Second Derivative of Developed Tension in Classifying Cardiotonics with Respect to Their Mechanisms of Action: Drugs Affecting cAMP Metabolism

Abstract: The second derivative of developed tension (T”, d²T/dt²) has not come into common use in the analysis of cardiac contractility, although it has been shown to give additional information on the myocardial contraction-relaxation cycle (CRC). In the present study a new way to use T”in the analysis of myocardial mechanics, including the time course of T”, is described. Profiles of the T”of the some drugs with established cardiotonic effects are presented. Experiments were carried out in spontaneously beating whole rat atria preparations. The effects of changing contraction frequency on the measured parameters were studied with electrically paced left atria. Qualitative inotropic effects of 1-methyl-3-isobutylxanthine (MIX), theophylline, caffeine, milrinone, isoprenaline and forskolin were studied. Concentrations equief-fective with respect to the force of contraction were tested. Inotropic profiles were evaluated at the time of maximal force of contraction. We found that methylxanthines have a mechanical behaviour quite distinct from other inotropic agents acting via cAMP. The effects of MIX were similar to those of theophylline in all respects. A tendency to increase the active relaxation phase of T”was a property common to methylxanthines. Caffeine also prolonged the phases of contraction, whereas MIX and theophylline have opposite effects. Milrinone in turn mimics the effects of isoprenaline and forskolin; abbreviation of the relaxation phase of T”was the feature most typical of them. Caffeine was the only agent which did not shorten the duration of CRC. The method proved valuable in basic research on drug effects on cardiac contractility.