Increased cardiac workload by adrenoceptor agonists for the estimation of potential antiischemic activity in a conscious rabbit model

Abstract

The antiischemic effect of drugs can be detected at a lower dose range if the cardiac workload is increased. A brief period of frequency-loading (ventricular overpacing = VOP) results in well-defined, reproducible changes in cardiac parameters in the conscious, chronically instrumented rabbit; however, rapid pacing frequently evoked ventricular tachycardia or even fatal ventricular fibrillation. Therefore, cardiac workload has been increased by i.v. administration of adrenoceptor agonists, such as isoproterenol (ISO), phenylephrine (PHE), and their combination, respectively. The doses applied (especially the combination of 2 μg/kg ISO and 16 μg/kg PHE, giving optimal changes) were sufficient to produce a marked elevation of both the ST segment in the intracavital electrogram and the left ventricular end-diastolic pressure, without evoking cardiac arrhythmias. We compared the effect of this adrenergic “test” stimulus with that of VOP on hemodynamic and electrophysiological parameters of the heart, and furthermore, on the modification of responses to both “test” stimuli by oral administration of the coronary vasodilator: Isosorbide-5-mononitrate (IS-5-N), given in a dose of 40 mg/kg. Both VOP- and ISO+PHE-induced changes were significantly attenuated by IS-5-N, and a temporal coincidence of the maximal effects was found as well. We reached the following conclusion: The combined administration of ISO and PHE not evoking fatal arrhythmias in the dose range applied can replace the more risky VOP as a “test” workload in the estimation of antiischemic action.