Haemodynamic actions of a novel sino-atrial node function modulator, ZENECA ZD7288, in the anaesthetized dog: a comparison with zatebradine, atenolol and nitrendipine.
1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows sinus node rate. Its effects on haemodynamic function have been studied in pentobarbitone anaesthetized dogs, in comparison with zatebradine, atenolol and nitrendipine. 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 dPLV/dtmax and right ventricular free wall developed force) decreased along with rate. Stroke volume increased as rate 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 reduction 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 reduced from 149 to 60.5 beats min-1 over the dose-range 0.02 to 1.0 mg kg-1, i.v.), except that dPLV/dtmax did not decrease with heart rate and increased during arial pacing. 5. Neither ZD7288 nor zatebradine had significant effects on atrio-ventricular conduction at intrinsic 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 with removal of beta-sympathetic cardiac drive. Atrial pacing was found not to restore the pre-atenolol heamodynamic state completely. 7. Nitrendipine up to 0.2 mg kg- 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 the effects of vasodilatation, but caused atrio-ventricular conduction block at doses above 0.5mgkg-1, i.v.8.data show ZD7288 has marked heart rate slowing properties and that accompanying haemodynamic changes appear to be secondary to the rate changes, being reversed by atrial pacing even in the continued presence of the drug. Heart rate slowing without depression of contractile function should prove to be of benefit in the treatment of myocardial ischaemia, particularly in the presence of myocardial dysfunction.
Vascular Inflammatory and Musculoskeletal Research Dept., ZENECA Pharmaceuticals, Alderley Park, Macclesfield, Cheshire.
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D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D009568:Nitrendipine / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects* / Q000502:physiology
D001552:Benzazepines; D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D011743:Pyrimidines; C082246:ICI D2788; D001262:Atenolol; D009568:Nitrendipine; C043636:zatebradine