Myocardial effects of cyclic AMP phosphodiesterase inhibition are dampened in thyroxine-induced cardiac hypertrophy.
We tested the hypothesis that the increase in myocardial O2 consumption (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), T4 vehicle (T4V, n = 7), and T4 milrinone (T4M, n = 9). Vehicle or milrinone (10(-3) M) were topically applied to the left ventricular epicardium for 15 min. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption. Cyclic AMP levels were determined by radioimmunoassay. T4 increased the heart weight to body weight ratio from 2.6 +/- 0.1 to 3.1 +/- 0.1 (g/kg). T4 rabbits had significantly higher baseline heart rates, blood pressures, and dP/dtmax and 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 T4 rabbits (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 T4 rabbits (CMEPI = 742 +/- 115, CMENDO = 698 +/- 101, T4MEPI = 742 +/- 103, T4MENDO = 690 +/- 55). Baseline MVO2 (ml O2/min/100 g) was significantly higher in T4 rabbits 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 MVO2 were 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 MVO2 was 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 T4 rabbit hearts and controls, the metabolic effects and cyclic AMP effects of milrinone were dampened in this form of hypertrophy.
Heart and Brain Circulation Laboratory, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635, USA.
M
M
Straznicka
R J
RJ
Leone
P M
PM
Scholz
H R
HR
Weiss
D000818:Animals; D001784:Blood Gas Analysis; D001835:Body Weight; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology*; D003326:Coronary Circulation; D000242:Cyclic AMP / Q000378:metabolism*; D004699:Endocardium / Q000201:enzymology*; D006339:Heart Rate; D020105:Milrinone; D010101:Oxygen Consumption / Q000502:physiology; D010496:Pericardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D013974:Thyroxine; D016277:Ventricular Function, Left
D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D000242:Cyclic AMP; D020105:Milrinone; D013974:Thyroxine