Myocardial Effects of Cyclic AMP Phosphodiesterase Inhibition Are Dampened in Thyroxine-Induced Cardiac Hypertrophy

Abstract

We tested the hypothesis that the increase in myocardial O2consumption (MVO2) and myocardial wall thickening in response to milrinone would not be limited by thyroxine (T4)-induced (0.5 mg/kg for 16 days) cardiac hypertrophy. Anesthetized open-chest New Zealand white rabbits were divided into four groups: control vehicle (CV,n= 5), control milrinone (CM,n= 8), T4vehicle (T4V,n= 7), and T4milrinone (T4M,n= 9). Vehicle or milrinone (10−3M) were topically applied to the left ventricular epicardium for 15 min. Coronary blood flow (radioactive microspheres) and O2extraction (microspectrophotometry) were used to determine O2consumption. Cyclic AMP levels were determined by radioimmunoassay. T4increased the heart weight to body weight ratio from 2.6 ± 0.1 to 3.1 ± 0.1 (g/kg). T4rabbits had significantly higher baseline heart rates, blood pressures, anddP/dtmaxand both subepicardial (EPI) and subendocardial (ENDO) blood flows. Topical application of milrinone did not have significant hemodynamic effects in either group. Baseline cyclic AMP levels (pmol/g) in the EPI and ENDO myocytes were comparable between control and T4rabbits (CVEPI= 599 ± 34, CVENDO= 532 ± 26, T4VEPI= 656 ± 42, T4VENDO= 657 ± 17). Milrinone increased cyclic AMP in all groups although the increases were less in the T4rabbits (CMEPI= 742 ± 115, CMENDO= 698 ± 101, T4MEPI= 742 ± 103, T4MENDO= 690 ± 55). Baseline MVO2(ml O2/min/100 g) was significantly higher in T4rabbits than controls (T4VEPI= 17.7 ± 3.5 vs CVEPI= 8.5 ± 1.5, T4VENDO= 17.2 ± 3.2 vs CVENDO= 9.2 ± 1.5). Significant increases in MVO2were noted with the addition of milrinone in control (CMEPI= 14.8 ± 3.0, CMENDO= 13.5 ± 1.6) and T4(T4MEPI= 25.5 ± 3.4, T4MENDO= 22.0 ± 3.3) rabbits; however, the percentage increase in MVO2was significantly greater in controls (CEPI= 73%, CENDO= 47%) than T4(T4,EPI= 44%, T4,ENDO= 28%). Thus, although the cyclic AMP phosphodiesterase activity was comparable between T4rabbit hearts and controls, the metabolic effects and cyclic AMP effects of milrinone were dampened in this form of hypertrophy.