In vivo pharmacological studies with SK&F 94836, a potent inotrope/vasodilator with a sustained duration of action

Abstract

4 The inodilator activity of SK&F 94836 in conscious and anaesthetized animals occurred in association with minimal changes in either blood pressure or heart rate. 5 Detailed studies carried out on anaesthetized cats indicated that SK&F 94836 caused a balanced dilatation of both resistance and capacitance blood vessels. 6 Haemodynamic studies in anaesthetized cats indicated that as a consequence of the inotropic/ vasodilator actions, SK&F 94836 caused significant increases in cardiac output and stroke volume. 7 Detailed studies in anaesthetized dogs indicated that significant inodilator activity occurred in the absence of an increase in myocardial oxygen consumption. 8 The duration of action of SK&F 94836 was sustained following both i.v. and oral administration. 9 We conclude that SK&F 94836, as an orally active inotropic/vasodilator agent with a sustained duration in vivo, has potential utility in the treatment of congestive heart failure.

Characterization of Coronary Arterial Lesions in the Dog Following Administration of SK&F 95654, a Phosphodiesterase III Inhibitor

“…Direct evidence for an effect on vascular wall tension is not available in the dog, although significant increases in coronary blood flow is a characteristic feature of the pharmacology of vasodilators inducing coronary arteriopathy. This is the case for minoxidil (7), hydralazine (3), dopamine (11), and the PDE III inhibitors SK&F 94836 and CI 914 (5,19). Although the arteriopathy following vasodilator administration may be related to the prolonged hemodynamic effects of these compounds, the exact relationships have as yet not been established and await further investigation.…”

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

“…It has been postulated that these lesions are the result of disturbances in critical wall tension due to vasodilator-related relaxation of the medial smooth muscle (23,33,34). Direct evidence of an effect on vascular wall tension is not available for many of the vasodilators reported to induce vascular lesions, but increased coronary blood flow has been demonstrated for minoxidil (21,33), hydralazine (9), endothelin receptor antagonist (32), and PDE III inhibitor SK&F 94836 (15).…”

The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function

“…Methods Siguazodan ((SK&F 94836) R,S-2-cyano-1-methyl-3-[4-(-methyl-6-oxo-1,4,5,6 tetrahydropyridazine-3-yl)phenyl]-guanidine), is a potent, selective inhibitor of guanosine 3': 5'-cyclic monophosphate (cyclic GMP)-inhibited cyclic nucleotide phosphodiesterase, (cGI-PDE (Beavo 1988), sometimes referred to as phosphodiesterase III), that has positive inotropic and vasodilating actions in various laboratory animals and is orally active with a long duration of action in conscious dogs (Gristwood et al, 1988). These properties suggested a utility in cardiac failure and siguazodan has undergone initial evaluation in man.…”