Pharmacologic and hemodynamic effects of combined beta-agonist stimulation and phosphodiesterase inhibition in the failing human heart.
OBJECTIVE
We measured the individual and combined effects of the beta-agonist dobutamine and the phosphodiesterase inhibitor enoximone both in vitro and in vivo in the failing human heart.


METHODS
This was an unblinded, prospective study.


METHODS
The in vitro measurements were performed on 20 hearts obtained from subjects with end-stage biventricular failure and from seven normal hearts. The in vivo measurements were performed in eight subjects with class IV heart failure.


METHODS
The in vitro measurements of enoximone, dobutamine, and the combination of these agents were phosphodiesterase activity using a sarcoplasmic reticulum-enriched preparation, cyclic adenosine monophosphate (cAMP) accumulation using particulate fractions, and tension response using isolated right ventricular trabeculae. The dose response to dobutamine, the combination of enoximone and dobutamine, and the combination of nitroprusside and dobutamine were measured in vivo using invasive hemodynamic monitoring.


RESULTS
In vitro, enoximone exhibited dose-dependent inhibition of phosphodiesterase activity. The addition of enoximone to dobutamine resulted in an upward and leftward shift of the dobutamine dose-response curve for both cAMP production and contractile response. In vivo, enoximone significantly shifted the dobutamine dose-response curves for cardiac index, left ventricular stroke work index, and heart rate upward and to the left; and shifted the dobutamine dose-response curves for right atrial, pulmonary arterial, and pulmonary wedge pressures downward and to the right.


CONCLUSIONS
Enoximone exerts favorable effects on cardiac performance that are additive to those produced by dobutamine. These effects are mediated by increasing cellular cAMP concentrations through independent, additive mechanisms.
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002303:Cardiac Output, Low / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism; D004280:Dobutamine / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D017335:Enoximone / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011446:Prospective Studies; D014665:Vasodilator Agents / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D004280:Dobutamine; D017335:Enoximone; D000242:Cyclic AMP