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1 Atenolol 0.2 mg/kg i.v., propranolol 0.2 mg/kg i.v. or placebo were given in a double‐blind crossover study to six healthy male subjects, and the effects of a subsequent infusion of epoprostenol (prostacyclin, PGI2) 0‐6 ng kg‐1 min‐1 monitored. 2 PGI2 caused a tachycardia, a fall in diastolic blood pressure, a rise in pulse pressure, reduction in pre‐ ejection period (PEP) and rise in left ventricular ejection time index (LVETI), headache and facial flushing at doses of PGI2 greater than 2 ng kg‐1 min‐1, (P less than 0.05). 3 Beta‐adrenoceptor blockade did not prevent the tachycardia in response to PGI2, and did not interact with any of the other dynamic effects of PGI2. 4 In vitro, PGI2 at 1 and 2 ng/ml inhibited platelet aggregation to ADP (P less than 0.01), although no significant effect on platelet aggregation was seen in the in vivo study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect this in vitro study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect in vitro effect of PGI2 on platelet aggregation. 5 Pretreatment with atropine 0.04 mg/kg i.v. in three subjects did not attenuate the tachycardia caused by PGI2 infusion, even though the baseline heart rate was increased. 6 Adverse effects to PGI2 infusion included sudden bradycardia, pallor and sweating, suggesting that the Bezold‐Jarisch reflex seen in animals in response to PGI2 may also occur in humans. 7 Neither increased sympathetic drive nor vagal withdrawal are likely causes of the tachycardia following PGI2 infusion.

The effects of 9 beta‐methyl carbacyclin, a chemically stable analogue of epoprostenol (prostacyclin, PGI2) were studied, in comparison with epoprostenol, both in vitro and in vivo in man. In vitro 9 beta‐methyl carbacyclin and epoprostenol inhibited platelet aggregation induced by ADP, collagen, the endoperoxide analogue U46619 and arachidonic acid. The potency of 9 beta‐methyl carbacyclin relative to epoprostenol was comparable in ADP and collagen‐aggregated platelet rich plasma (PRP), 9 beta‐methyl carbacyclin being 0.01 times as active as epoprostenol. The anti‐aggregatory potencies of the two compounds were comparable in PRP and whole blood. The phosphodiesterase inhibitor isobutyl methyl xanthine enhanced the anti‐aggregatory activity of both compounds in vitro. 9 beta‐methyl carbacyclin and epoprostenol elevated platelet cyclic AMP, 9 beta‐methyl carbacyclin being 0.04 times as active as epoprostenol. In a placebo controlled trial both drugs produces significant headache and facial flushing when compared with placebo. Nasal stuffiness, abdominal discomfort and nausea were reported on all three treatments. Both drugs caused significant and comparable increase in heart rate and decrease in pre‐ejection (PEP) and PEP/left ventricular ejection time (LVET) ratio compared with placebo. Systolic and diastolic blood pressure, LVET and QS2 index were unchanged. Platelet aggregation responses to ADP were significantly inhibited by all three doses of both drugs compared with placebo. Bleeding time was significantly longer during epoprostenol infusion than either placebo or 9 beta‐methyl carbacyclin infusion. Neither drug had significant effect, compared with placebo, on kaolin activated clotting time in PPP, PRP or in PRP in the presence of heparin, prothrombin time, partial thromboplastin time, thrombin clotting time, fibrinogen, fibrinogen degradation products or euglobulin clot lysis time. The pharmacodynamic effects and duration of action of 9 beta‐methyl carbacyclin and of epoprostenol are similar; 9 beta‐methyl carbacyclin is approximately 100 times less potent than epoprostenol in man.