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

Abstract

ABSTRACT. In contrast to mvocardium from adult rabAbbreviations bits, 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 cGMPinsensitive form, we postulated that selective inhibitors of this form of CAMP-specific PDE may increase cardiac contractility in newborns. Therefore, the inotropic effects PDE, phosphodiesterase SR, sarcoplasmic reticulum dT/dt, maximal rate of tension development NB, newborn IM, immature AD, adult IC50, concentration producing 50% inhibition RT, resting tension -dT/dt, maximal rate of relaxation of RO 20-1724 and S Q 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 pm, RO 20-1724 and S Q 65,442 depressed maximal rate of tension development to 67 f 4 and 70 f 2% of control, respectively, in NB papillary muscles. The NB response to RO 20-1724 differed significantly from the immature (127 f 2%) and adult (115 f 3%) groups ( p c 0.05), but the effects of S Q 65,442 were comparable among the three age groups. In contrast, trequinsin exerted a positive inotropic effect in the NB group (355 f 22% of control) that was substantially greater than the maximal response obtained in the immature (139 f 6% of control) or adult (131 2 5% of control) groups ( p < 0.01). These differences in inotropic responsiveness could not be explained 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. (Pediatr Res

Use of milrinone in the management of haemodynamic instability following duct ligation

“…Postnatal maturation of affinity and an agedependant increase in myocardial contractility has been demonstrated [1,5]. Studies in both the newborn and foetal animal (which may be extrapolated to the very preterm human infant) suggest milrinone and other PDE inhibitors are less effective for the immature myocardium as the cAMP PDE activity is low in the newborn myocardium [14,15]. While milrinone has a positive inotropic effect in the immature myocardium, it is quantitatively weaker than in older populations [15].…”

“…Studies in both the newborn and foetal animal (which may be extrapolated to the very preterm human infant) suggest milrinone and other PDE inhibitors are less effective for the immature myocardium as the cAMP PDE activity is low in the newborn myocardium [14,15]. While milrinone has a positive inotropic effect in the immature myocardium, it is quantitatively weaker than in older populations [15]. In a recent study, milrinone did not prevent low systemic blood flow during the first 24 h in very preterm infants [18].…”

Inotropes for Preterm Infants: 50 Years on Are We Any Wiser?

“…These findings are consistent with studies involving children post-cardiac surgery ( 64 , 72 ). However, the cAMP levels are decreased in the newborn myocardium, thus newborns may be less sensitive to the effect of milrinone ( 73 , 74 ).…”