The effect of reduced myocardial cyclic AMP content on the response to milrinone in the isolated guinea pig heart.
BACKGROUND
Cardiac beta receptor down-regulation is associated with a reduction of tissue cyclic adenosine monophosphate (AMP) content. Milrinone exerts its effects by inhibiting the metabolism of existing cyclic AMP. The purpose of this study was to evaluate the effect of reduced myocardial cyclic AMP content on the pharmacologic action of milrinone.


METHODS
A reduction of myocardial cyclic AMP content was produced by creating catecholamine depletion in the hearts of adult guinea pigs with intraperitoneal reserpine. Control animals received the reserpine vehicle. Isolated heart perfusion was maintained with modified Krebs buffer, and hearts were paced at 270 beats/min. A latex balloon and transducer-tipped catheter were inserted into the left ventricle. Isovolemic work was maintained at a constant balloon volume. Hearts from control and reserpine treated animals were perfused for 20 minutes with buffer containing either no milrinone, 1.7 x 10(-6), or 1.0 x 10(-4) mol/L milrinone (n = 12 for each dose). Maximal positive and negative dP/dt were assessed. The hearts were then frozen and cyclic AMP was measured.


RESULTS
Cyclic AMP content was significantly lower in the reserpine-treated hearts at each milrinone concentration (0.33 +/- 0.01 vs 0.46 +/- 0.01; 0.33 +/- 0.01 vs 0.53 +/- 0.01; 0.30 +/- 0.01 vs 0.61 +/- 0.02 pmol/mg wet weight, p < 0.05). Milrinone significantly increased positive and negative dP/dtmax (p < 0.05), but no difference was observed between control and reserpine-treated hearts.


CONCLUSIONS
Endogenous catecholamine depletion reduces myocardial cyclic AMP content but does not attenuate the response to milrinone in the isolated heart.
Kehler
C H
CH
Department of Anesthesiology, University of Minnesota, Minneapolis 55455, USA.
Hebl
J R
JR
Soule
C L
CL
Gallagher
W J
WJ
Houlton
A J
AJ
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D020105:Milrinone; D009206:Myocardium / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D012110:Reserpine / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D013565:Sympatholytics; D012110:Reserpine; D000242:Cyclic AMP; D020105:Milrinone