Mechanisms op desensitization to a phosphodiesterase inhibitor in conscious dogs with heart failure

Desensitization to catecholamines in heart failure (HP) is well recognized. However, the extent to which desensitization occurs, and the potential mechanisms involved, are not established for phosphodiesterase inhibition. The first goal of this study was to determine the effects of a phosphodiesterase inhibitor, milrinone, in 7 conscious dogs before and after HF was induced by rapid ventricular pacing (240 bpm). The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and dP/dt, arterial pressure, LV internal diameter, and wall thickness. Milrinone (10ug/kg/min x 5 min, i.v.) increased LV dP/dt by +1854*157 from 2701±105 mmHg/sec (p<0.05). After HP, the increase in LV dP/dt in response to milrinone was attenuated significantly (p<0.05), i.e., it increased by +615±67 from 1550±107 mmHg/sec, indicating marked desensitization (-67%) in HF. It is also well known that reflex effects are blunted and cardiac innervation is reduced in HF. We confirmed this in our model, i.e., reflex changes in heart rate induced by phenylephrine (PE, lOpg/kg, i.v.) and nitroglycerin (NTG, lOug/kg, i.v.) were depressed in HF (NTG; +28±6, PE; -26±4 bpm) as compared with prior to HP (NTG; +76±10, PE; -43±4 bpm) and LV tissue norepinephrine was depressed (166±33 pg/mg). This led us to hypothesize that depressed autonomie control and cardiac innervation may be responsible, in part, for the desensitization to milrinone in HF. Accordingly, we examined the effects of milrinone after autonomie effects were minimized with ganglionic blockade (hexamethonium bromide 30mg/kg, i.v.). In conscious dogs before HF, in the presence of ganglionic blockade, the response of LV dP/dt to milrinone was much less (p<0.01) than without ganglionic blockade, i.e, it increased LV dP/dt by +445±65 from 2153±58 mmHg/sec, i.e., similar to the response in HF without ganglionic blockade. Thus, a major fraction of the effects of milrinone normally depends upon intact autonomie control and cardiac innervation. Since autonomie control and the effects of milrinone are depressed in HP, part of the mechanism of milrinone deeensitization in HF may be the blunted autonomie control and cardiac denervation, characteristic of HP.