Mechanism of preserved positive lusitropy by cAMP-dependent drugs in heart failure

Abstract

In tachycardia-induced heart failure (HF), positive lusitropic effects of milrinone or dobutamine were assessed by evaluating the time constant of left ventricular (LV) pressure decay (τ) and Ca2+-ATPase activity of the sarcoplasmic reticulum (SR). The peak value of the positive first derivative of LV pressure (+dP/d t) was less increased, either by dobutamine (2–10 μg ⋅ kg−1 ⋅ min−1) or by milrinone (4–20 μg/kg), in HF than in control ( P< 0.05), whereas τ was shortened to an extent similar to that in control with dobutamine [ P = not significant (NS)] and to an even greater extent with milrinone ( P < 0.05). Ca2+-ATPase activity increased similarly in HF and control with dobutamine (1 μM; +11% in HF vs. +12% in control, P = NS), whereas it increased more with milrinone (1 μM; +19% in HF vs. +11% in control, P < 0.05). Ca2+-ATPase activity-cAMP relationships were shifted to the left by milrinone or dobutamine in HF compared with control. Thus, in HF, the sensitivity of Ca2+-ATPase activity to cAMP was increased on addition of cAMP-dependent inotropic agents, contributing to the preservation of positive lusitropy.