Influence of acidosis on cardiotonic effects of milrinone.
BACKGROUND
The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation.


METHODS
Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] approximately 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa approximately 7.2, BE < -9 mM; n = 7); or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 microg x kg(-1) x min(-1) were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10(-7) to 10(-4) M) and 8-bromo-cAMP (10(-4) to 10(-3) M) were determined.


RESULTS
In the control group of dogs, significant increases in LV dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 microg x kg(-1) x min(-1). In the mild acidosis group, 5 microg x kg(-1) x min(-1) milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10(-4) M milrinone was accompanied by a significant increase in intracellular cAMP content at apH of 7.4 but not 7.


CONCLUSIONS
These results indicate that the inotropic effect of milrinone is attenuated by acidosis due, at least in part, to decreased cAMP formation in acidotic muscle.
Tanaka
M
M
School of Medicine, Akita University, Japan. mtanaka@med.akita-u.ac.jp
Ishikawa
T
T
Nishikawa
T
T
Goto
K
K
Sato
S
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000138:Acidosis / Q000150:complications*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*
D002316:Cardiotonic Agents; D011728:Pyridones; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D020105:Milrinone