Effect of milrinone on left ventricular relaxation and Ca2+ uptake function of cardiac sarcoplasmic reticulum

Milrinone, a phosphodiesterase 3 (PDE3) inhibitor, is known to enhance left ventricular (LV) contractility by an inhibition of the breakdown of cAMP t hrough the mechanism inhibiting PDE3. However, it is unclear whether milrin one also exerts positive lusitropy, like dobutamine. Here, we assessed the effects of milrinone on in vivo LV relaxation, as well as the Ca2+-ATPase a ctivity and the Ca2+ uptake function of the cardiac sarcoplasmic reticulum (SR), compared with the effect of dobutamine on those functions. After dobu tamine (3 mu g.kg(-1).min(-1)) was administered, the peak value of the firs t derivative of LV pressure (+dP/dt) increased by 46%, whereas the time con stant (tau) of LV pressure decay decreased by 6.9%, respectively. After mil rinone (10 mu g/kg) was administered, the peak +dP/dt increased to a simila r extent as dobutamine (46%), whereas t decreased much more than dobutamine (19.9%; P < 0.05). In LV crude homogenate, the thapsigargin-sensitive, Ca2 +-ATPase activity-cAMP relationships was significantly less increased by mi lrinone compared with dobutamine (P < 0.05), indicating the higher sensitiv ity of the SR Ca2+-ATPase activity on cAMP by milrinone than by dobutamine. In the SR vesicles purified from LV muscles, the addition of cAMP increase d the SR Ca2+ uptake in a dose-dependent fashion, and the PDE3 inhibitors ( milrinone and cGMP) significantly augmented this response (P, 0.05). Hence, milrinone substantially improved LV relaxation in association with an acce leration of the SR Ca2+-ATPase activity and the SR Ca2+ uptake. This accele ration might be due to an inhibition of the membrane-bound PDE3 in the SR, leading to a local elevation of cAMP.