The cardiovascular pharmacology of ICI 170777 ((6RS)−6‐methyl‐5‐(pyrid‐4‐yl)−3H,6H‐1,3,4‐thiadiazin‐2‐one) a novel compound with positive inotropic and vasodilator effects

• Published in: British journal of pharmacology 1989-06, Vol.97 (2), p.409-418
• Main Authors: Collis, M.G., Keddie, J.R., Rouse, W.
• Format: Article
• Language: English
• Subjects: Anesthesia; Animals; Biological and medical sciences; Cardiotonic agents; Cardiovascular system; Cats; Dogs; Female; Heart Rate - drug effects; Hemodynamics - drug effects; Hindlimb - blood supply; In Vitro Techniques; Isoproterenol - pharmacology; Male; Medical sciences; Myocardial Contraction - drug effects; Papillary Muscles - drug effects; Pharmacology. Drug treatments; Pyridines - pharmacology; Regional Blood Flow - drug effects; Stimulation, Chemical; Thiadiazines - pharmacology; Thiazines - pharmacology; Vascular Resistance - drug effects; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1989.tb11968.x

1 This paper describes the cardiovascular effects of ICI 170777, a novel compound which enhances cardiac contractility and causes arterial and venous dilatation. 2 The positive inotropic effects of ICI 170777 on the heart were demonstrated by an increase in left ventricular dP/dtmax in the anaesthetized and conscious dog, and by an increase in tension development in isolated papillary muscles from the cat. 3 In the anaesthetized dog, the positive inotropic effects of ICI 170777 and of isoprenaline were attenuated by atenolol (5 mg kg−1, i.v.). Atenolol displaced the dose‐response curve to ICI 170777 to the right by 4 fold but displaced the isoprenaline dose‐response curve to the right by 247 fold. In vitro, however, atenolol (10 μm) had no significant effect on the positive inotropic response to ICI 170777. In the ganglion‐blocked anaesthetized dog, infusion of a low dose of ICI 170777 which had no effect on the basal left ventricular dP/dtmax, selectively potentiated the positive inotropic effects of isoprenaline. These results indicate that ICI 170777 has both a non‐adrenoceptor‐mediated positive inotropic effect on the heart and also facilitates the β‐adrenoceptor‐mediated control of contractility. 4 In the denervated and perfused hind‐limb of the dog, ICI 170777 reduced arterial perfusion pressure and increased limb circumference at a constant arterial flow and venous pressure. This indicates that ICI 170777 has direct dilator actions on both arterial and venous vessels. In this preparation, diazoxide exerted an arterial selective vasodilator effect and sodium nitroprusside was a relatively selective venous dilator. ICI 170777 exhibited a balanced arterial and venous dilator effect which was intermediate in profile between that of diazoxide and that of sodium nitroprusside. 5 In the conscious dog, low doses (2–5 mg kg−1, orally) of ICI 170777 evoked an increase in left ventricular dP/dtmax with no significant effect on heart rate or blood pressure. At a higher dose (10 mg kg−1, orally) it also reduced blood pressure and caused a significant increase in heart rate. The duration of the positive inotropic effect of 5 mg kg−1 (orally) of ICI 170777 was 10–12 hours. This response did not diminish following repeated administration of the compound. 6 The positive inotropic action and balanced arterial and venous dilator effect of ICI 170777 indicate that the compound may be useful in the treatment of congestive heart failure, a disorder that is characterized