examination revealed thrombus formation at the stenotic site and evidence of myocardial infarction. Four of these 12 dogs died suddenly of ventricular arrhythmias during persistent coronary occlusion; another 5 dogs died of reperfusion arrhythmias during CFVs with no evidence of myocardial infarction.Conclusions. Conscious dogs with CFVs closely correlated with clinical acute ischemic heart disease syndromes, suggesting them to be a useful model for investigating the complex mechanisms of cellular interactions in the pathogenesis of these syndromes.

Extraordinary unremitting endurance exercise and permanent injury to normal heart

This hypothesis is that permanent cardiac injury could develop in some endurance athletes despite the absence of coronary atherosclerosis and ventricular hypertrophy. The proposed mechanism by which this injury could arise involves two physiological "vicious cycles". The first vicious cycle would occur between severe ischaemia and high catecholamines, the second would be between coronary vasospasm (induced by high catecholamines) and endothelial injury. The likelihood of the injury becoming permanent might increase if there is insufficient time between bouts of endurance exercise for regression of ischaemia and endothelial repair. Furthermore, magnesium ion deficiency, which can be induced by exercise, could exacerbate these vicious cycles and also contribute to catecholamine-induced thrombogenesis. In addition to ischaemia, there are several mechanisms, including the effect of free fatty acids liberated by the lipolytic effect of high catecholamines, that could cause direct myocardial injury.

The role of oxygen free radicals during cyclic flow variations in canine model with coronary stenosis and endothelial injury

The role of oxygen free radicals during cyclic flow variations in canine model with coronary stenosis and endothelial injury

Coronary cyclic flow variations "precondition" ischemic myocardium.

Repeated brief episodes of myocardial ischemia performed by mechanical clamping of a coronary artery "precondition" the heart and reduce infarct size after a subsequent sustained ischemia. It is not known, however, whether spontaneous episodes of transient ischemia caused by formation of platelet thrombi, which may occur in unstable angina, have a similar cardioprotective effect. Therefore, our objective was to determine whether brief spontaneous thrombotic episodes of ischemia/reperfusion could limit infarct size and preserve contractile function following 60 minutes (protocol 1) or 90 minutes (protocol 2) of sustained ischemia and 4-4.5 hours of reperfusion in the canine model. Before the sustained coronary occlusion, dogs underwent a 30-minute "treatment" period consisting of: no intervention (control group), four repeated episodes of 3-minute mechanical occlusion plus 5-minute reperfusion (preconditioned group), or coronary artery stenosis and endothelial injury, resulting in a mean of four spontaneous episodes of cyclic flow variations (CFV group) caused by formation and dislodgment of platelet thrombi. In protocol 1 (60-minute sustained ischemia plus 4.5-hour reperfusion), infarct size was significantly smaller in both the preconditioned and CFV groups compared with controls (3.5 +/- 1.4%,* 3.4 +/- 2.1%,* and 9.9 +/- 2.7% of the myocardium at risk, respectively; *p less than 0.05 versus control). In contrast, neither preconditioning nor CFV preserved contractile function: Segment shortening during sustained occlusion was equally depressed at -15% to -20% of baseline values among the three groups and equally stunned at +12% to +18% of baseline during the 4.5 hours of reflow. In protocol 2 (90-minute sustained ischemia plus 4-hour reperfusion), only CFV continued to exert a cardioprotective effect: Infarct size averaged 15.0 +/- 4.1%, 7.4 +/- 2.5%,* and 16.5 +/- 4.4% of the region at risk in the preconditioned, CFV, and control groups, respectively (*p less than 0.05 versus control). Contractile function, however, was similar among all three groups both during 90 minutes of sustained occlusion and throughout 4 hours of reperfusion. We therefore conclude that repeated coronary thrombus formation preconditions the ischemic myocardium: In fact, in contrast to mechanical preconditioning, cardioprotection provided by CFV persisted following 90 minutes of sustained coronary occlusion. However, preconditioning by thrombotic or mechanical occlusion neither preserved myocardial contractile function during sustained coronary occlusion nor prevented stunning after reperfusion. These data raise the possibility that clinical episodes of unstable angina prior to acute myocardial infarction may precondition the ischemic myocardium.

Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion.

A possible cause of the coronary endothelial injury that occurs with ischemia and reperfusion is the local accumulation of leukocytes during these events. To investigate the role of leukocytes in coronary endothelial injury, we tested the effect of leukocyte removal by filtering on coronary endothelial function in a canine model of regional myocardial ischemia and reperfusion. Blood was supplied to the left anterior descending and circumflex arteries of anesthetized dogs via an extracorporeal circulation. A 60-minute left anterior descending occlusion was followed by 120 minutes of reperfusion either with (n = 6) or without (n = 6) leukocyte filters in the extracorporeal circuit. Regional myocardial blood flow was measured with radiolabeled microspheres. Radiolabeled autologous transferrin (113mIn) and erythrocytes (99mTc) were given intravenously during reperfusion for assessment of microvascular permeability. Left anterior descending and circumflex coronary artery rings were assessed in vitro for endothelium-dependent dilation to acetylcholine, ADP, and thrombin. In unfiltered dogs, ischemia and reperfusion increased the protein leak index of ischemic myocardium 2.3-fold compared with that of nonischemic myocardium (2.3 +/- 0.5 to 5.2 +/- 1.6, p less than 0.05). In filtered dogs, there was no difference in the protein leak index of nonischemic versus ischemic myocardium (1.5 +/- 0.4 versus 1.9 +/- 0.5, p = NS). There was impaired left anterior descending coronary artery relaxation (versus circumflex) in response to endothelium-dependent vasodilators in vitro. However, relaxation was not consistently improved by leukocyte filtering. We conclude that leukocytes are responsible for the endothelial injury secondary to ischemia and reperfusion in the coronary microvasculature but have little or no effect on the endothelial injury in epicardial coronary arteries.

Circulating immunoreactive endothelin in patients undergoing percutaneous transluminal coronary angioplasty

Circulating immunoreactive endothelin (ir-ET) in the coronary sinus (CS) and the femoral artery (Ao) was measured in patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Plasma ir-ET level in the CS was significantly increased from 1.6 ± 0.8 pg/mL to 2.0 ± 1.0 pg/mL after PTCA ( P < .05). Plasma ir-ET level in the Ao tended to increase after PTCA, but it was not significant. Plasma ir-ET level in the CS was not related to the plasma thromboglobulin level, plasma thrombin-antithrombin complex level, mean blood pressure, or heart rate. These results suggest that the increase of plasma ir-ET level in the CS may be associated with the coronary endothelial injury by PTCA.

Frequency and severity of cyclic flow alternations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury.

The role of recurrent platelet aggregation in the development of neointimal proliferation of coronary arteries was explored in this study, and the hypothesis was evaluated that recurrent platelet aggregation and the consequent frequency and severity of cyclic coronary blood flow variations are important pathophysiologic factors in the subsequent development of neointimal proliferation. In 24 chronically instrumented dogs, variable degrees of coronary artery neointimal proliferation were observed 3 weeks after mechanical injury of the arterial endothelium and the placement of an external coronary artery constrictor. The severity of neointimal proliferation at 21 days was closely related to the frequency and severity of cyclic coronary blood flow variations during the initial 7 days after instrumentation of the animals, itself a manifestation of recurrent platelet aggregation and dislodgement. Pharmacological therapy with a dual thromboxane A2 synthetase inhibitor and receptor antagonist and with a serotonin S2 receptor antagonist frequently was successful in abolishing cyclic blood flow variations and in retarding neointimal proliferation.

Role of thromboxane and serotonin as mediators in the development of spontaneous alterations in coronary blood flow and neointimal proliferation in canine models with chronic coronary artery stenoses and endothelial injury

Platelet-mediated obstruction of stenotic and endothelium-injured coronary arteries may be important in the abrupt progression from chronic stable to unstable coronary heart disease syndromes in patients. Transcardiac accumulation of thromboxane A2and serotonin has been demonstrated in patients as chronic stable angina is converted to unstable angina. In this study in anesthetized open chest dogs with coronary artery stenosis and endothelial injury, thromboxane A2and serotonin were shown to be important mediators of intermittent coronary obstruction caused by platelet aggregation and dynamic vasoconstriction. Furthermore, thromboxane A2synthesis inhibitors and receptor antagonists and serotonin receptor antagonists, singly and together, provided substantial protection against repetitive platelet aggregation and dislodgment in canine models with coronary artery stenosis and endothelial injury even when systemic catecholamine concentrations were markedly elevated. These same observations apply in chronically instrumented, awake, unsedated dogs with coronary artery stenosis and endothelial injury in which recurrent platelet attachment and dislodgment cause cyclic flow alterations that may be prevented by thromboxane A2synthesis inhibitors and receptor antagonists and serotonin receptor antagonists. Chronically instrumented dogs with coronary stenosis and endothelial injury in which recurrent platelet attachment and dislodgment occurred also developed neointimal proliferation of varying severity within 19 days to 3 weeks; the morphologic appearance of the neointimal proliferation was identical to that found in patients who develop restenosis after coronary angioplasty.

Effect of aspirin on local prostaglandin production and serotonin accumulation in a canine model with coronary cyclic flow variations or thrombosis

We have reported that thromboxane A 2 and serotonin are two important mediators of coronary cyclic flow variations (CFVs) caused by recurrent platelet aggregation and dislodgement on a stenosed coronary arterial wall with endothelial injury. To test the hypothesis that blocking the synthesis of thromboxane A 2 would not prevent serotonin release, 1.1, 4.6, and 9.2 mg/kg of aspirin were administered through the left atrium to 27 dogs with CFVs. The CFV elimination rate was 70% in the aspirin-treated dogs. Thromboxane B 2 and serotonin concentrations were measured in different coronary arterial segments. There were significantly lower thromboxane B 2 and 6-keto-PFG 1a levels in the stenosed left arterior descending (LAD) segments with increasing dosage of aspirin-208 ± 36, 24 ± 31, 50 ± 6 ng/g ( P<0.0001) and 125 ± 27, 58 ± 38, 25 ± 5 ng/g ( P<0.0001), respectively. Serotonin levels were significantly higher in stenosd LAD (265.7 ± 131.2 ng/g) than in LAD segments proximal or distal to the stenosis and in corresponding circumflex coronary artery segments, 17.1 ± 3.7, 18.6 ± 3.7, and 19.2 ± 5.1 ng/g, respectively ( P<0.05) following the highest dose of aspirin. In 41 additional dogs, electrical injury was used to initiate thrombosis in the circumflex artery and in those receiving aspirin (15mg/kg) ( n=5), occlusive thrombus formation was inhibited. However, the local accumulation of serotonin was not significantly different between the control (194 ± 27 ng/g) ( n=36) and the aspirin-treated group (167 ± 19 ng/g) ( n=5). In vitro platelet aggregation induced by arachidonic acid was inhibited by the in vivo adminstration of 1.1 mg/kg of aspirin and abolished by 4.6 + 1.1 and 9.2 + 4.6 + 1.1 mg/kg of aspirin. However, serotonin-induced platelet aggregation was not affected following all doses of aspirin. Thus, aspirin eliminates CFVs in 70% of dogs, and markedly diminishes thromboxane A 2 and prostacyclin concentrations in stenosed canine coronary arteries, but it does not prevent local serotonin accumulation. Similarly, aspirin prevents occlusive coronary thrombosis in dogs with electrically-induced endothelial injury, but it did not prevent local assumulation of serotonin. These experimental findings suggest that cyclo-oxygenese inhibition does not prevent serotonin accumulation at sites of coronary artery endothelial injury, and they thereby help provide a potential explanation of the lack of complete protection provided by aspirin in eliminating CFVs in this experimental model.

Serotonin and Thrombotic Complications

We believe that the abrupt conversion from chronic stable to unstable angina and the continuum to acute myocardial infarction may result from myocardial ischemia caused by progressive platelet aggregation and dynamic vasoconstriction themselves caused by local increases in thromboxane and serotonin at sites of coronary artery stenosis and endothelial injury. Platelet aggregation and dynamic coronary artery vasoconstriction probably result from the local accumulation of thromboxane and serotonin and also relative decreases in the local concentrations of endothelially derived vasodilators and inhibitors of platelet aggregation, such as endothelium-derived relaxing factor (EDRF) and prostacyclin. With severe reductions in coronary blood flow caused by these mechanisms, platelet aggregates may increase, and an occlusive thrombus composed of platelets and white and red blood cells in a fibrin mesh may develop. When coronary arteries are occluded or narrowed for a sufficient period of time by these mechanisms, myocardial necrosis, electrical instability, or sudden death may occur. We believe that unstable angina and acute myocardial infarction are a continuum in relation to the process of coronary artery thrombosis and vasoconstriction. When the period of platelet aggregation or dynamic vasoconstriction at sites of endothelial injury and coronary artery stenosis is brief, unstable angina or non-Q-wave infarction may occur. However, when the coronary artery obstruction by these mechanisms is prolonged for several hours. Q-wave myocardial infarction results. Chronic endothelial injury and coronary artery stenosis are probably associated with the accumulation of platelets, white and red blood cells, and a fibrin mesh at the site of stenosis and endothelial injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential usefulness of combined thromboxane A 2 and serotonin receptor blockade for preventing the conversion from chronic to acute coronary artery disease syndromes

Evidence suggests that unstable angina, non-Q-wave myocardial infarction and Q-wave myocardial infarcts represent a continuum, such that transient reduction in coronary blood flow associated with platelet aggregation and dynamic vasoconstriction at sites of coronary artery stenosis and endothelial injury lead to abrupt development of unstable angina. Factors potentially responsible for the conversion from chronic to acute coronary artery disease include endothelial injury at sites of stenosis. The endothelial injury may be the result of plaque fissuring or ulceration, hemodynamic factors (including systemic arterial hypertension or flow shear stress), infection, smoking, coronary arteriography or balloon angioplasty. Clinical and experimental animal studies suggest that interference with thromboxane and serotonin contributions to platelet aggregation and dynamic coronary artery constriction may prevent chronic coronary artery disease syndromes from converting to acute disease. To protect against this process may require both thromboxane and serotonin receptor antagonists or a combination of thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist. Further studies are needed to test this hypothesis.

Treadmill exercise promotes cyclic alterations in coronary blood flow in dogs with coronary artery stenoses and endothelial injury : Eidt JF, Ashton J, Golino P, et al: J Clin Invest 84:517–527, 1989

Treadmill exercise promotes cyclic alterations in coronary blood flow in dogs with coronary artery stenoses and endothelial injury : Eidt JF, Ashton J, Golino P, et al: J Clin Invest 84:517–527, 1989

Failure of nitroglycerin and diltiazem to reduce platelet-mediated vasoconstriction in dogs with coronary artery stenosis and endothelial injury: Further evidence for thromboxane A2 and serotonin as mediators of coronary artery vasoconstriction in vivo

This study was designed to test the efficacy of nitroglycerin and diltiazem in inhibiting in vivo platelet aggregation and reducing platelet-mediated vasoconstriction in a canine model of coronary artery stenosis and endothelial injury. Coronary artery diameter was measured in vivo by means of ultrasonic crystals sutured on the left anterior descending coronary artery (LAD) immediately distal to an external constrictor (LADI), 1 cm below (LAD2), and on the left circumflex coronary artery. Coronary diameter was continuously measured before, during cyclic flow variations (progressive declines in blood flow followed by sudden restorations of flow due to recurrent intracoronary platelet aggregation), during cyclic flow variations and intravenous infusion of nitroglycerin (5 l.ig/kg per min) or diltiazem (15 μg/kg per min), and after cyclic flow variations were abolished by administration of LY53857, a serotonin receptor antagonist (n = 7), or SQ29548, a thromboxane A2 receptor antagonist (n = 7).During control cyclic flow variations, at the nadir of coronary flow (6% to 11% of the nonstenosed values), LAD1 cross-sectional area decreased by 43 ± 8% and 44 ±3% in the two groups of dogs subsequently treated with LY53857 and SQ29548, respectively. Neither nitroglycerin nor diltiazem caused changes in cyclic flow variation frequency or severity. Furthermore, neither drug significantly reduced the vasoconstriction associated with cyclic flow variations, whereas they significantly increased circumflex artery crosssectional area. In contrast, LY53857 and SQ29548 were very effective in abolishing cyclic flow variations and the coronary vasoconstriction related to them. Five additional dogs received an intracoronary infusion of nitroglycerin (21 ± 5 μkg per min) and later diltiazem (15 μg/kg per min). Again, neither drug decreased the coronary vasoconstriction associated with cyclic flow variations. A modest antiplatelet effect was observed during intracoronary infusion of nitroglycerin as cyclic flow variation frequency decreased from 7.7 ± 0.4 to 5.6 ± 0.5 cycles/30 min during control cyclic flow variations (p < 0.05).It is concluded that nitroglycerin and diltiazem are relatively ineffective in inhibiting marked in vivo platelet aggregation and platelet-mediated vasoconstriction in this experimental model. This study provides further evidence that thromboxane A2 and serotonin are mediators of platelet-mediated vasoconstriction in this experimental model.

Thromboxane A2 and serotonin mediate coronary blood flow reductions in unsedated dogs.

We have shown in anesthetized open-chest dogs that recurrent platelet aggregation at the site of coronary artery stenosis and endothelial injury results in a pattern of cyclical variations in coronary blood flow (CFVs) and that serotonin and thromboxane A2 are important mediators of CFVs. In the present study, we tested the following hypotheses: 1) severe spontaneous reductions in coronary blood flow occur in awake closed-chest dogs with coronary artery stenoses and endothelial injury; 2) there is a progression from CFVs to persistent low coronary blood flow; and 3) serotonin and thromboxane A2 are important mediators of coronary blood flow reductions in this model. In 17 of 20 awake closed-chest unsedated dogs with experimental coronary artery stenoses and endothelial injury, either intermittent CFVs (n = 3), persistent low flow (n = 4), or progression from CFVs to low flow (n = 10) occurred during the first postoperative week. A serotonin receptor antagonist (ketanserin or LY 53857) or a thromboxane synthesis inhibitor (dazoxiben) or receptor antagonist (SQ 29548) abolished platelet-dependent CFVs in 80% of dogs. Thus 1) severe spontaneous reductions in coronary blood flow occur in awake closed-chest unsedated dogs with coronary artery stenoses and endothelial injury; 2) there is a progression from CFVs to persistent low coronary blood flow and final coronary artery occlusion; and 3) serotonin and thromboxane A2 are important mediators of coronary blood flow reductions in this experimental model.

Treadmill exercise promotes cyclic alterations in coronary blood flow in dogs with coronary artery stenoses and endothelial injury.

We have previously shown in anesthetized, open-chest dogs with coronary stenosis and endothelial injury that serotonin and/or thromboxane A2 (TXA2) receptor activation play a major role in the mediation of platelet-dependent, intermittent coronary occlusion. Using a similar model in awake, closed-chest dogs, we tested the following hypotheses: (a) treadmill exercise promotes the development of cyclic flow variations in dogs with coronary stenoses and endothelial injury; (b) ventricular pacing does not induce cyclic flow variations in the same dogs; and (c) TXA2 and/or serotonin are important mediators of exercise-induced cyclic flow variations in this model. The surgical preparation consisted of the application of a hard, flow-limiting constrictor and a Doppler ultrasonic flow probe around the left coronary artery of 11 dogs. Treadmill exercise resulted in the prompt development of cyclic flow variations in all 11 dogs. Ventricular pacing at rates as high as 170 beats/min induced cyclic flow variations in only one of five dogs. Exercise-induced cyclic flow variations were abolished by TXA2 and/or serotonin receptor antagonists in all but one dog. Thus, (a) treadmill exercise promotes the development of cyclic flow variations in dogs with coronary stenoses and endothelial injury; (b) ventricular pacing does not induce cyclic flow variations in most dogs in the same model; and (c) TXA2 and/or serotonin are important mediators of cyclic flow variations in this model.

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.