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 d iseases in which catecholamine infusions are commonly used, including asthma, sepsis, and multiple organ failure. To determine whether type TV phosphodiesterase inhibitors alter baseline or catecholamine-induce d changes in cardiac function or both, we examined the effects of Ro 2 0-1724 (PDE4 inhibitor) on several cardiac-performance parameters in t he absence and presence of norepinephrine, epinephrine, isoproterenol, and dobutamine infusions (3, 1, 0.1, and 3 mu g/kg/min, respectively) . Male Sprague-Dawley rats received either Ro 20-1724 (10 mu g/kg/min; n = 7) or vehicle (n = 6). After a left ventricular catheter was plac ed and connected to a heart-performance analyzer, each animal received each of the four catecholamines in randomized order (10 min per catec holamine with a 30-min washout period between infusions). In the absen ce of catecholamines, Ro 20-1724 significantly but mildly (i.e., <10%) increased heart rate but did not alter significantly any other measur ed cardiac parameter. In addition, Ro 20-1724 did not significantly al ter norepinephrine-, epinephrine-, or dobutamine-induced changes in ca rdiac-performance parameters. There was, however, a significant attenu ation of the isoproterenol-induced increase in a single measure of car diac contractility (maximum dP/dt normalized to pressure). PDE4 inhibi tion does not cause significant cardiac toxicities in rats, both in th e absence and presence of catecholamines. Our data suggest that PDE4 i nhibitors may be safely used in critically ill patients receiving cate cholamines. A clinical trial of this family of drugs in patients with critical illness is now being planned.