Inotropic Responses to Selective |[lpar]|RO 20|[ndash]|1724 and SQ 65, 442|[rpar]| and Nonselective |[lpar]|Trequinsin|[rpar]| Inhibitors of Cyclic AMP-Specific Class IV Phosphodiesterase in Newborn, Immature, and Adult Rabbit Myocardium

摘要

In contrast to myocardium from adult rabbits, myocardium from newborns is insensitive to the inotropic effects of selective inhibitors (e. g. amrinone, milrinone, and indolidan) of the cGMP-inhibited high-affinity cAMP phosphodiesterase (PDE) localized in the sarcoplasmic reticulum. This difference may be explained at least partially by our recent observation that this camp PDE activity is low in sarcoplasmic reticulum from newborns. Furthermore, because the predominant cytosolic high-affinity cAMP PDE activity in newborns is a cGMP-insensitive form, we postulated that selective inhibitors of this form of cAMP-specific PDE may increase cardiac contractility in newborns. Therefore, the inotropic effects of RO 20–1724 and SQ 65, 442 (selective inhibitors of cGMP-insensitive, high-affinity cAMP PDE) were compared with trequinsin (a potent, less selective PDE inhibitor) in right ventricular papillary muscles isolated from newborn (NB; 24–48 h), immature (14–16 d), and adult New Zealand White rabbits. At a drug concentration of 100 $mUm, RO 20–1724 and SQ 65, 442 depressed maximal rate of tension development to 67 ± 4 and 70 ± 2% of control, respectively, in NB papillary muscles. The NB response to RO 20–1724 differed significantly from the immature (127 ± 2%) and adult (115 ± 3%) groups (p < 0.05), but the effects of SQ 65, 442 were comparable among the three age groups. In contrast, trequinsin exerted a positive inotropic effect in the NB group (355 ± 22% of control) that was substantially greater than the maximal response obtained in the immature (139 ± 6% of control) or adult (131 ± 5% of control) groups (p < 0.01). These differences in inotropic responsiveness could not be ex- plained by differences in sensitivity to drug-induced inhibition of cAMP or cGMP hydrolysis in cytosolic fractions from the three age groups. Thus, selective inhibitors of the predominant form of high-affinity cAMP PDE in NB myocardium do not exert a positive inotropic response in NB papillary muscles. The age-specific cardiotonic effects of trequinsin suggest that other PDE isozymes could contribute to the modulation of contractility during postnatal maturation.