Selective thromboxane A2 synthetase inhibition in vasospastic angina pectoris

To investigate whether thromboxane A2 is responsible for the initiation of vasospastic angina pectoris, thromboxane B2 levels were measured in the great cardiac vein and the arterial blood of 12 patients with clinically and angiographically proved vasospastic angina and therapeutic trials were performed with selective thromboxane A2 synthetase inhibitor OKY-046, an imidazole derivative. During ergonovine-provoked (11 cases) and spontaneous (1 case) anginal attacks, great cardiac vein thromboxane B2 increased from 121 +/- 27 to 430 +/- 382 pg/ml (p less than 0.05, n = 12), arterial thromboxane B2 increased from 93 +/- 18 to 122 +/- 33 pg/ml (NS, n = 12) and thromboxane B2 production increased from 3.18 +/- 1.88 to 25.16 +/- 22.32 ng/min (p less than 0.05, n = 6). Subsequently, OKY-046, 400 mg/day orally, was administered to 7 of the 12 patients, while a continuous electrocardiogram was recorded on a dual channel Holter monitor during a 3 day placebo period and the 3 day OKY-046 regimen. Although peripheral plasma thromboxane B2 levels decreased significantly from 98 +/- 15 to 12 +/- 8 and 28 +/- 10 pg/ml (1 and 6 hours after ingestion, respectively) (p less than 0.05 for both), 6-keto-prostaglandin F1 alpha production in serum increased significantly from 0.48 +/- 0.22 to 2.3 +/- 0.72 (1 hour) and 1.8 +/- 0.46 ng/ml (6 hours) (p less than 0.05 for both) during OKY-046 administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.     

Fibrinopeptide A and platelet factor levels in unstable angina pectoris

Fibrinopeptide A, platelet factor 4, beta-thromboglobulin, thromboxane B2, and 6-keto-prostaglandin F1 alpha were estimated by radioimmunoassay on venous plasma samples taken within 48 hr of admission from 16 consecutive patients with unstable angina and 15 patients with stable angina matched for clinical variables. The ratio of circulating platelet aggregates, platelet aggregation to increasing concentrations of ADP (0.455 to 1.82 micrograms/ml), and platelet thromboxane B2 production in vitro were also tested. The two groups of patients were statistically similar in terms of sex distribution, age, presence of risk factors, use of medication, extent of coronary artery disease and history of previous myocardial infarction. Mean plasma levels of fibrinopeptide A were 2.7 +/- 0.4 ng/ml (geometric means +/- SEM, range 1.5 to 5.5) in patients with stable angina vs 5.5 +/- 1.8 ng/ml (range 2.4 to 32; p less than .001) in those with unstable angina. In the latter group, after 6 to 8 days, fibrinopeptide A levels decreased to 3.6 +/- 0.5 ng/ml (range 1.5 to 9.3; p less than .04 vs admission). All other variables measured were statistically identical in the two groups. We conclude that plasma fibrinopeptide A levels, as opposed to platelet factors, discriminate between patients with unstable and stable angina, indicating an activation of the coagulation system in unstable angina.     

Evaluation of thromboxane production and complement activation during myocardial ischemia in patients with angina pectoris

BACKGROUND. The complement system and arachidonic acid metabolites are involved in severe myocardial ischemia such as myocardial infarction. Furthermore, there is experimental evidence for C5a participation in thromboxane production. METHODS AND RESULTS. We examined whether C5a and thromboxane are produced during brief and reversible episodes of myocardial ischemia induced in patients with stable angina. Twenty-five patients underwent either atrial pacing or percutaneous transluminal coronary angioplasty associated with arterial and coronary sinus blood sampling. Rapid atrial stimulation of patients with effort angina caused significant ST segment depression (delta ST = -1.7 +/- 0.2 mm), decreased fractional lactate extraction (from +12.8 +/- 2.5% baseline to -13.7 +/- 4.6% at peak ischemia, n = 13, p less than 0.001), and increased coronary sinus plasma thromboxane B2 levels (from 345 +/- 85 pg/ml baseline to 1,684 +/- 64 pg/ml at peak ischemia, p less than 0.01). Changes of fractional lactate extraction correlated significantly with changes of coronary sinus plasma levels of thromboxane B2. There was no change of coronary sinus 6-keto-PGF1 alpha levels. Similar pacing of control subjects (n = 6) did not cause release of lactate or thromboxane. Seventeen other patients underwent exercise testing with noninvasive measurements of thromboxane and prostacyclin metabolites in urinary samples collected before and after the test. No detectable increase of urinary 11-dehydrothromboxane B2 was measured in patients with stable angina after exercise-induced myocardial ischemia. However, basal 11-dehydrothromboxane B2 levels were significantly higher in patients with angina (105 +/- 25 pg/mmol creatinine, n = 9) than in control patients (45 +/- 8 pg/mmol creatinine, n = 8, p less than 0.05 between groups). Coronary sinus plasma levels of the anaphylatoxin C5a always remained below 4 ng/ml in patients undergoing pacing. More severe myocardial ischemia after coronary angioplasty (percent lactate extraction decreased from +24.8 +/- 2.7% baseline to -41.6 +/- 22.4% at peak ischemia, p less than 0.05) was not associated with C3a or C5b-9 generation. In all patients, there was neither platelet sequestration nor platelet alpha-granule release (no changes of beta-thromboglobulin/platelet factor 4 levels) into the coronary sinus plasma. CONCLUSIONS. Patients with stable angina have chronically increased thromboxane synthesis as assessed by excretion of urinary metabolites. Thromboxane is acutely released into the coronary sinus during pacing-induced ischemia without significant intracoronary platelet aggregation. Complement does not appear to be activated in stable angina during brief and reversible episodes of myocardial ischemia and does not contribute to thromboxane production.     

Hemodynamic, platelet and clinical responses to prostacyclin in unstable angina pectoris

The hemodynamic and platelet effects of prostacyclin (PGI2) were investigated in 27 patients with unstable angina (14 treated patients; 13 control subjects) given a 72-hour infusion (5 ng/kg/min) or placebo. This randomized study was double-blind and conducted as a substudy of a multicenter trial testing the clinical efficacy of PGI2. The clinical and angiographic features were identical in the 2 groups. Blood pressure and heart rate were not modified significantly by PGI2. A recurrence of angina during infusion occurred in 8 treated patients (57.1%) and in 8 control subjects (61.5%). Two patients receiving PGI2 and none in the control group developed a myocardial infarction. Levels of 6-keto-prostaglandin F1 alpha, a stable metabolite of PGI2, increased from baseline values (less than 20 pg/ml) to 605 +/- 41 pg/ml during infusion. Levels of fibrinopeptide A, beta-thromboglobulin, platelet factor 4, thromboxane B2 and the platelet aggregates ratio in blood were similar between the 2 groups before, during and after PGI2 infusion. Prostacyclin reduced ex vivo platelet aggregation to adenosine diphosphate and thromboxane B2 generation by approximately 50% during the infusion period with return of aggregation to baseline and platelet thromboxane B2 production to above baseline after the discontinuation of PGI2. Thus, despite favorable effects of PGI2 upon platelet aggregation and systemic hemodynamics, the prostanoid failed to improve the clinical evolution of unstable angina.     

Effects of a selective thromboxane synthetase inhibitor (OKY-046) in patients with coronary artery disease during exercise

We studied the levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), platelet aggregability, beta-thromboglobulin and platelet factor 4 in 30 coronary artery disease (CAD) patients and 21 normal subjects during exercise. During treadmill exercise, 13 of 30 CAD patients reported chest pain. We administered a selective thromboxane synthetase inhibitor (OKY-046) for 2 weeks to 10 CAD patients with exercise-induced chest pain and studied its effects. At rest, the plasma TXB2 levels and platelet aggregation were significantly lower in normal subjects than in CAD patients, and there was no difference between CAD patients with and without exercise-induced chest pain. On treadmill testing, plasma TXB2 levels and platelet aggregation increased significantly only in the CAD patients with exercise-induced chest pain. Plasma 6-keto-PGF1 alpha levels in normal subjects were significantly higher than those in CAD patients both at rest and during exercise. After administration of OKY-046, mean exercise time increased significantly from 7.5 to 8.6 min (p less than 0.001). Plasma TXB2 level and platelet aggregation decreased significantly after OKY-046 administration both at rest and during exercise. These results suggest that a marked increase in TXA2, with only a minimal change in PGI2, during exercise may contribute to exercise-induced myocardial ischemia, and that OKY-046 is useful in the treatment of CAD patients.     

Abnormal cardiocoronary thromboxane A2 production in patients with unstable angina

Thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2), was measured in the coronary sinus and in aortic blood before and after cold pressor test (CPT) in 21 patients suffering from ischemic heart disease (7 affected by stable effort angina and 14 by unstable angina) and in 12 patients not suffering from myocardial ischemia (control group) during coronary angiography. Aspirin (10 mg/kg intravenously) was administered before catheterization in order to prevent platelet and leukocyte TXA2 formation. Control subjects and patients with effort angina had TXB2 resting levels lower than unstable angina patients without a transcardiac gradient which, on the contrary, was found in unstable angina patients. Only in these patients CPT resulted in a significant TXB2 increase more marked in the coronary sinus (from 50.0 +/- 18.9 pg/ml to 73.0 +/- 35.1 pg/ml, p less than 0.001) than in the aorta (from 33.4 +/- 17.1 pg/ml to 42.6 +/- 24.0 pg/ml, p less than 0.05), so that the transcardiac TXB2 gradient significantly increased. In all but two unstable angina patients, TXB2 elevation was not associated with a fall of cardiac lactate extraction. The resting and CPT-induced TXB2 gradients were unrelated to the presence and severity of coronary angiographic lesions. These results indicate that unstable angina patients show an abnormal cardiocoronary capacity to synthesize TXA2, which seems not to be elicited by the occurrence of myocardial ischemia.     

Intravenous infusion of a selective inhibitor of thromboxane A2 synthetase in man: influence on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation

The effect of the selective thromboxane A2 synthetase inhibitor OKY-1581, a pyridine derivative [sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methyl-2-propenoate], on thromboxane B2 and 6-keto-prostaglandin F1 alpha levels and platelet aggregation was studied in human volunteers. To clarify its effectiveness as an enzyme inhibitor, OKY-1581, at doses of 17, 83, 167, 417, 833, and 1667 micrograms/kg (n = 5 for each group), was injected intravenously, or was infused (10 micrograms/kg/min; n = 5) over 3 hr on 3 successive days. OKY-1580 (OKY-1581 free acid) was rapidly converted to its main beta-oxidized product, OKY-1565, and its reduced form, OKY-1558. During the study, plasma thromboxane B2 levels, inhibition of thromboxane B2 production in serum, and inhibition of rabbit platelet thromboxane A2 synthetase were monitored continuously. Twenty-five minutes after the injection of the above doses, plasma thromboxane B2 levels decreased by 4 +/- 7%, 40 +/- 14%, 57 +/- 7%, 68 +/- 6%, 93 +/- 5%, and 96 +/- 5% (mean +/- SD), respectively. Thromboxane B2 production in serum was decreased by 2 +/- 8%, 70 +/- 10%, 75 +/- 8%, 81 +/- 10%, and 96 +/- 8%, respectively, and rabbit platelet thromboxane A2 synthetase by 2 +/- 7%, 52 +/- 8%, 79 +/- 10%, 80 +/- 9%, 96 +/- 8%, and 95 +/- 7%. These parameters returned to the control levels 24 hr after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thromboxane release in coronary artery disease: spontaneous versus pacing-induced angina

To determine thromboxane A2 release in coronary artery disease, we measured its stable metabolite thromboxane B2 by radioimmunoassay in 20 patients. In 15 patients with stable disease (last angina episode greater than 96 hours before study), coronary venous thromboxane B2 concentrations were lower than in aortic blood (mean 109 +/- 36 vs 194 +/- 40 pg/ml, p less than 0.001). In contrast, in five other patients with spontaneous angina, coronary venous thromboxane B2 concentrations were higher than aortic thromboxane B2 concentrations during the angina episode (mean 1716 +/- 316 vs 875 +/- 388 pg/ml, p less than 0.02). Plasma thromboxane B2 levels were in the normal range (mean 175 +/- 35 pg/ml) in patients with stable angina but significantly (p less than 0.02) higher in patients with spontaneous angina. With atrial pacing to the point of chest pain and/or ECG changes in patients with stable coronary artery disease, aortic thromboxane B2 concentrations increased in 10 of 13 patients (mean 283 +/- 70 pg/ml, p less than 0.02). Coronary venous thromboxane B2 concentrations increased in seven patients at peak pacing rates (mean 223 +/- 76 pg/ml) and in three other patients after termination of pacing. These data indicate that release of thromboxane A2 is much greater during spontaneous angina than with pacing stress in patients with coronary artery disease. Thromboxane A2 released during spontaneous or pacing-induced angina may modulate coronary and systemic vascular tone. Enhanced thromboxane A2 activity may either precede or follow myocardial ischemia and could be a factor in the initiation and propagation of the ischemic episode.     

Effect of OKY-046, a thromboxane A2 synthetase inhibitor, on arachidonate-induced platelet aggregation: possible role of "prostaglandin H2 steal" mechanism

To clarify the mode of action of a selective thromboxane A2 (TXA2) blockade in platelet reactivity, we examined the effect of (E)-3-[4-(1-imidazolylmethyl) phenyl]-2-propenoic acid hydrochloride (OKY-046), a potent TXA2 synthetase inhibitor, on human platelet aggregation induced by arachidonic acid (1 mM) in the absence and presence of aspirin-treated aortic microsomes containing prostacyclin (PGI2) synthetase activity ex vivo. The production of TXA2 and PGI2 in platelet rich plasma was determined by the amounts of their stable catabolites, TXB2 and 6-keto-PGF1 alpha respectively, measured by radioimmunoassay. In the absence of aortic microsomes, OKY-046 (greater than 10(-5) M) produced more than 90% inhibition of TXA2 production, whereas platelet aggregation was less inhibited, about 40% inhibition over control, by OKY-046 in that concentration. In the presence of aortic microsomes, the inhibitory effect of OKY-046 on platelet aggregation was markedly augmented in a dose-dependent manner in proportion to the increment of PGI2 production, which paralleled the OKY-046-induced inhibition of TXA2. These results suggest that a selective TXA2 blockade produces effects on platelet aggregation mainly in dual fashion in the presence of PGI2 synthetase: one is due to mere inhibition of TXA2 synthetase and the other is due to the enhancement of PGI2 production probably involving "prostaglandin H2 (PGH2) steal" mechanism, in which PGH2 accumulated in platelets is partly converted to a substrate of PGI2 synthetase in aortic microsomes to produce PGI2.     

Platelet dysfunction and alteration of prostaglandin metabolism after chronic alcohol consumption

To study the effects of chronic alcohol consumption on platelet functions, the rate of arachidonate-induced platelet aggregation, the production of malondialdehyde in platelets, and plasma levels of prostaglandin endoperoxide metabolites were examined in 88 chronic alcoholics and 24 healthy controls. The rate of platelet aggregation and the production of malondialdehyde in platelets were greater in chronic alcoholics both on admission and 1 week after. However, these alterations returned to the level of healthy controls within 4 weeks of abstinence from alcohol and were independent of the number of circulating platelets. Furthermore, on admission, plasma levels of thromboxane B2 were significantly increased in chronic alcoholics when compared with those of healthy controls (400.8 +/- 36.5 versus 241.7 +/- 28.9 pg/ml plasma; p less than 0.025) and were also significantly correlated with malondialdehyde production in washed platelet debris (r = 0.6049; p less than 0.001). In contrast, plasma levels of 6-keto prostaglandin F1 alpha and prostaglandin E were not altered after chronic alcohol consumption. As a result, the ratio of 6-keto prostaglandin F1 alpha to thromboxane B2 was markedly decreased in chronic alcoholics (0.31 +/- 0.03 versus 0.62 +/- 0.13; p less than 0.001). These results strongly suggest that the imbalance in prostaglandin endoperoxide metabolites is produced by chronic alcohol ingestion. Moreover, a significant correlation was observed between platelet aggregation rate and malondialdehyde production during platelet aggregation (r = 0.559; p less than 0.005). Thus, we conclude that chronic alcohol consumption alters platelet thromboxane metabolism, which is likely associated with the increased ability of platelets to aggregate.     

Augmented thromboxane A2 generation and efficacy of its blockade in acute myocardial infarction

Serial changes in thromboxane B2, a stable catabolite of thromboxane A2, were measured by radioimmunoassay in peripheral plasma of 55 patients with acute myocardial infarction. Twenty two of 31 patients who were admitted within 6 hr after the onset of acute myocardial infarction, exhibited high thromboxane B2 levels (greater than 300 pg/ml plasma) during the first 24 hr, whereas thromboxane B2 levels of 9 patients never exceeded 300 pg/ml during that period. The former cases were associated with a higher frequency of transmural myocardial infarction, accompanying higher cumulative creatine kinase release (1173 +/- 134 mIU/ml, mean +/- SEM), as compared with the latter cases (393 +/- 104 mIU/ml, P less than 0.001). To evaluate the efficacy of selective thromboxane A2 blockade on diminution of propagating acute myocardial infarction, another group of patients (24 cases) showing transmural myocardial infarction were subjected to therapeutic examination employing OKY-1581, a potent thromboxane A2 synthetase inhibitor. Eleven randomly selected patients were treated with an infusion of OKY-1581 (initiated within 6 hr after onset, 2-3 micrograms/kg per min) for 48 hr, while 13 patient served as controls. The treated patients exhibited a precipitous decrease in thromboxane B2 levels, as compared with the controls, returning to the normal range within 12 hr. The creatine kinase release in the treated patients was markedly reduced (978 +/- 97 mIU/ml) as compared with that in the control patients (1295 +/- 95 mIU/ml, P less than 0.05). These results indicate that a marked increase in thromboxane B2 levels is seen during the early phase of transmural myocardial infarction, and that OKY-1581-induced reduction of thromboxane B2 levels is effective in diminishing creatine kinase release. We suggest that an excessive generation of thromboxane A2 is associated with the evolution of transmural myocardial infarction.     

Platelet function during ticlopidine and eicosapentaenoic Acid administration in patients with coronary heart disease

Antiplatelet drugs have been reported to be useful in unstable angina. This study was designed to investigate the effects of simultaneous administration of ticlopidine and eicosapentaenoic acid (EPA) on platelet function in coronary heart disease (CHD) patients. Ticlopidine significantly reduced platelet aggregation induced by ADP and collagen with no effect on arachidonate metabolism. The aggregation responses to collagen, ADP and arachidonate were not altered significantly by EPA (as fish oil) intake whereas thromboxane A(2) formation was reduced, but not completely inhibited. Combined therapy seems to achieve a more marked degree of inhibition of aggregation together with a fall in the urinary excretion of 11-dehydrothromboxane B(2) metabolite. Therefore, in CHD patients ticlopidine therapy plus fish oil administration could be useful to inhibit two different mechanisms (TxA(2)- and ADP-dependent) of platelet activation.     

Platelet activation during thrombolysis and percutaneous transluminal coronary angioplasty in the acute phase of myocardial infarction

To clarify the mechanism of recanalization and reocclusion in thrombolysis and percutaneous transluminal coronary angioplasty (PTCA), the plasma concentrations of beta-thromboglobulin (beta-TG), thromboxane B2 (TXB2) and platelet aggregation adenosine diphosphate (ADP) (2 microM/ml, collagen 2 micrograms/ml) were assessed in 11 normal subjects and in 19 patients with acute myocardial infarction whose infarct-related vessels were recanalized by thrombolysis and/or PTCA. In patients with acute myocardial infarction, the plasma concentrations of beta-TG and TXB2 were significantly higher than those in normal subjects (beta-TG: 128 +/- 132 ng/ml vs 38 +/- 17 ng/ml, TXB2: 131 +/- 154 pg/ml vs 36 +/- 18 pg/ml). Collagen-induced platelet aggregation decreased significantly in patients with acute myocardial infarction; whereas, ADP-induced platelet aggregation showed no significant difference. Infarct-related vessels recanalized by thrombolysis (seven patients: group 1) and PTCA (seven patients: group 2) were patent on the follow-up angiograms. Infarct-related vessels were reoccluded in five patients immediately after PTCA or during the follow-up angiography (group 3). Beta-TG and TXB2 did not change before and after recanalization in groups 1 and 2, but increased significantly after recanalization in group 3 (beta-TG: 155 +/- 185 ng/ml----269 +/- 233 ng/ml, TXB2: 104 +/- 87 pg/ml----169 +/- 91 pg/ml). Platelet aggregation did not differ significantly among the three groups. We concluded that platelets are not activated during thrombolysis and/or PTCA in cases without reocclusion, while platelets are markedly activated during PTCA in cases with reocclusion. Thus, it is suggested that platelet activation plays an important role in the mechanism of reocclusion.     

Sex related differences in platelet function: the effect of aspirin

There is evidence from clinical studies and animal experiments that aspirin has a greater antithrombotic activity in males compared to females. We investigated platelet function in vitro and in vivo in rabbits before and after the administration of a dose of aspirin (5 mg/kg) which inhibited collagen stimulated thromboxane B2 generation. Infusion of collagen into untreated animals resulted in a 38 +/- 4% (m +/- SE, n = 13) decrease in platelet count (assessed by whole blood radioactivity) in the male animals, and a 27 +/- 3% (m +/- SE, n = 13) in the female animals. Pretreatment with aspirin resulted in a significant inhibitory effect in the male but not the female animals (p less than 0.05). The male animals had significantly greater thromboxane B2 generation in vivo than did the female animals following an equal dose of collagen (males, 2.64 +/- 0.7 ng/ml thromboxane B2, n = 14; females, 1.67 +/- 0.4 ng/ml thromboxane B2, n = 15, p less than 0.05). In contrast no sex related difference in the inhibitory effect of aspirin on maximal collagen induced aggregation was found when platelets were studied in vitro. The greater reactivity of male patients in vivo may be accounted for by the observed increase in thromboxane B2 generation. This might also explain the greater thrombotic tendency of males, and the observed difference in the antithrombotic effect of aspirin in males and females.     

Newly developed stenocardia: functional activity of thrombocytes

Platelet function (aggregation, circulating platelet aggregates, platelet factor 4, beta-thromboglobulin, thromboxane B2, 6-keto-PGF1 alpha, platelet count) was evaluated in patients with angina of new onset, as compared to individuals without coronary heart disease, and patients with angina of long standing (28 +/- 4.6 months). Some of the patients with angina of new onset were examined repeatedly 6 to 12 months after the onset of angina. Platelet activity was shown to be significantly higher in patients with stable angina of new onset, as compared to patients with lasting angina, where ADP and serotonin were used as inductors. Platelet aggregation, induced by platelet activation factor and collagen, was similar in all groups. Repeated investigation 6 to 12 months after the first anginal attacks demonstrated that most of platelet functional parameters declined or tended to decline.     

Platelet function in acute respiratory failure

To assess the role of platelets in thrombohemorrhagic complications of acute respiratory failure (ARF), we studied platelet function in 13 ARF patients admitted for intensive care, in six acutely ill intensive care patients without evidence of acute lung injury (non-ARF), and in 10 normal subjects. Platelet counts in ARF and non-ARF patients were similar to the normal range. The bleeding time of the ARF patients (8.5 +/- 0.9 min) was significantly longer (p less than 0.01) than the normal (4.8 +/- 0.2 min) but similar to non-ARF patients (5.4 +/- 0.8 min). The bleeding time prolongations in ARF patients were unrelated to platelet concentration. Platelet aggregation induced by ADP and thrombin was normal in both ARF and non-ARF patient groups. The epinephrine response was impaired in one non-ARF patient and in three ARF patients; collagen-induced aggregation was absent in two ARF patients, with a prolonged bleeding time. Levels of VIII:C and vWF in both groups of patients were similar to the normal level, but VIIIR:Ag levels in ARF patients (407 +/- 45% of normal) were higher (p less than 0.01) than in both non-ARF patients (210% +/- 10%) and normal subjects (106% +/- 4). The electrophoretic mobility of VIIIR:Ag was abnormal in ARF patients. The prolonged bleeding time in ARF patients appears to result from the qualitative and quantitative VIIIR:Ag defect. beta-Thromboglobulin levels were greater (p less than 0.01) in ARF patients (87.6 +/- 6.9 ng/ml; p less than 0.001) than in non-ARF patients (46.2 +/- 3.1 ng/ml) or in normal subjects (25.3 +/- 2.5 ng/ml p less than 0.0001). However, platelet factor 4 plasma levels in ARF patients (18 +/- 1.6 ng/ml) did not differ from those in non-ARF patients (15.0 +/- 3.0 ng/ml), but both were significantly different from normal (6.1 +/- 0.8 ng/ml). Plasma thromboxane B2 (T X B2) levels were not different from normal values in either ARF or non-ARF patients, but 6-keto-PGF1 alpha levels were significantly reduced (p less than 0.01) in ARF patients (215 +/- 43 pg/ml) compared to normal values (381 +/- 34 pg/ml). Non-ARF patients had 6-keto-PGF1 alpha levels (285 +/- 111 pg/ml) midway between the normal values and those of ARF patients. Our results suggest that in vivo platelet activation occurs in ARF. ARF patients have quantitative and qualitative platelet defects that may contribute to thrombotic and hemorrhagic complications.     

Evidence against a platelet cyclooxygenase defect in uraemic subjects on chronic haemodialysis

Defective platelet thromboxane synthesis has been described in uraemia and attributed to a 'functional cyclooxygenase defect'. We have studied platelet aggregation and generation of immunoreactive thromboxane B2 (TXB2) in 11 subjects on a chronic haemodialysis programme. The platelet function abnormality of uraemia was confirmed, maximal aggregation in response to collagen (2 and 4 micrograms/ml) and sodium arachidonate (1.5 and 3.0 mM) being significantly depressed. However, increased platelet aggregation in response to sodium arachidonate 0.75 mM was noted. Due to the reduced haematocrit, the platelet concentration in platelet-rich plasma (PRP) of uraemic subjects was significantly lower than that of controls; when TXB2 generation in PRP adjusted to 200 X 10(9) platelets/l was assessed, no evidence for a defect of cyclooxygenase was found, although reduced synthesis of TXB2 in response to thrombin was noted. Furthermore, increased thromboxane generation by uraemic PRP in response to sodium arachidonate 0.75 mM was detected. We conclude that the mild platelet abnormality in uraemic subjects treated by haemodialysis is not explained by a 'functional cyclooxygenase defect', although an abnormality of thrombin-induced thromboxane synthesis may be present. Furthermore, the tendency to increased aggregation and thromboxane synthesis in response to a low concentration of arachidonic acid may contribute to the thrombotic tendency which is also described in such subjects.     

Coronary sinus blood thromboxane and prostacyclin in spontaneous myocardial ischemia]

The blood levels of 6-keto-PGE1 alpha and thromboxane B2 were measured in the coronary sinus of 15 males during and just after a spontaneous myocardial ischemic episode. The comparison was made in 30 males with coronary heart disease in the presence of exercise-induced angina in whom coronary sinus blood samples were taken during myocardial ischemia provoked by pacing and 6 males suffering from cardialgias without signs of coronary atherosclerosis. The patients with spontaneous anginal attacks had lower baseline 6-keto-PGE1 alpha (179.0 +/- 47.8 pkg/ml) than those with exercise-induced angina (336.0 +/- 65.7 pkg/ml; p less than 0.1). This difference became greater during ischemia (165.0 +/- 49.0 and 350.0 +/- 69.5 pkg/ml, respectively, p less than 0.05) and just after its elimination (166.0 +/- 48.7 and 413.0 +/- 76.0 pkg/ml, respectively, p less than 0.05). Coronary sinus blood thromboxane B2 levels were not substantially different in the presence or absence of myocardial ischemia. Thus, a decrease in the prostacyclin-forming function of the coronary endothelium plays a definite role in the genesis of spontaneous myocardial ischemic episodes.     

Plasma noradrenaline as an index of sympathetic tone in coronary arterial disease: the confounding influence of clearance of noradrenaline

Kinetics of [3H]noradrenaline in the plasma were compared with plasma noradrenaline concentration in assessing overall sympathetic activity in six groups totalling 118 subjects. Arterial plasma noradrenaline in 21 control subjects was 204 +/- 14 pg/ml, similar to 20 patients with stable angina not treated with beta-blockers (194 +/- 25 pg/ml) and to 31 patients with stable angina treated with beta-blockers (232 +/- 19 pg/ml). Plasma noradrenaline was increased in 17 patients with unstable angina (366 +/- 50 pg/ml, P less than 0.01), in 14 patients with recent acute myocardial infarction (460 +/- 44 pg/ml, P less than 0.001) and in 15 patients with treated cardiac failure (582 +/- 78 pg/ml, P less than 0.001). Whole body clearance of noradrenaline from plasma was, however, reduced in each of the last three groups compared to controls by 20% (P less than 0.05), by 34% (P less than 0.01) and by 31% (P less than 0.01), respectively. In the 31 patients with stable angina on beta-blockers, clearance of noradrenaline was also reduced by 20% (P less than 0.05). Whole body noradrenaline spillover, a potentially more accurate measure of overall sympathetic activity than concentration of noradrenaline in plasma, was 235 +/- 20 ng min-1 m-2 in controls, was similar in subjects with stable angina (no beta-blockers; 260 +/- 34 ng min-1 m-2, beta-blockers; 200 +/- 17 ng min-1 m-2), but was increased in patients with unstable angina (310 +/- 27 ng min-1 m-2, P less than 0.05), with recent acute myocardial infarction (346 +/- 40 ng min-1 m-2, P less than 0.05) or with heart failure (438 +/- 65 ng min-1 m-2, P less than 0.01). Overall sympathetic activity is unchanged in stable angina, but is progressively increased in patients with unstable angina, recent myocardial infarction or heart failure. Plasma concentration of noradrenaline fails accurately to reflect this as a result of decreased clearance of noradrenaline in these patients. The results show the potential limitations of measurement of noradrenaline in the plasma as an index of overall sympathetic activity and the importance of assessing clearance.