The cardiotoxicity and haemodynamic changes induced by IV administration of high doses of SK&F 94120, a novel positive inotrope/vasodilator, were studied in the dog. Inotropism was observed at a dose of 0.375 mg/kg. Mean blood pressure was reduced in a dose-related manner, reaching a nadir of 43.7 mm Hg at 24 mg/kg. Heart rate was increased at doses of 1.5 mg/kg and above. ECG examination revealed a shortening of PR interval and an increase in T-wave amplitude. At doses of 15 mg/kg and above, occasional AV dissociation with accrochage were sometimes seen shortly after the start of the infusion. Ventricular extrasystoles were only seen at doses of 120 mg/kg and above. A dose-related increase in severity and incidence of haemorrhages, deposition of haemosiderin and fibroplasia were seen in the left ventricular endocardium and atrioventricular valves at doses of 15 mg/kg and above. Focal myocardial necrosis, predominantly of the left ventricular papillary muscle, and mild periarteritis of medium-sized extramural arteries, mostly in the right atrium, were seen at doses of 45 mg/kg and above. Intimal proliferation of intra- and extramural coronary vessels was observed. A necrotising peri/panarteritis of these arteries was noted at doses of 200 and 400 mg/kg. The cardiotoxicity observed was considered to be due to the exaggerated pharmacologic effects seen at these high dose levels.
The pharmacological properties of SK&F 94120 on the cardiovascular system have been studied in laboratory animal species. The compound was shown to have positive inotropic activity on hearts from guinea-pig, cat, dog and marmoset in-vitro and in cat and dog in-vivo. These responses in-vivo occurred in association with minimal changes in heart rate. Positive inotropic activity was not caused by SK&F 94120 in rat or hamster hearts in-vitro, thereby indicating a species dependence in myocardial response. SK&F 94120 was shown to have vasodilator activity in cats in-vivo. Detailed studies carried out on anaesthetized cats indicated that the compound caused a balanced dilatation of both resistance and capacitance blood vessels. Haemodynamic studies in anaesthetized cats indicated that, as a consequence of the positive inotropic and vasodilator actions, SK&F 94120 causes significant increases in cardiac output and stroke volume. Studies in conscious dogs showed the compound to be active as a positive inotrope after oral administration. The above properties suggest that this compound possesses useful haemodynamic properties for the treatment of congestive heart failure.
SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts AL6 9AR 1 SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 g1M. The IC50 values were greater than 100 1M for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 1M) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 LM). 2 In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3 Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dpldtM,, in the range 10-50 tg kg-'. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtma, were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4 SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (ICm = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5 The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets. 6 Collagen-induced aggregation of rat PRP was also inhibited by SK&F 95654 (ICso = 65 nM). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg-', SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI-PDE inhibitors studied (siguazodan and SK&F 94120). 7 In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine-or U46619-induced bronchoconstriction in the anaesthetized, ventilated guinea-pig. 8 Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.
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