MYOCARDIAL EFFECTS OF CYCLIC-AMP PHOSPHODIESTERASE INHIBITION ARE DAMPENED IN THYROXINE-INDUCED CARDIAC-HYPERTROPHY

We tested the hypothesis that the increase in myocardial O-2 consumpti on (MVO2) and myocardial wall thickening in response to milrinone woul d not be limited by thyroxine (T-4)-induced (0.5 mg/kg for 16 days) ca rdiac hypertrophy. Anesthetized open-chest New Zealand white rabbits w ere divided into four groups: control vehicle (CV, n = 5), control mil rinone (CM, n = 8), T-4 vehicle (T4V, n = 7), and T-4 milrinone (T4M, n = 9). Vehicle or milrinone (10(-3) M) were topically applied to the left ventricular epicardium for 15 min. Coronary blood flow (radioacti ve microspheres) and O-2 extraction (microspectrophotometry) were used to determine O-2 consumption. Cyclic AMP levels were determined by ra dioimmunoassay. T-4 increased the heart weight to body weight ratio fr om 2.6 +/- 0.1 to 3.1 +/- 0.1 (g/kg). T-4 rabbits had significantly hi gher baseline heart rates, blood pressures, and dP/dt(max) and both su bepicardial (EPI) and subendocardial (ENDO) blood flows. Topical appli cation of milrinone did not have significant hemodynamic effects in ei ther group. Baseline cyclic AMP levels (pmol/g) in the EPI and ENDO my ocytes were comparable between control and T-4 rabbits (CVEPI = 599 +/ - 34, CVENDO = 532 +/- 26, T4VEPI = 656 +/- 42, T4VENDO = 657 +/- 17). Milrinone increased cyclic AMP in all groups although the increases w ere less in the T-4 rabbits (CMEPI = 742 +/- 115, CMENDO = 698 +/- 101 , T4MEPI = 742 +/- 103, T4MENDO = 690 +/- 55). Baseline MVO2 (ml O-2/m in/100 g) was significantly higher in T-4 rabbits than controls (T4VEP I = 17.7 +/- 3.5 vs CVEPI = 8.5 +/- 1.5, T4VENDO = 17.2 +/- 3.2 vs CVE NDO = 9.2 +/- 1.5). Significant increases in MVO2 were noted with the addition of milrinone in control (CMEPI = 14.8 +/- 3.0, CMENDO = 13.5 +/- 1.6) and T-4 (T4MEPI = 25.5 +/- 3.4, T4MENDO = 22.0 +/- 3.3) rabbi ts; however, the percentage increase in MVO2 was significantly greater in controls (C-EPI = 73%, C-ENDO = 47%) than T-4 (T-4,T-EPI = 44%, T- 4,T-ENDO = 28%). Thus, although the cyclic AMP phosphodiesterase activ ity was comparable between T-4 rabbit hearts and controls, the metabol ic effects and cyclic AMP effects of milrinone were dampened in this f orm of hypertrophy. (C) 1998 Academic Press.