Klin Wochenschr (1988) 66:1 6 Kiinische Wochen- schrift © Springer-Verlag 1988 )bersicht The Effectiveness of Inotropic Agents in Isolated Cardiac Preparations from the Human Heart E. Erdmann Medizinische Klinik I der Universit~it Miinchen, Klinikum GroBhadern, Mtinchen Summary. This review analyses the present knowl- edge on differences in human and animal heart preparations in respect to positive inotropic stimu- lation. The pharmacological effects of new positive inotropic drugs usually are evaluated in cardiac preparations from healthy and young animals. Hu- man myocardium, especially from patients with heart failure has, however, distinctly different properties in respect to the positive inotropic effec- tiveness of several agents. This fact prohibits the extrapolation of results of experiments in laborato- ry animals to the diseased human heart. The partial ineffectiveness of several established positive ino- tropic substances in papillary muscles from failing human hearts indicates a membrane defect not present in healthy animal myocardium. Key words: Human heart - Positive inotropism - fl-Adrenoceptors - Phosphodiesterase inhibitors It is generally accepted that positive inotropic agents in mammalian cardiac muscle enhance the intracellular Ca 2÷ concentration, increase the responsiveness of the contractile apparatus to cal- cium, or exert both types of effects [14]. Apart from a few substances that have been shown to increase calcium sensitivity of the contractile pro- teins [2], the maiority of drugs lead to an increased intracellular Ca 2 ÷ concentration. The subcellular mechanism of action of many of these drugs is well known (Fig. 1). They either lead to an in- creased activity of adenylate cyclase and hence in- Abbrev&tions: db-cAMP: dibutyryl-cyclic-adenosine-mono- phosphate; DPI 201-106: 4-(3~(4-diphenyl-methylpiperazine-]- yl)-hydroxypropoxy)- 1H-indole-2-carbonitril;IBMX: 3-isobu- tyl-I-methyl-xanthine tracellular cAMP production (e.g., fl-adrenoceptor agonists, histamine, glucagon), a decreased cAMP breakdown by inhibition of phosphodiesterase (e.g., theophylline, IBMX, milrinone, amrinone), inhibition of (Na ÷ + K ÷)-ATPases (cardiac glyco- sides), increased Ca 2+ influx by activating Ca 2 ÷ channels (Bay K 8644) or by increasing the Na + influx (DPI 201-106) [2]. If all these different mechanisms have a final common pathway, i.e., the increase of intracellular Ca 2÷ concentration, one would expect that the maximal positive inotropic effects of these drugs are similar in cardiac muscle. In fact, in experi- ments on isolated, electrically stimulated papillary muscles from several animal species, it has been shown the maximal increase of force of contraction by Ca 2+, dobutamine, dopamine, isoprenaline, milrinone, theophylline, IBMX, histamine, di- goxin, ouabain, and Bay K 8644 are similar [5]. This indicates a similar effectiveness of those drugs under identical conditions. After a maximal posi- tive inotropic effect had been elicited by one drug (for instance, dobutamine) addition of any other positive inotropic agent did not augment force of contraction further, but led instead to arrhythmia or contracture [5]. Thus, the maximal positive ino- tropic effect seems to depend on a definite intracel- lular Ca 2 ÷ concentration, which cannot be further increased without negative side effects and maxi- mal force of contraction can be achieved by any of the drugs mentioned above - irrespective of the exact mechanism involved (Table 1). These results, obtained in animal experiments, are not consistent with practical clinical experi- ence. It is well known, that the heart in myocardial failure gets resistant to the inotropic effects of some drugs (for instance dobutamine [17]). In the past, the reduced sensitivity of the human cardiac