Overall cardiac functional effect of positive inotropic drugs with differing effects on relaxation

Recent interest in so-called calcium-sensitizing positive inotropic drugs h as highlighted the potential problem of a positive effect on force developm ent being offset, at least partially, by the negative effect that many of t hese drugs have on relaxation. The purpose of this study was to examine the interplay of contraction and relaxation in determining the overall cardiac effect of different positive inotropic drugs. Using a buffer-perfused isol ated rabbit heart preparation, we studied four drugs (calcium, dobutamine, EMD 57033, and CGP 48506) that were given at doses sufficient to increase s imilarly left ventricular pressure-generating capability by similar to 20%. We show that, even though they produce equivalent changes in pressure-gene rating capability, these four agents produce dissimilar changes in relaxati on capability, with dobutamine speeding relaxation, EMD 57033 slowing relax ation, and calcium and CGP 48506 having little effect of relaxation. Simila r relative effects were observed for drug-induced changes in the timing of pressure-generation events. These effects combine to produce different drug -induced changes in overall cardiac pump function judged by the relation be tween cardiac output and heart rate. Dobutamine shifted the maximal cardiac output to a higher heart rate, in contrast, both calcium sensitizers shift ed the maximum in cardiac output to a lower heart rate, whereas calcium had no effect. Thus even though positive inotropic drugs may have similar effe cts on left ventricular pressure generation, the overall benefit of such dr ugs on ventricular pump function will depend on how the drug also affects v entricular relaxation and ejection capabilities.