Rj. Leone et al., POSITIVE FUNCTIONAL-EFFECTS OF MILRINONE AND METHYLENE-BLUE ARE NOT ADDITIVE IN CONTROL AND HYPERTROPHIC CANINE HEARTS, The Journal of surgical research (Print), 77(1), 1998, pp. 23-28
This study was designed to test whether increased inotropy caused by r
aising intracellular cAMP would add to the positive inotropy caused by
reducing cGMP and whether this relationship was affected by experimen
tal hypertrophy. We used open chest anesthetized dogs with left ventri
cular hypertrophy (LVH) induced by valvular aortic stenosis and age ma
tched controls (CON). Hearts were instrumented to measure local segmen
t shortening, force, and regional work. Milrinone (MIL), a selective c
yclic AMP-phosphodiesterase inhibitor, and methylene blue (MB), a guan
ylate cyclase inhibitor, were used to alter cAMP and cGMP levels. Ten
CON and 11 LVH animals were randomly assigned to receive first either
MIL (1 mu g/kg/min) or MB (2 mg/ kg/min) intracoronary (i.c.) infusion
. After 10 min, simultaneous i.c. infusion of the other agent was begu
n. MIL increased regional minute work (g x mm/min) in both CON (1311 /- 207 to 2072 +/- 285) and LVH (1052 +/- 136 to 1371 +/- 351) hearts.
MB did not increase work significantly, but did increase contractile
force. MIL + MB increased work from baseline; however, the combination
did not increase work more than either agent alone (1961 +/- 510 CON;
1390 +/- 285 LVH). Myocardial cAMP levels (pmol/g) were significantly
increased by MIL in both CON (329 +/- 53 to 437 +/- 13) and LVH heart
s (351 +/- 67 to 538 +/- 32), and the addition of MB further raised cA
MP (879 +/- 115 CON; 741 +/- 96 LVH). MB resulted in decreased myocard
ial cGMP (pmol/g) (3.20 +/- 0.61 to 2.16 +/- 0.92 CON; 5.21 +/- 1.15 t
o 2.46 +/- 0.56 LVH), while MIL increased cGMP (3.20 +/- 0.61 to 6.24
+/- 1.79 CON; 5.21 +/- 1.15 to 6.53 +/- 0.41 LVH). Both MIL and MB cau
sed increases in O-2 consumption, with MIL + MB together increasing O-
2 consumption further. The current findings demonstrate a potentiation
of cAMP production in the presence of MIL + MB above either agent alo
ne, but this did not lead to potentiation of positive functional effec
ts. High levels of cGMP caused by milrinone may have limited the posit
ive functional effects of cAMP. (C) 1998 Academic Press.