LAD Blood Flow Research Articles

Sevoflurane selectively increases coronary collateral blood flow independent of KATP channels in vivo.

Volatile anesthetic agents produce coronary vasodilation via activation of adenosine triphosphate-sensitive potassium (KATP) channels. The authors tested the hypothesis that sevoflurane selectively increases coronary collateral blood flow and assessed the role of KATP channel activation in this process. Experiments were conducted in dogs 8 weeks after long-term implantation of a left anterior descending coronary artery (LAD) ameroid constrictor to stimulate coronary collateral growth. Dogs were instrumented for measurement of retrograde LAD blood flow (an index of large coronary collateral blood flow) and LAD tissue flow (via radioactive microspheres; an index of small collateral blood flow). Coronary collateral perfusion and normal (left circumflex coronary artery [LCCA]) zone tissue blood flow were determined in four groups of dogs pretreated with intracoronary glyburide (50 microg/kg) or vehicle in the presence or absence of sevoflurane (1 minimum alveolar concentration). Dose-response relationships to the KATP channel agonist nicorandil were established in each dog using doses (25, 50, and 100 microg/min) previously shown to increase coronary collateral blood flow. Sevoflurane increased blood flow through large and small collaterals and increased collateral vascular conductance in the presence of glyburide but did not affect LCCA blood flow or conductance. In contrast, nicorandil increased blood flow through small but not large collaterals. Nicorandil also increased LCCA blood flow and conductance, actions that were attenuated by glyburide. The results demonstrate that sevoflurane selectively increases large and small coronary collateral blood flow via mechanism(s) independent of KATP channel activation.

The effects of mechanical cardiac stabilization on left ventricular performance.

Mechanical cardiac stabilization is beneficial for precise coronary anastomoses on the beating heart. However, the effect of mechanical cardiac stabilization on hemodynamics, left ventricular performance, and the degree of injury to underlying tissue are uncertain. Twelve swine (20-30 kg) underwent median sternotomy and a mechanical stabilizing device (United States Surgical, Norwalk, CT) was positioned astride a segment of left anterior descending coronary artery (LAD). Coronary blood flow was measured by Doppler. Sonomicrometry crystals were placed distal to the stabilizer in a region of myocardium subtended by the LAD, and a left ventricular micromanometer was inserted. Regional myocardial function was determined using the preload recruitable stroke work (PRSW) relationship. Data were acquired at three time points: 20 min before (PRE) and after placing the stabilizer (EXPT); and 20 min after removing the stabilizer (POST). Tissue subjacent to the stabilizer was then biopsied. Means +/- standard deviation are reported. The mechanical stabilizer caused a decrease in cardiac output from 4.2+/-1.5 to 3.6+/-1.3 l/min (P < 0.05), which returned to baseline values after its removal. Regional myocardial function (percent systolic shortening and MW and x-intercept of the PRSW relationship) was unchanged. Blood pressure, heart rate, and LAD blood flow remained constant. Histologic findings included a layer of myocyte necrosis less than 1 mm in depth immediately beneath the stabilizer. These data demonstrate that mechanical stabilization of the LAD may temporarily decrease cardiac output. This is not attributed to impaired contractility or ischemia, but is secondary to direct ventricular compression with reduced stroke volume. Injury to underlying tissue is negligible.

Effect of dopamine and atrial pacing on stunned myocardium1

Post-ischaemic stunned myocardium shows an impaired function at restored coronary blood flow, but performance can be normalized by positive inotropic stimulation. The power of stunned myocardium, however, is not augmented with increasing heart rate by atrial pacing, which is in contrast to intact areas. This pathological response is mitigated by inhibiting the degradation of cyclic AMP. The present experiments studied the effect of stimulating cyclic AMP formation by dopamine on the response of stunned myocardium to atrial pacing. In anaesthetized (piritramide) open chest pigs, heart rate, left ventricular and aortic pressure, left descending (LAD) and circumflex (LCX) coronary artery and aortic blood flow, myocardial systolic shortening in the LAD and LCX area were monitored, and myocardial power was calculated. The LAD region was subjected to ischaemia and reperfused for 2 h. Subsequently, heart rate was raised by right atrial pacing before and during intravenous infusion of dopamine (10 microg/kg per min). The ischaemic/reperfused area was sliced post mortem and stained by triphenyl tetrazolium chloride to exclude myocardial infarction. Data from 11 experiments are presented. After 2 h LAD reperfusion, LAD blood flow and power were 100% and 36% of pre-ischaemic control, respectively, indicating myocardial stunning. The power of the intact area was not changed significantly (111% of control). Increasing heart rate by +36 and +70 from 94 beats/min increased the power of the intact area to 161% and 183% of control; the power of the stunned myocardium decreased to 34% and 19% of pre-stunning control. Dopamine increased the power of the stunned region to 143% of the pre-stunning level and the power of the intact area to 206% of control. Increasing heart rate by +34 and +70 from 113 beats/min during dopamine, increased the power of the intact myocardium to 288% and 344% of control and the power of the stunned region to 177% and 174% of the pre-stunning level. The data confirm the pathological response of stunned myocardium to atrial pacing and the recruitment of a functional reserve by catecholamines. The adverse effect of pacing on the function of stunned myocardium is abolished by positive inotropic stimulation. Possibly, the cyclic AMP system is involved in the normal response to pacing and this pathway is disturbed in stunned myocardium; other defects are not excluded or supported, however. Physiologically increased heart rate by an increased activity of the sympathetic nervous system, is probably not accompanied by a reduced power of stunned myocardium, due to the associated positive inotropic stimulation.

Doppler tissue imaging quantitates regional wall motion during myocardial ischemia and reperfusion.

Quantification of regional myocardial function is a major unresolved issue in cardiology. We evaluated the accuracy of pulsed Doppler tissue imaging (DTI), a new echocardiographic technique, to quantify regional myocardial dysfunction induced by acute ischemia and reperfusion. In nine open-chest anesthetized pigs, various degrees of regional wall motion abnormalities were induced by graded reduction of left anterior descending coronary artery (LAD) blood flow. Pulsed Doppler tissue imaging was performed from an epicardial apical four-chamber view with the sample placed within the middle part of the septal wall. Peak septal velocities were calculated during systole, isovolumic relaxation, and early and late diastole. Regional myocardial blood flow and systolic and diastolic dysfunctions were assessed by radioactive microspheres and ultrasonic crystals, respectively. Ischemia resulted in a significant rapid reduction of systolic velocities and an early decrease in the ratio of early to late diastolic velocities. Both changes were detected by pulsed DTI within 5 seconds of coronary artery occlusion. The decrease in systolic velocity significantly correlated with both systolic shortening (r=.90, P<.0001) and regional myocardial blood flow (r=.96, P<.0001) during reduction of LAD blood flow. These results suggest that DTI may be a promising new tool for the quantification of ischemia-induced regional myocardial dysfunction.

Effect of milrinone and atrial pacing on stunned myocardium.

Most mammalian cardiac muscles show a positive force-frequency relation, which is turned into a negative relation in failing hearts. Stunned myocardium shows similar defects as failing myocardium, it has a functional reserve recruitable by positive inotropic interventions, and possibly shows a disturbed response to increased heart rate. The present experiments compare in vivo the response of stunned and intact myocardium to atrial pacing before and during inotropic stimulation by milrinone. In anaesthetised (piritramide) open chest pigs, heart rate, left ventricular and aortic pressure, left descending (LAD) and circumflex (LCX) coronary artery and aortic blood flow, myocardial systolic shortening in the LAD and LCX area were monitored, and myocardial power was calculated. The LAD region was subjected to ischaemia and reperfused. Heart rate was raised by right atrial pacing after 90 min reperfusion before and during i.v. milrinone (105 microg/kg bolus + 8 microg/kg per min infusion). The ischaemic/reperfused area was sliced post mortem and stained by triphenyl tetrazolium chloride to exclude myocardial infarction. Data from ten experiments are presented. After 90 min LAD reperfusion, LAD blood flow and power were 110 and 36% of preischaemic control, respectively, indicating myocardial stunning. The power of the intact area was not changed (102% of control). Pacing from 87 to 164 per min increased the power of the intact area (+96%), the power of the stunned myocardium decreased (-64%). Milrinone increased the power of the stunned region to 72% of the pre-stunning level and the power of the intact area by +51%. Pacing from 111 to 164 per min during milrinone increased the power of the intact myocardium to the same level as before milrinone, the power of the stunned region did not change. Stunned myocardium responds pathologically to atrial pacing with a negative staircase in contrast to the positive staircase of intact myocardium. Inotropic stimulation by the phosphodiesterase inhibitor milrinone recruited the functional reserve of stunned myocardium. Milrinone did not restore a positive staircase in stunned myocardium, but power was maintained during atrial pacing. The pathological staircase of stunned myocardium may arise from an impaired availability of cyclic AMP, but the data do not exclude defects in calcium handling, a dysfunction of the sarcoplasmic reticulum, or an impaired Ca-sensitivity of the myofilaments.

Intraoperative monitoring of IMA flow: What does it mean?

This study examines whether the measurement of internal thoracic artery (ITA) graft flow can determine the adequacy of the ITA-left anterior descending coronary artery (LAD) anastomosis. To study a wide range of clinical problems, we used a computer simulation of the cardiovascular system. The model included a time-varying elastance model of the heart, a systemic circulation represented by a multielement nonlinear model of the aorta and its major branches, a nonlinear model of the LAD circulation, and a model of the ITA bypass graft. With a mild LAD stenosis, ITA graft flow was low and flow reversal occurred. As the percent stenosis increased, ITA flow and the percentage of ITA-to-total LAD flow increased. The ITA graft helped to maintain resting LAD blood flow. A partial obstruction (40%) at the ITA-LAD anastomosis reduced ITA graft flow at similar levels of LAD stenosis. However, overlap in flow values comparing a normal with a partially obstructed anastomosis occurred. Flow patterns in the ITA are highly dependent on the degree of stenosis of the LAD as well as the integrity of the anastomosis. The predictive power of ITA flow measurement increases with severe stenosis or total occlusion of the proximal LAD and with high coronary blood flow demands.

907-101 Reduced Infarct Size and Improved Myocardial Blood Flow Following Ischemia and Reperfusion by a Non-peptide Endothelin Receptor Antagonist

The aim of the present study was to investigate the effect of the non-peptide endothelin receptor antagonist Ro 47-0203 (Bosentan) on hemodynamic responses and infarct size following myocardial ischemia and reperfusion (MlR) in anesthetized open chest pigs. Ischemia was induced by ligation of the left anterior descending coronary artery (LAD) for 45 min followed by 4 h of reperfusion. Ro 47-0203 was administered as a systemic iv bolus injection(5 mg/kg) 15 min before induction of ischemia (n = 6) or by coronary venous retroinfusion (4 μg/kg/min) for 25 min starting at 30 min of ischemia (n = 4). Control groups received saline iv (n = 6) or by coronary venous retroinfusion (n = 5). Systemic iv administration of Ro 47-0203 reduced mean arterial blood pressure from 96 ± 5 to 88 ± 5 mmHg (P &lt; 0.05) but did not affect heart rate or coronary vascular resistance. During Ml-R arterial blood pressure, heart rate and the rate pressure product were not significantly different between the Ro 47-0203 iv group and controls. In the control group, LAD blood flow was reduced from 11.2 ± 2.3 ml/min before ischemia to 5.4 ± 1.1 ml/min (P &lt; 005) at the end of reperfusion. Blood flow at the end of reperfusion in the group given Ro 47-0203 iv (1 0.8 ± 1.6 ml/min) was higher than in the control group (P &lt; 0.05) and similar to the pre-ischemic value (11.4 ± 1.3 ml/min). The infarct size was significantly smaller in the Ro 47-0203 iv group than in the control group (32 ± 5 vs 77 ± 3% of the myocardial area at risk; P &lt; 0.01). Local administration of Ro 47-0203 by coronary venous retroinfusion reduced the infarct size to the same extent as systemic iv administration without affecting systemic blood pressure. The study shows that the nonpeptide endothelin receptor antagonist Ro 47-0203 reduces the infarct size and improves blood flow in the reperfused myocardium. The effect seems to be mediated via a local action. These results indicate that endogenous endothelin is of pathophysiological significance for the development of MI-Rinjury.

Effects of R56865, an Na(+)- and Ca(2+)-overload inhibitor, on myocardial injury in ischemic, reperfused porcine hearts.

The cardioprotective effect of R56865, an Na(+)- and Ca(2+)-overload inhibitor, was studied in 20 regionally ischemic reperfused (I/R) porcine hearts. Ten pigs were treated with a single intravenous (i.v.) injection of 0.4 mg/kg 15 min before occlusion of the distal left anterior descending coronary artery (LAD) for 45 min. Ten other animals served as controls. Infarct size (IS) was determined as percentage of infarcted (tetrazolium method) to ischemic (dye technique) myocardium after 24-h reperfusion. Regional systolic shortening (SS) was determined by sonomicrometry. Fifteen minutes after i.v. administration of R56865, a significant decrease in heart rate (HR) (from 83 +/- 15 to 74 +/- 16 beats/min), dP/dtmax (from 2,033 +/- 604 to 1,822 +/- 524 mm Hg/s), LAD blood flow (BF, from 17 +/- 7 to 14 +/- 7 ml/min), and calculated global myocardial O2 consumption (MVO2) (from 5.9 +/- 0.9 to 5.4 +/- 0.9 ml O2/min x 100 g) was observed. Although this investigational drug attenuated the increase in HR during early reperfusion, the incidence of ventricular fibrillation (VF) was not affected during either ischemia or reperfusion. R56865 reduced IS by 24% from 67.1 +/- 16% (control group) to 50.8 +/- 13%. In addition, this treatment improved systolic shortening after 24-h reperfusion from 6 +/- 8% (control group) to 15 +/- 9%. Our results support the concept that inhibition of intracellular Na(+)- and Ca(2+)-overload is a promising new principle in treatment of myocardial I/R.

Regional and Systemic Platelet Function Is Altered by Myocardial Ischemia-Reperfusion.

Background: Myocardial reperfusion after short durations of ischemia causes prolonged contractile dysfunction (myocardial stunning). Recently it has also been suggested that ischemia-reperfusion results in impaired coronary endothelial function. Since platelet function is, in part, regulated by an intact functioning endothelium, platelet function could be expected to change during ischemia-reperfusion. However, the effect of ischemia and reperfusion on regional and systemic platelet function is unknown. The purpose of this study was to determine the effect of a brief period of myocardial ischemia followed by reperfusion on regional and systemic platelet function. Methods: Fourteen swine in an open-chest model underwent left anterior descending coronary artery (LAD) occlusion for 15 minutes followed by 120 minutes of reperfusion. Platelet aggregability in response to 5 µM ADP was determined simultaneously in the femoral (systemic; N = 14) and great cardiac (regional; N = 9) venous blood at baseline, during occlusion, and at 40 and 90 minutes after reperfusion. LAD blood flow and regional myocardial function were determined by standard methods. Results: Hemodynamics remained stable in all animals. During LAD occlusion platelet aggregability, increased only in the regional coronary circulation (126% of baseline, p =.0001). At 40 minutes of reperfusion systemic platelet aggregahility decreased (86% of baseline, p =.0001) and subsequently increased at 90 minutes at reperfusion in both the systemic (127% of baseline, p =.0001) and regional circula. tions (156% of baseline, p =.0001). Ischemia was evident by the absence ofdistal LAD flow during occlusion that returned during reperfusion and a typical response ofmyocardial stunning in each animal (stunning time = 47.7 +/- 5.2 minutes). Conclusions: This study demonstrates that platelet function is not static during ischemia-reperfusion. Instead, during ischemia regional platelet aggregability is increased. Systemic and regional platelet aggregability also increase during myocardial reperfusion. The mechanism of these responses is unknown but may be related to regional endathelial dysfunction created by ischernia. The response observed could also be explained by the release of proaggregatory mediators in the connary and/or systemic circulation during ischemia-reperfusion. The relative hyeraggregability observed following reperfusion may be relevant for further investigations of coronary artery reocclusion occurring after the relief of myocardial ischemia.

Intracoronary propofol does not decrease myocardial contractile function in the dog

The intravenous administration of propofol is associated with a considerable decrease in arterial blood pressure. The present study was undertaken to test the hypothesis that myocardial function is not affected by propofol and therefore does not contribute to the hypotensive effect of this anaesthetic agent. Propofol was administered in anaesthetized, open-chest dogs by direct arterial infusion into the left anterior descending coronary artery (LAD). Mean arterial blood pressure, heart rate, left ventricular pressure, dP/dt, regional lactate and oxygen extraction, as well as coronary blood flow were measured. Diastolic function was determined by calculation of the time constant of isovolumetric relaxation from the left ventricular pressure measurement and dP/dt. Contractility was evaluated by measuring regional systolic shortening in an area of the myocardium supplied by the LAD. This was compared with systolic shortening in the distribution of the circumflex (CIRC) artery and with the effects obtained with the intracoronary administration of thiopentone. Intracoronary infusions of propofol and thiopentone did not produce any change in systemic arterial blood pressure, heart rate, or left ventricular end diastolic pressure. Propofol, at a concentration of 5 or 10 micrograms.ml-1 did not decrease systolic shortening in the area perfused by the LAD while thiopentone (40 micrograms.ml-1) reduced systolic shortening by 33% (P < or = 0.05). Neither drug had an effect on systolic shortening in the CIRC area, LAD blood flow or diastolic function. The results of this study suggest that propofol does not have an effect on myocardial contractility. The hypotension associated with the intravascular administration of propofol is more likely due to either a direct vascular or a central effect.

Myocardial oxygenation in dogs during partial and complete coronary artery occlusion.

Regional myocardial oxygenation was assessed during partial and complete coronary artery occlusion using near infrared spectroscopy. In eight open-chest dogs, partial occlusions resulting in an approximately 42% decrease in left anterior descending coronary artery (LAD) blood flow produced an approximately 21% decrease in tissue O2 stores (tissue oxyhemoglobin plus oxymyoglobin) and no change in the oxidation level of mitochondrial cytochrome aa3. An approximately 81% reduction in LAD blood flow produced nadir levels of tissue oxyhemoglobin plus oxymyoglobin, maximal levels of deoxyhemoglobin plus deoxymyoglobin, a decline in tissue blood volume, and an approximately 39% decrease in cytochrome aa3 oxidation level. These changes were associated with an approximately 52% decrease from the preischemic baseline in mean transmural myocardial blood flow, measured by radiolabeled microspheres, and an approximately 41% decrease in myocardial O2 consumption. Complete occlusion resulted in further decreases in myocardial blood flow, O2 consumption, tissue blood volume, and cytochrome aa3 oxidation state but also produced increases in tissue O2 stores to above the nadir levels noted during partial occlusion. These results indicate that decreases in O2 delivery during partial coronary occlusion increase O2 extraction to sustain mitochondrial O2 availability, but as little as a 52% reduction in myocardial blood flow produces maximal O2 extraction and depletion of tissue O2 stores. Mitochondrial O2 availability is restricted further during complete occlusion because of limited O2 delivery and, possibly, decreases in tissue blood volume and O2 extraction.

Transthoracic high-frequency two-dimensional echocardiography, Doppler and color flow mapping to determine anatomy and blood flow patterns in the distal left anterior descending coronary artery

Combined high-frequency transthoracic ultrasound, pulsed Doppler and color flow mapping were used to image and assess blood flow velocity in the distal left anterior descending artery (LAD) in 56 consecutive patients. All patients subsequently underwent coronary angiography. The LAD was imaged in 19 patients (34%), and the diameter was measured in 12 with high-quality images (mean diameter 1.8 mm ± 0.08). In 1 patient, the penetrating branches of the LAD were imaged. The distal LAD appeared normal by ultrasound in 18 patients, and a significant stenosis was detected in 1; angiography confirmed the ultrasound findings. There were no false negative results. Characteristic biphasic flow with higher velocities in diastole were noted in all 19 patients. Color flow mapping demonstrated normal laminar flow, except in the patient with a distal stenosis. Pulsed Doppler confirmed an increased velocity distal to the stenosis in this patient. This study is the first transthoracic evaluation of the hemodynamic effects of a coronary artery stenosis, and the first in vivo description of blood flow disturbance at a distal coronary stenosis in humans. The clinical use of this technique is limited, because only the distal portion of the LAD is visualized. However, it may provide a noninvasive means of assessing distal LAD diameter and blood flow, and changes in these parameters under a variety of physiologic, pharmacologic and interventional stimuli.

A new model of myocardial infarction in yucatan minipigs

Myocardial infarction studies in pigs have been complicated by the use of antiarrhythmic drugs or the high incidence of ventricular fibrillation. We report on a new model of experimental myocardial infarction in thiamylal-anesthetized Yucatan minipigs. These studies were performed in the absence of intravenous antiarrhythmic drugs. No animals required resuscitation during either surgery or reperfusion and only 19% were resuscitated during occlusion. Extensive systemic hemodynamic, regional contractility and coronary blood flow measurements were continuously obtained during left anterior descending coronary artery (LAD) occlusion (45 min) and reperfusion (240 min). Mean arterial blood pressure and left ventricular + dP/dt decreased during occlusion, and both declined further upon reperfusion. Persistent dysfunction (segmental shortening from 24.8 ± 1.3 to 3.9 ± 0.9% ( p < 0.001); pre-occlusion and 5 min post-occlusion, respectively) occurred immediately after occlusion in the myocardium perfused by the LAD, while late declines in segmental shortening (19.6 ± 0.9 to 17.2 ± 1.2%; pre-occlusion and 240 min post-reperfusion, respectively) were observed in myocardium perfused by the left circumflex coronary artery. While heart rate did not change during occlusion, tachycardia occurred at the onset of reperfusion. Although initial reactive hyperemia following reperfusion was manually inhibited, high LAD blood flow following reperfusion occured early (0 to 60 min) but returned below pre-occlusion values late (180 to 240 min). The area at risk represented23.1 ± 0.9% ( n = 34) of the left ventricle and 39.0 ± 3.2% of this area was infarcted. Therefore, 9.2 ± 0.9% of the left ventricle was infarcted. These data suggest that myocardical infarction in anesthetized minipigs can be achieved without the aid of intravenous antiarrhythmic drugs and reduced cardioversion. Therefore, this new model can be utilized in the evaluation of therapeutic compounds focused on altering the detrimental consequences of myocardical infarction.

Determination of effective and safe dose for intracoronary administration of nicorandil in dogs

The aim was to evaluate the effective and safe dosage for intracoronary administration of nicorandil (2-nicotinamidoethyl nitrate) in dogs. Five ml of saline with or without nicorandil (0.025, 0.25, 1.0 or 2.5 mg) was constantly infused into the left anterior descending coronary artery (LAD) in 1 min without blood flow reduction in group A (normoxic group, n = 5) and with 50% blood flow reduction of the control value in group B (ischaemic group, n = 5). 10 mongrel dogs of either sex were used, weight 14.6-20.5 kg. The myocardial weight of the perfused area was 33.2(SD 7.9) g. In group A, LAD blood flow increased from 28.4(8.6) to 86.3(25.0) ml.min-1, p less than 0.05, following intracoronary infusion of 0.25 mg nicorandil. Higher doses caused no further increase. In both groups, high doses (1.0 mg or more) suppressed regional myocardial contraction, expressed as % segment shortening, from 20.0(4.7) to 10.0(9.0)%, p less than 0.05, in group A, and from 12.7(8.5) to 6.5(5.6)%, p less than 0.05, in group B. Multiple ventricular premature beats developed in both groups only at the dose of 2.5 mg: 6.8(5.5) beats.min-1 in group A and 4.5(4.2) beats.min-1 in group B. Ventricular fibrillation developed in two dogs in group B. Nicorandil did not affect the local bipolar electrocardiogram of the subendo- and subepicardium in the perfused area in either group. Intracoronary administration of 0.25 mg of nicorandil was effective for coronary vasodilatation without deleterious mechanical or electrical effects. Larger doses of the agent showed adverse effects depending on the dosages.

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)

Effect of Nifedipine on Regional O2 Consumption in Ischemic Myocardial Tissue

The effect of intravenous (i.v.) nifedipine (5 micrograms/kg/min) on regional O2 supply/consumption variables was determined in 14 anesthetized open-chest dogs subjected to left anterior descending coronary artery (LAD) stenosis sufficient to reduce blood flow 50%. Myocardial blood flow was measured using radioactive microspheres, and regional arterial and venous O2 saturations were determined using microspectrophotometry. During LAD occlusion, blood flow and O2 consumption were decreased in the ischemic region while O2 extraction was increased. With nifedipine treatment, LAD flow (flow probe) was increased 44% as compared with the initial occluded value, with most of this increase going to the subepicardium (microspheres). Flow to the ischemic subendocardium was not changed with nifedipine treatment. Ischemic subepicardial O2 consumption increased slightly in nifedipine-treated animals as compared with saline values, whereas O2 extraction decreased slightly. In the subendocardial region, nifedipine resulted in a significant decrease in O2 extraction, with a slight decrease in O2 consumption as compared with saline controls. The O2 supply/demand ratio was significantly improved with nifedipine only in the subendocardium of the ischemic region. This suggested that nifedipine could increase O2 consumption in the ischemic subepicardium through proportional increase in O2 supply while it decreased O2 consumption in the subendocardium relative to O2 supply.

Coronary hemodynamic responses during local hemodilution in canine hearts.

To evaluate the effect of hemodilution per se on coronary hemodynamics, experiments were performed in 36 anesthetized, open-chest dogs whose left anterior descending coronary artery (LAD) was perfused selectively with either normal arterial blood or arterial blood diluted with lactated Ringer solution. LAD blood flow (CBF) was measured with an electromagnetic flowmeter and its transmural distribution assessed with 15-microns radioactive microspheres. LAD perfusion pressure was set at the normal level (approximately 100 mmHg) or at 50% of that level to simulate coronary insufficiency. Dilator reserve capacity was calculated from ratio of reactive hyperemic peak flow following release of 90-s occlusion to control (preocclusion) flow. Systemic hemodynamic parameters were maintained near control values during coronary hemodilution. With perfusion pressure normal, graded hemodilution caused progressive, transmurally uniform increases in CBF that showed a nonlinear relationship to inflow hematocrit. Increased peak reactive hyperemic flow and decreased dilator reserve ratio indicated that both reduced viscosity and vasodilation contributed to increased CBF during hemodilution. Hypotension alone reduced CBF, with greater effect in the subendocardium. Additional hemodilution returned CBF to normotensive value, but relative subendocardial hypoperfusion persisted. The present study provides fundamental information on effects of hemodilution on coronary hemodynamics without the systemic responses that complicated previous studies utilizing whole body exchange transfusions.

Mediation of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissue-type plasminogen activator in a canine preparation of coronary thrombosis.

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) and serotonin (5HT) in mediating this phenomenon. Accordingly, coronary thrombosis was induced in anesthetized, open-chest dogs by insertion of 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. Thrombolysis was achieved with rt-PA (0.05 mg/kg bolus + micrograms/kg/min infusion) in 23 +/- 3 min. rt-PA was then discontinued and each animal received a bolus of heparin (150 U/kg) every hour. Reperfusion was followed by repeated cycles of gradual occlusions followed by spontaneous restorations of blood flow (cyclic flow variations, CFVs) before a persistent occlusion recurred. In control dogs (n = 6), heparin alone did not prevent CFVs and reocclusion time was 25 +/- 4 min. Administration of an intravenous bolus of 0.2 +/- 0.06 mg/kg SQ29548, a TxA2/prostaglandin H2-receptor antagonist, and an intravenous bolus of 0.2 +/- 0.04 mg/kg ketanserin, a 5HT2-receptor antagonist, completely abolished CFVs in six of six dogs and reocclusion time was greater than 158 +/- 14 min (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Perfusion with non-oxygenated Tyrode solution causes maximal coronary vasodilation in canine hearts.

1. Coronary vasodilator effects of non-ischaemic hypoxia (perfusion with non-oxygenated Tyrode solution) and ischaemic hypoxia (coronary occlusion) were compared. 2. The left anterior descending coronary artery (LAD) of six in situ canine hearts was perfused selectively at controlled pressure with normal arterial blood or with non-oxygenated Tyrode solution. LAD flow was measured continuously with an electromagnetic flowmeter. Reactive hyperaemic blood flow responses following 3 min Tyrode perfusion were compared with responses following 3 min complete coronary occlusion. 3. Control LAD blood flow was 26.9 +/- 4.6 ml/min. A 3 min period of Tyrode perfusion caused a peak reactive hyperaemic blood flow of 151 +/- 31 ml/min, which was not significantly different from that caused by 3 min occlusion, 123 +/- 17 ml/min. The duration and total volume of reactive hyperaemia flow following Tyrode perfusion were smaller than values following occlusion. 4. The present findings demonstrate that myocardial hypoxia per se is a sufficient vasodilatory stimulus to account for the peak reactive hyperaemic flow following 3 min occlusion, but that the prolonged reactive hyperaemic response depends on vasodilator metabolites which accumulate in ischaemic myocardium.

Effects of intracoronary leukotriene D4 infusion on the coronary circulation, hemodynamics, and prostanoid release in porcine experiments.

The effects of leukotriene (LT) D4 (0.5 microgram/min) infusion into the left anterior descending coronary artery (LAD) of anesthetized pigs were studied in the absence or presence of indomethacin (5 mg/kg i.v.). In some pigs, arteriocoronary venous (A-V) blood plasma concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured by RIA technique during LTD4 actions. LTD4 changed LAD blood flow at 5 and 30 s, 2, 4 and 5 min by -46% (p less than 0.01), -93% (p less than 0.001), -45% (p less than 0.01), -28% (p less than 0.05) and 16%, respectively. Thus, the coronary constriction disappeared despite sustained LTD4 infusion and was followed by reactive hyperemia. Indomethacin did not affect the coronary flow or hemodynamic responses to LTD4 infusion. The A-V difference in prostanoids did not change during LTD4 administration. Cyclooxygenase products of arachidonic acid may not be responsible for early constriction and later escape phases of LTD4 effects on the coronary circulation. However, intracoronary bolus injection of LTD4 stimulated prostacyclin release from the vasculature in a dose-dependent manner causing significant reactive hyperemia after temporary blood flow cessation. Release of a LTD4-induced vasodilating factor from the coronary vessels unrelated to prostanoids may cause escape from vasoconstriction during LTD4 infusion.