Proeta8landin.s Leukotrienes and Medicine 17: 147-148, 1985

THE STABLE PROSTACYCLIN ANALOGUE ILOPROST ALLEVIATES CAROIOVASCULAR SYMPTOMS OF SYSTEMIC ANAPHYLAXIS IN ANAESTHETIZED CATS

Bernd Milller, Bernhard MaaB and Martin Haberey Research Laboratories of Schering AG, MBllerstraHe 170-178, D-1000 Berlin 65 (West), FRG

Introduction. Animal studies have shown, that activation of platelets and subsequent release of vasoactive and aggregation-inducing platelet contents are major contributing factors to cardiovascular and pulmonary dysfunction in systemic anaphylaxis (1,2). Consequently, prosta- cyclin (PGI2) which potently inhibits platelet activation and aggregation and promotes re- dispersion of aggregates (31, can be expected to alleviate cardiovascular symptons of ana- phylaxis. Therefore, the effects of Iloprost, a chemically stable PGI2 analogue with a pharmacological profile closely resembling PG12 (A), on cardiovascular consequences of systemic anaphylaxis were investigated in anaesthetized cats.

Materials and methods. Cats weighing 3.6 - 5.0 kg were anaesthetized with 70 mg/kg cr-Chloralose i.v. and given heparine (450 I.U. i.v.>. Rectal body temperature and blood gases were monitored. Pulmoflex catheters were introduced into the inferior jugular vein and pulmo- nary artery (via right jugular vein), a polyethylene catheter into one femoral vein and a thermistor probe into the abdominal aorta (via right femoral vein and -artery), and tip mano- meter catheters into the left ventricle of the heart and the thoracic aorta (via left carotid and axillary arteries). An electromagnetic flow probe was placed around the right carotid artery. Arterial, pulmonary arterial, central venous, and left ventricular blood pressures and left ventricular dp/dtmax, ECG and carotid blood flow were monitored continuously. Cardiac output was determined with the thermodilution method. Serial blood samples for count of circulating platelets (Technicon autocounter) were drawn from the aortic catheter. Cats were passively presensitized with rabbit anti chicken ovalbumin-serum (Behring Institute, 0.2 ml/kg i-v.) followed by antigen challenge with 50 pg/kg ovalbumin i-v. 60 min thereafter. Iloprost or vehicle (0.9 % NaCl + 0.125 % NaHCO3) were continuously infused i-v. starting 30 min before antigen challenge.

Results and discussion. Before antigen challenge, i-v. infusion of Iloprost at 0.2 pg/kg/ min had no effect on cardio- and haemodynamics, while 1.0 ug/kg/min slightly lowered total peripheral resistance and pulmonary arterial pressure and -resistance, and marginally in- creased cardiac output. Antigen challenge in vehicle-treated cats within 2-5 min led to transient profound arterial hypotension, decrease of carotid blood flow, sharp increases in pulmonary arterial pressure and -resistance as well as central venous pressure, and cardiac depression with decreases of cardiac contractility and cardiac output and rise of left ventricular filling pressure. Ini- tially, frequent ventricular ectopic beats were observed in all animals. As demonstrated by the results shown in Figure 1, Iloprost in a dose-dependent manner attenuated the cardio- vascular consequences of systemic anaphylaxis. Arrhythmias were observed in 3 out of 6 and

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only 1 out of 6 animals with Iloprost at 0.2 and 1.0 ug/kg/min, respectively. In vehicle- treated cats, circulating platelet count initially decreased by more than 80 % and did not entirely recover during the 120 min observation period. With Iloprost, the initial thrombo- cytopenia was only moderately attenuated. As also concluded from findings in guinea pig ana- phylaxis (51, this suggests that initial anaphylactic thrombocytopenia is at least partly beyond the control of PGIZ-like platelet effects. However, in contrast to vehicle-treated cats, with Iloprost platelet count rapidly and completely returned to normal which is in favour of a beneficial effect mediated by PGIZ-like effects on the extent of platelet activa- tion and/or size of platelet aggregates and velocity of aggregate redispersion.

Fig. I: Effects of Iloprost on cardiovascular and thrombocytopenic responses to ovalbumin injection in passively presensitized anaesthetized cats (N = 6 per group). Columns in the upper part represent mean percent maximum changes + s.e.m. after antigen challenge, while the lower part shows the course of circulating platelet count. Asterisks indicate significant differences from vehicle group (p 5 0.05; rank sum test).

References

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2. Bunting S, Castro S, Salmon JA, Moncada S. The effect of cyclooxygenase and thromboxane synthetase inhibitors on shock induced by injection of heterologous blood in cats. Thrombosis Research 30: 609, 1983

3. Aiken JW, Shebuski RJ. Comparison in anaesthetized dogs of the antiaggregatory and hemo- dynamic effects of prostacyclin and a chemically stable prostacyclin analogue, 6cr-carba- PGI2. Prostaglandins 19: 629, 1980

4. Casals-Stenzel J, Buse M, Losert W. Comparison of the vasodepressor action of ZK 36 374,a stable prostacyclin derivate, PGIR and PGEl with their effect on platelet aggregation and bleeding time in rats. Prostaglandins Leukotrienes and Medicine IO: 197, 1983

5. Vargaftig BB, Lefort J. Differential effects of prostacyclin and PGEl on bronchoconstric- tion and thrombocytopenia during collagen and arachidonate infusion and anaphylactic shock in the guinea pig. Prostaglandins 18: 519, 1979

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