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.
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 microns, 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 less than 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 less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Oquist
N L
NL
Department of Pediatrics, University of South Alabama College of Medicine, Mobile 36617.
Strada
S J
SJ
Artman
M
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000145:classification; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D005260:Female; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology*; D009539:Nicotinic Acids / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D044005:Tetrahydroisoquinolines
D007546:Isoquinolines; D009539:Nicotinic Acids; D044005:Tetrahydroisoquinolines; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; C027166:SQ 65442; C035964:trequinsin; D015105:3',5'-Cyclic-AMP Phosphodiesterases