Adenosine deaminase attenuates canine coronary vasodilatation during regional non-ischaemic myocardial hypoxia

To test the hypothesis that adenosine contributes to the coronary hyperaemia produced by regional non-ischaemic myocardial hypoxia coronary blood flow and myocardial oxygen extraction and consumption were continuously monitored in 21 anaesthetised open chest dogs under the following conditions: control 1--postinstrumentation, steady state control; hypoxia 1--3-5 min of regional (LAD) hypoxaemia (partial pressure of oxygen, PO2, 21.4(2.0) mmHg (3.1(0.2) kPa), coronary arterial oxygen content, CaO2, 3.9(0.4) ml.100 ml-1 (39(4) ml.litre-1): control 2--repeat steady state control; and hypoxia 2--3-5 min repeat regional hypoxaemia (PO2 18.9(2.4) mmHg (2.5(0.3) kPa); CaO2 3.6(0.6) ml.100 ml-1 (36(6) ml.litre-1) blood). Left anterior descending artery perfusion pressure was held constant for all conditions. Control 2 and hypoxia 2 were performed in the presence of locally infused adenosine deaminase (n = 16) or saline vehicle (n = 5). The 16 dogs given adenosine deaminase were further subdivided into those perfused with blood deoxygenated by a donor canine lung (group 1, n = 11) and those perfused with blood from a paediatric oxygenator (group 2, n = 5). Systemic haemodynamics, heart rate, and coronary arterial PO2 and O2 contents were similar during the two control periods and during the two exposures to hypoxia in all three groups. Left anterior descending artery blood flow increased by approximately 400% (p less than 0.05) in all three groups during the first exposure to hypoxia. Myocardial oxygen consumption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intravenous nitroglycerin on left ventricular function and ST segment changes in acute myocardial infarction.

It has been shown previously that 30-minute infusions of intravenous nitroglycerin in patients with acute myocardial infarction are able to lower left ventricular filling pressure and improve left ventricular function while lowering mean arterial pressure by only 7 mmHg (0.9 kPa). A decrease in sigmaST in praecordial ST segment mapping studies during nitroglycerin infusion in patients with anterior infarction suggested a decrease in the extent of myocardial ischaemia. In the present study, 30 patients with acute myocardial infarction received 1- to 3-hour infusions of intravenous nitroglycerin at infusion rates sufficient to lower mean arterial pressure by an average of 22 mmHg (2.9 kPa). An improvement in ventricular function was noted in that subgroup of patients with the msot severe left ventricular dysfunction. All patients with anterior myocardial infarction underwent serial ST segment mapping and, irrespective of the presence or absence of left ventricular failure, showed a decrease in sigmaST during nitroglycerin infusion (P less than 0.005). These findings suggest that infusion of nitroglycerin improves left ventricular function and/or alters left ventricular compliance in patients with left ventricular failure complicating myocardial infarction and furthermore decreases sigmaST in all patients, irrespective of the presence or absence of left ventricular failure, suggesting that the extent of myocardial ischaemia is decreased.     

Hemodynamic and coronary effects of intravenous verapamil in coronary insufficiency

Verapamil inhibits calcium influx through the slow calcium canals. The coronary an haemodynamic effects of intravenous Verapamil were studied in 8 patients with chronic coronary insufficiency documented by coronary arteriography. The following measurements were made in spontaneous rhythm and during atrial pacing under basal conditions and 10 minutes after intravenous Verapamil (0.10 to 0.17 mg/kg) relayed with a continuous infusion of 5 x 10(-3) mg/Kg/mn: heart rate, cardiac output, left ventricularr pressure (Millar 5 F micromanometer), femoral artery pressure, coronary sinus flow by continuous thermodilution, oxygen and lactate concentrations in arterial and arterio-venous oxygen difference, and index of myocardial oxygen consumption and the coefficient of lactate extraction were then calculated. The coronary and haemodynamic effects of atrial pacing were similar before and after Verapamil at a given rate. Left ventricula end diastolic pressure decreased, cardiac output and total systemic resistance were unchanged, dP/dt max increased but to a lesser degree after Verapamil (P less than 0.05). Coronary arterio-venous oxygen difference decreased after Verapamil. The coronary and haemodynamic effects of Verapamil were similar in spontaneous rhythm and during atrial pacing. In spontaneous rhythm, the heart rate and left ventricular end diastolic pressure increased. In spontaneous and paced rhythm, femoral artery pressure, total systemic resistance and dP/dt max decreased. Cardiac output remained the same. Myocardial oxygen consumption decreased mainly because of a reduced coronary arterio-venous oxygen difference and because of unchanged coronary flow in spontaneous rhythm oxygen consumption seems to have a favourable effect on the myocardial energy equilibrium as shown by the increased coefficient of lactate extraction during atrial pacing after Verapamil. This study shows the negative inotropic and arterial vasodilator effects of Verapamil to be responsible for the reduced myocardial oxygen consumption. It also caused coronary artery vasodilation.     

Abnormalities in myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy: metabolic evidence for myocardial ischemia

This study tested the hypothesis that in the chronically hypertrophied left ventricle pacing stress may cause abnormalities of perfusion that result in myocardial ischemia. Left ventricular hypertrophy (LVH) was produced by banding the ascending aorta of 10 dogs at 6 weeks of age, and studies were carried out after the animals had reached adulthood and when mean left ventricular/body weight ratio was 74% greater than in eight control dogs. Myocardial blood flow was measured with microspheres during pacing at 100, 200, and 250 beats/min, while aortic and coronary sinus blood samples were obtained for determination of concentrations of lactate and the adenosine metabolites inosine and hypoxanthine. In the control dogs, increasing heart rates were associated with an increase in mean myocardial blood flow while subendocardial flow was maintained at a level equal to or greater than subepicardial flow. Myocardial lactate uptake ranged from +60% to -5%, and adenosine metabolites were not detected in coronary sinus blood (less than 0.5 microM/l). In four dogs that underwent aortic banding no production of lactate or adenosine metabolites was observed at any heart rate; in these animals subendocardial flow was maintained at a level equal to or greater than subepicardial flow at all pacing rates. The remaining six dogs with LVH demonstrated net lactate production significantly greater than control during pacing at 250 beats/min; five of these six animals also produced adenosine metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postischemic reperfusion injury can be attenuated by oxygen tension control

Oxygen-derived free radicals cause cytotoxic damage during reperfusion after a period of ischemia and the production of these free radicals may be proportionate to oxygen tension (PO2). The present study tested the hypothesis that oxidative damage may be limited by maintaining a more physiologic PO2 following ischemia. An experimental study in Wistar rats were mounted on a Langendorff apparatus was conducted to estimate baseline aortic flow (AF), coronary flow (CF), cardiac output (CO), systolic pressure (SP), heart rate (HR), and the rate-pressure product (RPP: HRxSP). The hearts were divided into 3 groups (n=7, hearts/group): group 1, hypoxic (PO2=300+/-50 mmHg) reperfusion; group 2, middleoxic (PO2=500+/-50 mmHg) reperfusion; and group 3, hyperoxic (PO2=700+/-50 mmHg) reperfusion. Following 30 min of warm ischemia, hearts in all groups were reperfused at each oxygen pressure. The recovery of cardiac function of each heart was measured at the end of reperfusion. Concentrations of lactate (LAC), lactate dehydrogenase (LDH), and creatine kinase (CK) in the coronary perfusate during reperfusion were measured. The recovery rate of CO, SP, and RPP in group 2 were all significantly better than in the other 2 groups. CK leakage in group 2 was significantly lower than in group 3. A clinical study was also conducted during elective coronary artery bypass grafts in 16 consecutive patients who underwent either hyperoxic (n=8, PO2=450-550 mmHg) or more physiologic (n=8, PO2=200-250 mmHg) cardiopulmonary bypass after aortic unclamping. The clinical study assessed CK-MB, LDH, LAC, and malondialdehyde (MDA) in patient blood prior to starting the surgical procedure and at 30 min and 3, 9, and 21 h after unclamping. Cardiac index (CI), central venous pressure, pulmonary capillary wedge pressure, systolic arterial pressure, and the dose of cathecholamines were also measured. Although no significant differences were present in the dose of cathecholamines, the CI in the more physiologic oxygen tension group was significantly higher than in the hyperoxic group at 3 and 6 h after unclamping. The levels of MDA in the more physiologic PO2 group was significantly lower at 30 min after aortic unclamping than in the hyperoxic group. The present results suggest that in the experimental as well as in the clinical study, high PO2 leads to myocardial reperfusion damage; however, maintaining a more physiologic PO2 during reperfusion following ischemia may attenuate reperfusion injury.     

Influence of adenosine on the stimulatory effect of isoprenaline and insulin on myocardial contractility in vivo.

STUDY OBJECTIVE--In vitro investigations have indicated that adenosine can inhibit beta adrenergic stimulated increases in cardiac contractility. The present study was designed to determine the ability of adenosine to inhibit isoprenaline induced increases in contractility in vivo. Adenosine has been reported to exert its inhibitory effects on contractility by inhibiting adenylate cyclase. Thus, adenosine should have no effect on positive inotropic agents that act independently of adenylate cyclase. We therefore assessed the ability of this nucleoside to inhibit the positive inotropic effect of insulin, a hormone that exerts a positive inotropic effect independently of alterations in cyclic AMP. DESIGN--Saline or adenosine (10 mumol.ml-1) was infused into the circumflex artery at 1 ml.min-1 as a background. Isoprenaline (20 or 200 pmol.min-1) was infused into the artery during saline or adenosine infusion. The response to insulin was determined during hyperinsulinaemic euglycaemic clamp. SUBJECTS--16 adult mongrel dogs were anaesthetised with pentobarbitone. Five dogs were used in isoprenaline studies, and 11 dogs in insulin studies. MEASUREMENTS AND MAIN RESULTS--Dogs were instrumented to obtain measurements of mean arterial blood pressure, heart rate, circumflex artery blood flow (Q), instantaneous left ventricular pressure, and posterior left ventricular wall thickness. We used the slope of the end systolic pressure-dimension relationship (Ees) as an index of myocardial contractility, previously shown to reflect changes in myocardial inotropic state independent of influence from afterload and preload. Left ventricular dP/dtmax was derived from left ventricular pressure with respect to time, and Ees was determined from left ventricular pressure and wall thickness. Neither adenosine, isoprenaline, nor insulin alone caused any significant changes in mean arterial pressure or heart rate. Adenosine caused a significant increase in Q. Both left ventricular dP/dtmax and Ees were significantly increased by either insulin or both doses of isoprenaline. Adenosine inhibited the increases in these indices caused by isoprenaline, but not those caused by insulin. CONCLUSIONS--Adenosine is capable of inhibiting the positive inotropic effect of isoprenaline in vivo. The results suggest that adenosine does not inhibit positive inotropic responses that act independently of the stimulation of adenylate cyclase.     

Comparison of left and right ventricular blood flow responses during arterial pressure reduction in the autonomically blocked dog: evidence for right ventricular autoregulation

The effect of reducing systemic arterial pressure with an arteriovenous fistula on left and right ventricular myocardial blood flow was studied in 17 anaesthetised, open chest, autonomically blocked dogs. Global and regional myocardial blood flows were measured with radioactive microspheres. As mean arterial pressure was reduced from 133 mmHg to 78 mmHg left ventricular myocardial blood flow and the left ventricular inner to outer flow ratio decreased progressively. By contrast, right ventricular myocardial blood flow remained constant (range 78-81 ml.min-1.100 g-1) whereas right ventricular vascular resistance fell linearly (from 235 to 130 kPa.litre-1.min.100 g-1). The inner to outer right ventricular free wall flow ratio (range 1.04-1.10) and blood flow to the right side of the interventricular septum also did not change significantly. It is concluded that the right ventricular myocardium shows effective autoregulation of total and regional tissue blood flow during changes in coronary perfusion pressure.     

Volatile anesthetics and regional myocardial perfusion in chronically instrumented dogs: Halothane versus isoflurane in a single-vessel disease model with enhanced collateral development

The influence of halothane and isoflurane on regional myocardial blood flow was investigated in chronically instrumented dogs with a well developed coronary collateral circulation. Dogs were implanted with an Ameroid constrictor on the left anterior descending (LAD) coronary artery to produce slowly progressive coronary artery occlusion and collateral development. Contractile function in the collateral-dependent region was ascertained periodically during brief balloon cuff occlusion or during atrial pacing to characterize the degree of ongoing collateral development. Following documentation of enhanced collateral perfusion by the lack of contractile dysfunction during brief balloon cuff occlusion or atrial pacing at 50 days postimplantation, dogs were anesthetized (inhalation induction) with halothane (1.5% or 2.5%; n = 7) or isoflurane (2.0% or 3.0%; n = 8) using equihypotensive inspired concentrations of either agent. Radioactive microspheres were administered to measure regional myocardial perfusion during the conscious state and at stable hemodynamic states during both low and high concentrations of each volatile anesthetic. Myocardial blood flow during anesthesia was also determined following the adjustment of arterial pressure and heart rate to conscious levels by administration of phenylephrine and atrial pacing, respectively. Over the course of collateral development, balloon cuff-induced contractile dysfunction and pacing-induced contractile dysfunction in the collateral-dependent zone were reduced, indicating extensive collateral development. Halothane and isoflurane decreased global and regional indices of contractility and arterial pressure in a dosedependent manner, but only isoflurane reduced coronary vascular resistance. Both anesthetics decreased myocardial perfusion within normal and collateral-dependent regions; however, flow was restored to levels found in the conscious state coincidental with control of arterial pressure and heart rate. Neither anesthetic alone, nor with concomitant control of arterial pressure and heart rate, produced a maldistribution of blood flow transmurally or between normal and collateral-dependent zones. The results suggest that both halothane and isoflurane, although decreasing major determinants of myocardial oxygen demand, do not unfavorably alter the regional distribution of coronary blood flow in a single-vessel disease model with enhanced collateral development.     

Distribution of cardiac output, oxygen consumption and lactate production in canine endotoxin shock

Endotoxin causes shock accompanied by compensatory changes such as redistribution of cardiac output and increased oxygen extraction. We studied these effects in anaesthetised dogs (etomidate: 4 mg X kg-1 X h-1, n = 14) randomly assigned to a control (n = 6) and a shock group (endotoxin 1.5 mg X kg-1; n = 8). We measured left ventricular pressure, LVEDP and LVdP/dt (Millar microtip), mean systemic, central venous and pulmonary artery pressure (Statham P23Db), cardiac output (thermodilution), organ flow (microspheres, 15 micron, 5 labels), bloodgases (PO2, PCO2), pH and lactate. All measurements were performed before and at 60, 90, 120 and 150 min after endotoxin or saline. Sixty minutes after endotoxin mean systemic pressure, LVdP/dt and cardiac output had decreased (by 60, 50 and 35%), while heart rate had increased (by 30%). Arterial PO2 was lower after endotoxin (-29%), haematocrit and mixed venous PCO2 were higher (+16 and +38%) and arterial pH had decreased from 7.34 to 7.14. After endotoxin perfusion of heart and adrenals did not change but muscle perfusion increased (by 33% at t = 90). Endotoxin caused vasoconstriction in spleen and kidneys: the percentage of cardiac output to these organs thus decreased (by 50 and 69%). Sixty minutes after endotoxin we found vasodilatation in the hepatic arterial, pancreatic, and gastrointestinal beds. Later the percentage of cardiac output to these beds decreased. Systemic arterio-venous shunting fell (from 6.5 to 0.7%). Systemic and splanchnic oxygen extraction increased (by 66 and 71% at t = 60): oxygen consumption hardly changed; 60 min after endotoxin it tended to decrease. During shock serum lactate rose (by 167% at t = 60) before oxygen consumption fell. Myocardial oxygen consumption did not alter during shock but the tension time index decreased.     

Acute hemodynamic and antiischemic effects of intravenous amiodarone

The acute hemodynamic and antiischemic properties of amiodarone were investigated in 16 patients with more than 70% diameter reduction of a left coronary artery. Two successive atrial pacing stress tests (APST I and II) were performed, with an interval of 40 minutes in between, and amiodarone, 5 mg/kg/5 min, was infused 30 minutes after APST I. Hemodynamic changes during amiodarone administration consisted of a 20% decrease in left ventricular (LV) systolic pressure, a 13% decrease in systemic vascular resistance and an 18% decrease in stroke work. Coronary vascular resistance was reduced 19% and coronary sinus flow increased 23%. Despite a secondary 14% increase in heart rate, contractility decreased 21%, accompanied by a 45% increase in LV end-diastolic pressure, which persisted until APST II. Although most hemodynamic changes were observed only during the infusion, contractility and LV systolic pressure were still diminished at the beginning of APST II and remained so during pacing, resulting in a reduction in myocardial oxygen demand compared to APST I. Although overall myocardial oxygen consumption and coronary flow were equal during both pacing tests, amiodarone significantly reduced pacing-induced myocardial ischemia. Lactate metabolism remained normal during APST II (lactate extraction 12 +/- 3% vs -28 +/- 8% (APST I) at maximal pacing rates [p less than 0.05]), while ST-segment depression, LV end-diastolic pressure postpacing and angina were also significantly reduced during APST II. Thus, in humans, intravenous amiodarone reduces vascular resistance and contractility and inhibits pacing-induced myocardial ischemia, presumably by reducing myocardial oxygen demand.     

Effects of diltiazem on cardiac and coronary circulation, at rest and during rapid auricular electric stimulation

The effects on cardiac performance and systemic and coronary blood flow of rapid atrial pacing alone and associated with an intravenous infusion of a slow calcium channel inhibitor, diltiazem, at a dose of 20 mg/kg were studied in 20 patients with chronic coronary artery disease. Atrial pacing increased coronary flow and myocardial oxygen consumption: it decreased coronary arterial resistance and the coronary arteriovenous difference in lactates. Left ventricular end diastolic pressure rose significantly compared to the basal state in the period following pacing. The administration of diltiazem was associated with a significant fall of femoral arterial pressure, of coronary arteriovenous difference and myocardial consumption of oxygen, and an increase in the coronary arteriovenous difference in lactate. Left ventricular end diastolic pressure did not differ significantly from the basal values recorded after terminating atrial pacing. Left ventricular end diastolic volume decreased. Diltiazem opposed or cancelled the undesirable effects of rapid atrial pacing with respect to coronary arteriovenous difference in lactate content. The beneficial action of diltiazem does not seem to be closely related to its hemodynamic effects. It could be related to a reduction in myocardial oxygen demands due to a decrease in systolic ventricular strain and the specific metabolic effects of the drug, and also to an increase in myocardial oxygen supply due to the reduction in left ventricular end diastolic stress and the coronary vasodilation caused by the drug.     

Effects of pharmacologically-induced hypertension on myocardial ischemia and coronary hemodynamics in patients with fixed coronary obstruction

Twenty patients with fixed coronary artery obstruction were studied during rapid atrial pacing and methoxamine infusion. During pacing to heart rates of 142 +/- 4 (mean +/- SEM) beats per minute coronary sinus flow increased from 108 +/- 8 to 187 +/- 15 cc/min and myocardial oxygen consumption increased by + 80 +/- 11%. During methoxamine infusion that raised arterial systolic pressure to 196 +/- 5 mm Hg, similar increases in coronary sinus flow (to 179 +/- 13 cc/min) and myocardial oxygen consumption (+ 77 +/- 12%) occurred. Chest pain and ischemic ST segment changes developed in 17 and 14 patients respectively during atrial pacing, an incidence significantly greater (P less than 0.05) than during infusion of methoxamine (6 and 3 patients). Myocardial lactate extraction which averaged 26 +/- 4% during control was decreased to 10 +/- 8% during pacing and to 24 +/- 7% during methoxamine; the difference between decreases was not significant. The data show that at similar increases in myocardial oxygen consumption stress of increased heart rate results in more myocardial ischemia than stress of increased afterload.     

Lack of ouabain effect on pacing-induced myocardial ischemia in patients with coronary artery disease

Sixteen patients with significant two and three vessel coronary artery disease but without clinical congestive heart failure were studied during rapid atrial pacing before and after infusion of 0.015 mg/kg of ouabain. Seven patients with a decreased (less than 50 percent) election fraction and nine patients with a normal election fraction had a significant (P < 0.05) increase in resting arterial systolic pressure after the administration of ouabain. However, resting values for coronary sinus flow, coronary vascular resistance, myocardial oxygen consumption and myocardial lactate extraction did not change significantly in either group. During pacing, patients with a decreased ejection fraction demonstrated more ischemia than patients with a normal ejection fraction; however, the administration of ouabain did not significantly alter pacing-related changes in coronary sinus flow, myocardial oxygen consumption, myocardial lactate extraction, ischemic electrocardiographic changes or onset of chest pain in either group. The administration of ouabain has a negligible effect on coronary hemodynamics, myocardial metabolism or clinical signs of ischemia in patients with coronary artery disease with normal or abnormal left ventricular function.     

Effect of aortocoronary bypass surgery on coronary circulation and myocardial metabolism during atrial pacing

Summary Eleven patients with coronary heart disease, in whom at least one of several bypass grafts to the left coronary artery was patent, were selected for the study. The hemodynamics, coronary sinus blood flow, myocardial oxygen consumption, and myocardial lactate metabolism were evaluated at rest and during atrial pacing stress test before and after surgery.There were no significant improvements in the cardiac index, pulmonary arterial end-diastolic pressure, and left ventricular ejection fraction after aortocoronary bypass surgery. However, significant improvement of coronary sinus blood flow, myocardial oxygen consumption, and myocardial lactate extraction and consumption were found during postoperative atrial pacing compared with the preoperative findings.These results suggest that successful bypass grafting may improve myocardial lactate metabolism in ischemic lesions and contribute to the postoperative relief of angina.     

Afterload as a predeterminant of haemodynamics and segmental wall motion following coronary artery occlusion.

Maximal changes in haemodynamics and segmental wall motion were seen 2 min after coronary occlusion and were examined in relation to the loading conditions of the left ventricle before occlusion in 20 open chest dogs. There was a significant inverse relationship between the preligation mean aortic pressure and the percentage decrease in stroke volume following ligation. This relationship was observed whether afterload was distributed randomly (mean aortic pressure ranging from 9.7 to 17.6 kPa [73 to 132 mmHg]) between all dogs (r = 0.65; P less than 0.001) or altered by methoxamine (+4 kPa [+30 mmHg]) and nitroprusside (-3.2 kPa [-24 mmHg]) within the same dog (r = 0.82; P less than 0.001; n = 8). Although occlusion of the anterior descending artery caused a small (+5.5%) but significant increase in end-diastolic length of the non-ischaemic epicardial segment, the capacity for compensatory ventricular dilatation was not dependent on preligation afterload. However, the capacity of the ischaemic segment to undergo systolic expansion was significantly greater (+30.2% of end-systolic segment length) in those dogs with the lowest preligation MAP (8 to 12 kPa [60 to 90 mmHg]) compared with systolic lengthening of only 15.8% in the high afterload group (15 to 18 kPa [112 to 135 mmHg]). These data indicate that the loading conditions of the left ventricle predetermine the extent of global and segmental left ventricular dysfunction during the early phase of acute ischaemic injury.     

Effects of isosorbide dinitrate on the response to atrial pacing in coronary heart disease.

To study the efficacy of isosorbide dinitrate in prevention of myocardial ischemia, 20 patients with angiographically proved coronary artery disease underwent atrial pacing (mean rate 138/min) before (P1), 10 minutes after (P2) and 65 minutes after (P3) sublingual administration of 5 mg of isosorbide dinitrate. The symptomatic, hemodynamic and metabolic responses were evaluated at rest and during each pacing period. Angina occurred in all subjects during P1. Angina did not recur or was less severe in 17 of 19 patients during P2 and in 19 of 20 patients during P3. Resting left ventricular end-diastolic pressure for the group was normal at 11 plus or minus 4 mm Hg (mean plus or minus standard deviation). On interruption of pacing at 4.5 minutes during P1, average end-diastolic pressure during sinus rhythm was abnormal (18 plus or minus 6 mm Hg). After administration of isosorbide dinitrate mean left ventricular end-diastolic pressure was significantly decreased at rest and remained normal when pacing was interrupted during P2 and P3. Brachial arterial pressure, cardiac index, tension-time index, left ventricular stroke work index and maximal rate of rise of left ventricular pressure were all diminished at rest before and during P2 and P3. S-T segment depression was less during P2 and P3 than during P1. Before isosorbide dinitrate was given, resting myocardial lactate extraction was 15 plus or minus 11 percent during P1 lactate extraction decreased to minus2 plus or minus 25 percent. Lactate extraction was significantly greater during P2 and P3 than during P1. This study demonstrates that sublingual administration of 5 mg of isosorbide dinitrate has a significant protective effect against pacing-induced myocardial ischemia at 10 and 65 minutes after administration.     

The effects of trapidil on left ventricular function and platelet aggregation in patients with coronary artery disease subjected to pacing.

The effects of the intravenous administration of 100 mg of trapidil on systolic and diastolic left ventricular functions and coronary sinus blood flow, as well as on myocardial lactate metabolism and platelet aggregation, were investigated before and after pacing in 12 patients with coronary artery disease. Pacing without administration of trapidil provoked angina in 6 of these patients. During rest, trapidil decreased the mean blood pressure by an average of 5 mmHg (from 112 +/- 15 to 107 +/- 8 mmHg, p less than 0.05) and the left ventricular end-diastolic pressure by an average of 4 mmHg (from 10 +/- 3 to 6 +/- 2 mmHg, p less than 0.05). Trapidil also caused both the max dp/dt and the coronary sinus blood flow to increase slightly, although it had no significant effect on diastolic function, myocardial lactate metabolism, or platelet aggregation. During the pacing that followed trapidil administration, chest pain was not provoked in the same 6 patients who had previously experienced chest pain on pacing. The extent of ST-segment depression also improved from -1.6 +/- 0.3 to -0.9 +/- 0.7 mm (p less than 0.05) and there was a significant suppression of the production of myocardial lactate. When pacing was terminated, trapidil caused a decrease in left ventricular systolic pressure from 173 to 156 mmHg (p less than 0.05), and also caused a decrease of the left ventricular end-diastolic pressure, from 16 +/- 4 to 8 +/- 2 mmHg (p less than 0.05). Trapidil had no significant effect on platelet aggregation activity with either a 1 microM or a 2 microM dose of ADP (adenosine diphosphate). However, the beta-TG level was suppressed, decreasing from 119 +/- 14 to 99 +/- 19 ng/ml in the arterial blood (p less than 0.1) and from 114 +/- 9 to 103 +/- 17 ng/ml (p less than 0.1) in the coronary sinus blood. Reductions in the preload and afterload by trapidil were of far greater magnitude than either its coronary dilatory or positive chronotropic effects in patients with coronary artery disease. Thus trapidil, a new antianginal agent appears to inhibit the production of platelet derived growth factors and may, therefore, protect the arteries from atherosclerosis as it promotes beneficial systemic hemodynamics in patients with depressed ventricular function.     

Role of the autonomic nervous system in the pressor response to calcium in conscious dogs

The effects of acute hypercalcaemia on arterial pressure and vascular tone have been poorly understood. We analysed the effect of a bolus of calcium chloride (15 mg . kg-1 iv) on arterial pressure, total peripheral resistance, and left ventricular function in 25 conscious dogs studied with or without pharmacological autonomic blockade. Without autonomic blocking drugs, the maximum response to calcium included increases of +139.4 kPa . s-1 (+1046 mmHg . s-1) in maximum rate of change of left ventricular pressure, +2.2 cm3 in stroke volume, +2.6 kPa (+ 19.2 mmHg) in aortic systolic pressure, and +0.6 kPa (+4.4 mmHg) in mean aortic pressure, but total peripheral resistance was unchanged. During beta-adrenergic blockade with propranolol, calcium again increased maximum rate of change of pressure and stroke volume, increased mean aortic pressure (2.2 kPa [+16.5 mmHg]), and increased resistance by 35%. When calcium was given during alpha-adrenergic blockade with phenoxybenzamine or phentolamine, mean aortic pressure did not rise, and resistance fell by 19%. The calcium-induced rise in resistance during beta-adrenergic blockade was abolished by surgical adrenalectomy. We conclude that excess extracellular calcium ion may influence vascular resistance by increasing autonomic nervous system excitation of alpha- and beta-adrenergic vascular receptors. A major mechanism by which the sympathetic nervous system effects occur is through increased release of catecholamines from the adrenal medulla.     

Role of adenosine in mediating the coronary vasodilative response to acute hypoxia

To test the hypothesis that adenosine is required to mediate the coronary vasodilative response to acute hypoxia haemodynamic indices, regional myocardial blood flow, and oxygen and lactate metabolism were measured in nine closed chest anaesthetised domestic swine at control, after 3-5 min of 100% nitrogen inhalation, at second control, and after 3-5 min of 100% nitrogen inhalation plus adenosine deaminase infusion in the left anterior descending coronary artery. Cardiac lymph adenosine deaminase concentration was also measured in a separate group of four animals previously reported on. Heart rate was held constant by atrial pacing during the study. Aortic mean pressure did not change. Changes in arterial and anterior interventricular vein pH, PO2, PCO2, and oxygen content were similar for each intervention. Transmural left anterior descending artery zone flow increased significantly (p less than 0.01) compared with control (1.22(0.23) ml.min-1.g-1; mean(SD)) in response to hypoxia (2.73(0.92)). Intracoronary adenosine deaminase infusion (167 nmol.s-1), however, failed to blunt the flow response to hypoxia (1.33(0.30) to 2.79(1.32); second control to hypoxia plus adenosine deaminase respectively, p less than 0.01). Mean adenosine deaminase activity (nmol.s-1) in cardiac lymph was 105(85) at the end of 10 min of intracoronary infusion (167 nmol.s-1) and 203 (148) nmol.s-1 at the end of 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of propranolol on the hemodynamic,coronary sinus blood flow and myocardial metabolic response to atrial pacing

The hemodynamic, coronary sinus blood flow and myocardial metabolic effects of 0.15 mg/kg body weight of intravenously administered propranolol were studied in 19 patients with coronary artery disease and 6 normal patients. Atrial pacing was performed in all patients and produced angina in 15 of the 19 patients with coronary artery disease. In these patients propranolol reduced heart rate from 78 to 69 beats/min, cardiac index from 3.0 to 2.6 liters/min per m² and left ventricular stroke work index from 47 to 43 g-m/m²; it increased total peripheral resistance from 24 to 28 units and lactate extraction from 16.3 to 22.5 percent. There was no significant change in mean arterial pressure, left ventricular end-diastolic pressure, coronary sinus blood flow or myocardial oxygen consumption. During a second pacing stress propranolol produced clinical improvement in 9 of the 15 patients who experienced angina initially. The improvement was associated with less severe abnormalities in S-T depression and left ventricular end-diastolic pressure, increased lactate extraction and no significant change in coronary sinus blood flow or myocardial oxygen consumption. Thus, propranolol appears to be capable of modifying the anginal threshold as determined with atrial pacing, and the clinical response appears to be independent of global changes in coronary sinus blood flow and myocardial oxygen consumption.