Effects of type IV phosphodiesterase inhibition on cardiac function in the presence and absence of catecholamines.
Type IV phosphodiesterase (PDE4) inhibitors may be useful in several diseases in which catecholamine infusions are commonly used, including asthma, sepsis, and multiple organ failure. To determine whether type IV phosphodiesterase inhibitors alter baseline or catecholamine-induced changes in cardiac function or both, we examined the effects of Ro 20-1724 (PDE4 inhibitor) on several cardiac-performance parameters in the absence and presence of norepinephrine, epinephrine, isoproterenol, and dobutamine infusions (3, 1, 0.1, and 3 microg/kg/min, respectively). Male Sprague-Dawley rats received either Ro 20-1724 (10 microg/kg/min; n = 7) or vehicle (n = 6). After a left ventricular catheter was placed and connected to a heart-performance analyzer, each animal received each of the four catecholamines in randomized order (10 min per catecholamine with a 30-min washout period between infusions). In the absence of catecholamines, Ro 20-1724 significantly but mildly (i.e., <10%) increased heart rate but did not alter significantly any other measured cardiac parameter. In addition, Ro 20-1724 did not significantly alter norepinephrine-, epinephrine-, or dobutamine-induced changes in cardiac-performance parameters. There was, however, a significant attenuation of the isoproterenol-induced increase in a single measure of cardiac contractility (maximum dP/dt normalized to pressure). PDE4 inhibition does not cause significant cardiac toxicities in rats, both in the absence and presence of catecholamines. Our data suggest that PDE4 inhibitors may be safely used in critically ill patients receiving catecholamines. A clinical trial of this family of drugs in patients with critical illness is now being planned.
Herzer
W A
WA
Center for Clinical Pharmacology, Department of Pharmacology, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA.
Thomas
N J
NJ
Carcillo
J A
JA
Tofovic
S P
SP
Jackson
E K
EK
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002395:Catecholamines; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D004280:Dobutamine; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine