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Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212
The goal of this study was to determine the
extent to which the effects of milrinone were desensitized in heart
failure (HF) and to determine the mechanisms, i.e., whether these
effects could be ascribed to changes in cAMP or phosphodiesterase (PDE)
activity in HF. Accordingly, we examined the effects of milrinone in
seven conscious dogs before and after HF was induced by rapid
ventricular pacing at 240 beats/min. The dogs were chronically
instrumented for measurements of left ventricular (LV) pressure and
first derivative of LV pressure
(dP/dt), arterial pressure, LV
internal diameter, and wall thickness. Milrinone (10 µg · kg
1 · min1
iv) increased LV dP/dt by 1,854 ± 157 from 2,701 ± 105 mmHg/s (P < 0.05) before HF. After HF the increase in LV
dP/dt in response to milrinone was
attenuated significantly (P < 0.05);
it increased by 615 ± 67 from 1,550 ± 107 mmHg/s, indicating
marked desensitization. In the presence of ganglionic blockade the
increases in LV dP/dt (+445 ± 65 mmHg/s) in response to milrinone were markedly less (P < 0.01), and milrinone increased
LV dP/dt even less in HF (+240 ± 65 mmHg/s). cAMP and PDE activity were measured in endocardial and
epicardial layers in normal and failing myocardium. cAMP was decreased
significantly (P < 0.05) in LV
endocardium (
26%) but not significantly in LV epicardium
(14%). PDE activity was also decreased significantly
(P < 0.05) in LV endocardium
(18%) but not in LV epicardium (4%). Thus significant
desensitization to milrinone was observed in conscious dogs with HF.
The major effect was autonomically mediated. The biochemical mechanism
appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to
maintain cAMP levels in HF. Reductions in cAMP and PDE levels were
restricted to the subendocardium, suggesting that the increased wall
stress and reduced coronary reserve play a role in mediating these changes.
adenosine 3',5'-cyclic monophosphate; phosphodiesterase; cardiac function
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