15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Angina-Pectoris

The effect of the specific thromboxane receptor blocking drug AH23848 was investigated in two double blind placebo controlled studies in male patients with exercise induced angina pectoris and angiographically verified coronary lesions. In the first study cardiac pacing was performed in twenty patients after coronary angiography. Patients were then randomised into two groups and received either AH23848 (70 mg orally) or placebo. One hour later cardiac pacing was repeated. Neither treatment had any significant effect upon time to angina or the rate-pressure product at the onset of chest pain in these patients. In the second study twenty male patients were randomised to seven days' treatment with AH23848 (70 mg three times a day) or placebo followed by a crossover to the other treatment for a further seven days. Clinical assessment was performed before treatment and at the end of each treatment period. There was no significant difference between the placebo and AH23848 treatment periods in exercise tolerance, the rate-pressure product at angina after exercise testing, the number of ischaemic attacks as determined from 24 hour ambulatory electrocardiograms, the number of attacks of pain, or the number of glyceryl trinitrate tablets consumed. This lack of a clinical effect with AH23848 was seen despite a profound inhibition of ex vivo platelet aggregation stimulated by the thromboxane A2-mimetic U-46619. Because in experimental animals in vivo AH23848 blocks vascular thromboxane receptors as well as platelet thromboxane receptors the lack of effect of AH23848 in cardiac pacing and exercise induced angina is unlikely to be the result of inadequate blockade of thromboxane receptors. The lack of effect of the drug is more likely to indicate that thromboxane A2, is not a factor in the aetiology of the pain experienced by these patients during exercise or cardiac pacing.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Angina Pectoris; Biphenyl Compounds; Clinical Trials as Topic; Double-Blind Method; Humans; Male; Middle Aged; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Random Allocation; Receptors, Prostaglandin; Receptors, Thromboxane

The thromboxane A2 receptor agonist, U-46619 ((5Z, 9 alpha, 11 alpha, 13E, 15(S))-9,11-(methanoepoxy)prosta-5,13-dien-1-oic acid) (10 micrograms/kg), induced a typical ischemic change (ST elevation) in the electrocardiogram on intracoronary arterial administration in the rat. The elevation of the ST segment induced by U-46619 was significantly reduced by pretreatment with anti-endothelin-1 rabbit serum. The plasma concentration of endothelin-1 dose dependently increased at the time of ST segment elevation after U-46619. These results indicate that endogenous endothelin-1 partly contributes to coronary spasmodic angina induced by thromboxane A2 in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angina Pectoris; Animals; Electrocardiography; Endothelins; Injections, Intra-Arterial; Male; Myocardial Ischemia; Prostaglandin Endoperoxides, Synthetic; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Adult; Angina Pectoris; Coronary Disease; Humans; Middle Aged; Platelet Adhesiveness; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2

Platelet prostaglandin generation (malondialdehyde production) and platelet sensitivity to prostacyclin (a vasodilator and platelet aggregation inhibitor) and to epoxymethanodienoic acid (EMA) (a vasoconstrictor and platelet aggregation stimulant endoperoxide analog) were studied in patients with angina pectoris and in control subjects. Platelet malondialdehyde production was higher in patients than in control subjects (mean +/- standard error of the mean 2.50 +/- 0.30 versus 1.70 +/- 0.13 nmol/10(9) platelets, p < 0.02). Platelets from patients were significantly less sensitive to prostacyclin's antiaggregatory effects than were those from control subjects (amount of prostacyclin required for 50 percent platelet aggregation inhibition 1.90 +/- 0.35 versus 0.68 +/- 0.05 ng, p < 0.02). Furthermore, less EMA was required to induce 50 percent platelet aggregation in patients with angina pectoris than in the normal subjects (133 +/- 8 versus 194 +/- 16 ng, p < 0.001). These observations suggest that increased platelet prostaglandin generation and abnormal platelet sensitivity to prostacyclin and endoperoxide analog in certain patients with coronary artery disease are important potential mechanisms in the pathogenesis of myocardial ischemia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Angina Pectoris; Blood Platelets; Coronary Disease; Epoprostenol; Humans; Malondialdehyde; Middle Aged; Platelet Function Tests; Prostaglandin Endoperoxides, Synthetic; Prostaglandins