The Biphasic Effect of Amrinone on Tension Development in Newborn Mammalian Myocardium

Abstract

ABSTRACT. The effect of the bipyridine compound, amrinone, on tension generation in neonatal and adult myocardium was studied over the concentration range 30-500 pglmL. Increasing concentrations of amrinone caused a monotonic increase in twitch tension and the rate of tension development in adult papillary muscles. In contrast, lower concentrations of amrinone (30 and 100 pg/mL) caused a decrease in twitch tension and dP/dt in newborn papillary muscles, whereas 500 pg/mL amrinone caused a significant increase in both parameters in the younger age group. Lactic acid, used to dissolve amrinone, was shown to have no effect on tension development. Half relaxation time was decreased in adult preparations at all concentrations of amrinone. In comparison, the decrease in half relaxation time produced by amrinone in the newborn was significant only at a concentration of 500 pg/mL. Action potential duration in the newborn was significantly shortened by 30 pg/mL amrinone. In voltage clamp experiments, 30 pg/mL amrinone was shown to have no effect on tension accompanying two second voltage clamp steps to the plateau potential in newborn myocardium. Developed tension at 400 ms into the clamp step, final tension, and the ratio of early peak tension to final tension were all unchanged by the low concentration of amrinone. In contrast, 500 pg/mL amrinone in the newborn increased tension at 400 ms and final tension but had no effect on the ratio of early peak tension to final tension. These results suggest that the negative inotropic effect of lower concentrations of amrinone on neonatal myocardium is the result of changes in action potential configuration and not a true alteration in basic mechanisms of intracellular Ca2+ regulation. Further, the positive inotropic effect of higher concentrations of amrinone appears to result from enhancement of transmembrane Ca2+ influx as well as augmentation of Ca2+ sequestration and rerelease by the sarcoplasmic reticulum. (Pediatu Res 27: 144-147,1990) Abbreviations SR, sarcoplasmic reticulum dP/dt, the first derivative of tension development HRT, half relaxation time TdO0, tension measured at 400 ms into a voltage clamp step

Inotropic Responses to Selective (RO 20–1724 and SQ 65, 442) and Nonselective (Trequinsin) Inhibitors of Cyclic AMP-Specific Class IV Phosphodiesterase in Newborn, Immature, and Adult Rabbit Myocardium

“…Myocardium from NB animals is relatively insensitive to this class of agents (14)(15)(16)(17), consistent with our observation of diminished cGMP-inhibited class I11 PDE activity in NB SR (12). Unlike that in AD rabbits, highaffinity cAMP PDE activity in the cytosolic fraction from NB myocardium is predominantly the class IV, cGMP-insensitive, cardiotonic drug-insensitive form (12).…”

“…However, the effects of DMSO at concentrations near drug IC50 values were negligible (basal activity inhibited by less than 5%). of milrinone, a selective inhibitor of cGMP-inhibited class I11 Figure 1 illustrates the inotropic responses in papillary muscles PDE in the SR (14)(15)(16)(17). We attributed this lack of response in each age group increasing Ro NB rabbits to a relative deficiency of SR-associated class 111 PDE 20-1724' In the NB group, loo pM Ro 20-1724 reduced dT/dt activity (12).…”

“…Furthermore, the previously reported lack of a positive inotropic response to selective inhibitors (e.g. milrinone) of the SR-associated cGMPinhibited class I11 cAMP PDE (14)(15)(16)(17) suggests that inhibition of this PDE isoform alone is not sufficient to account for the mechanism of action of trequinsin in the NB.…”

Effects of different inotropic interventions on myocardial function in the developing rabbit heart

“…In human neonates, cAMP-dependent inotropic agents are known to be less effective than in adults (38). Additionally, positive inotropic effects of phosphodiesterase inhibitors, such as milrinone or amrinone, are less pronounced or even inverted in newborn compared to adult animals (20,34). Therefore, substances with a cAMP-independent mode of action may be useful in the treatment of cardiac failure in neonates.…”

The effects of milrinone in the neonatal pig heart

“…The difference in inotropic effect between milrinone and amrinone is in agreement with the results of Binah et al [5], who also found that these agents produced opposite inotropic effects on ventricular papillary muscles from neonatal dogs. Recently, Klitzner et al suggested that the negative inotropic effect of amrinone in neonatal hearts may result from a reduction in action potential duration (thus decreasing calcium influx), rather than an alteration of calcium regulation [28]. To our knowledge, the influence of milrinone on the action potential duration in the neonatal heart has not been examined.…”