A pattern analysis of inotropic actions was carried out on isotonically chortening cat papillary muscles exposed to (+/-)-verapamil and (+/-)-D 600 and compared to other Ca-antagonistic interventions. 1. (+/-)-Verapamil (1--5mug/ml) leaves contraction amplitudes nearly unchanged at 6/min, whereas at 60/min more than 90% depression (5 mug/ml) occurs. (+/-)-D 600 is about twice as effective as (+/-)-berapamil. 2. An increase of [Ca2+]O in the presence of (+/-)-verapamil or (+/-)-D 600 does not restitute the normal amplitude-frequency relationship. There is only a shift toward higher contraction amplitudes. 3. (+/-)-Verapamil and (+/-)-D 600 lead to typical biphasic inotropic transients after step changes of the friving rhythm. First a fast and (at higher frequencies) very pronounced negative staircase occurs, followed by a rather slowly developing positive staircase. 4. These drug effects contrast to the effects of lowering [Ca2+]O or of adding Ni2+ or La3+, which all produce a rather uniform depression of contraction amplitudes at all frequencies and do not elicit staircase phenomena such as seen under the influence of (+/-)-verapamil or (+/-)-D 600. 5. In contrast to the action of Ni2+, La3+ or low [Ca2+]O, (+/-)-verapamil slows down the restitution kinetics of Ca-reavailability from internal stores as determined by the amplitude of test contractions elicited after various periods of rest. 6. Drug-induced changes in the time course of the transmembrane action potential as depending on frequency may partially but not fully explain the contractile phenomena. 7. Possible interpretations as to the sites where (+/-)-verapamil or (+/-)-D 600 interferes with cardiac excitation-contraction coupling are given by the aid of a multicompartment model. This model describes excitation-contraction coupling in terms of transmembrane and intracellular Ca-movements.

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Background/Aims: Common systems for the quantification of cellular contraction rely on animal-based models, complex experimental setups or indirect approaches. The herein presented CellDrum technology for testing mechanical tension of cellular monolayers and thin tissue constructs has the potential to scale-up mechanical testing towards medium-throughput analyses. Using hiPS-Cardiac Myocytes (hiPS-CMs) it represents a new perspective of drug testing and brings us closer to personalized drug medication. Methods: In the present study, monolayers of self-beating hiPS-CMs were grown on ultra-thin circular silicone membranes and deflect under the weight of the culture medium. Rhythmic contractions of the hiPS-CMs induced variations of the membrane deflection. The recorded contraction-relaxation-cycles were analyzed with respect to their amplitudes, durations, time integrals and frequencies. Besides unstimulated force and tensile stress, we investigated the effects of agonists and antagonists acting on Ca²⁺ channels (S-Bay K8644/verapamil) and Na⁺ channels (veratridine/lidocaine). Results: The measured data and simulations for pharmacologically unstimulated contraction resembled findings in native human heart tissue, while the pharmacological dose-response curves were highly accurate and consistent with reference data. Conclusion: We conclude that the combination of the CellDrum with hiPS-CMs offers a fast, facile and precise system for pharmacological, toxicological studies and offers new preclinical basic research potential.