HEMODYNAMIC ACTIONS OF A NOVEL SINOATRIAL NODE FUNCTION MODULATOR, ZENECA ZD7288, IN THE ANESTHETIZED DOG - A COMPARISON WITH ZATEBRADINE, ATENOLOL AND NITRENDIPINE

1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)- 1,2-dimethyl-6-(methylamin o) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial n ode function modulator which selectively slows sinus node rate. Its ef fects on haemodynamic function have been studied in pentobarbitone ana esthetized dogs, in comparison with zatebradine, atenolol and nitrendi pine. 2 ZD7288 lowered heart rate in the dose-range 0.02 to 1.0 mg kg( -1) i.v. from 152 to 77 beats min(-1). Myocardial contractile function (measured as both dP(LV)/dt(max) and right ventricular free wall deve loped force) decreased along with rate. Stroke volume increased as rat e decreased. Cardiac output decreased at doses in excess of 0.2 mg kg( -1), i.v. 3 These haemodynamic changes were reversed when heart rate r eduction was reversed by atrial pacing and are, therefore, considered to be indirect consequences of heart rate changes induced by ZD7288. 4 The effects of zatebradine paralleled those of ZD7288 (heart rate red uced from 149 to 60.5 beats min(-1) over the dose-range 0.02 to 1.0 mg kg(-1), i.v.), except that dP(LV)/dt(max) did not decrease with heart rate and increased during arial pacing. 5 Neither ZD7288 nor zatebrad ine had significant effects on atrio-ventricular conduction at intrins ic heart rates, but both significantly and dose-dependently prolonged the atrio-ventricular conduction interval during atrial pacing at 180 beats min(-1). 6 The observed effects of atenolol were commensurate wi th removal of beta-sympathetic cardiac drive. Atrial pacing was found not to restore the pre-atenolol haemodynamic state completely. 7 Nitre ndipine up to 0.2 mg kg(-1) i.v. induced changes indicative of direct vasodilatation accompanied by reflex compensation, followed by cardiac depression at higher doses. Atrial pacing failed to compensate for th e effects of vasodilatation, but caused atrio-ventricular conduction b lock at doses above 0.5 mg kg(-1), i.v. 8 The data show ZD7288 has mar ked heart rate slowing properties and that accompanying haemodynamic c hanges appear to be secondary to the rate changes, being reversed by a trial pacing even in the continued presence of the drug. Heart rate sl owing without depression of contractile function should prove to be of benefit in the treatment of myocardial ischaemia, particularly in the presence of myocardial dysfunction.