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A previous investigation has suggested that the hyperpolarization-activated cation current Ih does not contribute to the spontaneous firing of midbrain dopaminergic neurons. This conclusion was reached using Cs. We have re-examined this question with extracellular recordings in slices using the more specific blocker ZD7288. In two-thirds of the cells, low concentrations of ZD7288 induced a decrease of the spontaneous firing. The maximal inhibition was about 40 and the mean IC50was 1.6 μM. This effect was probably direct because it persisted in the presence of antagonists of various receptors. These concentrations of ZD7288 had no effect in the remaining one third of the examined cells. However, the highest concentration of ZD7288 (300 μM) abolished the firing of all dopaminergic neurons, probably by a mechanism unrelated to the blockade of Ih. We conclude that Ihcontrols to a certain extent the firing of a majority of midbrain dopaminergic neurons.

We studied the effects of oral administration of pimobendane on hemodynamics, blood gas levels, the renin-angiotensin system, and plasma catecholamines in 11 patients who were affected by severe chronic congestive heart failure. Following the administration of 5 mg, the cardiac index increased from 2.0 ±0.2 to 2.5 ±0.2 L/min/m2(p<0.01), and the pulmonary wedge pressure decreased from 28 ± 3 to 17 ± 4 mm Hg (p<0.01). The maximal changes were noted five hours after intake of the drug. In spite of a significant decrease in arterial oxygen pressure (PaO2) (from 81 ± 4 to 67 ± 5 mm Hg; p<0.05), a significant increase in the oxygen delivery index was seen (from 322 ±32 to 436 ± 38 ml/min/m2; p<0.01). The patients who were submitted to long-term treatment (5 mg twice daily) and who were reassessed after at least one month exhibited an improved cardiac index from 1.9±0.2 to 2.5±0.1 L/min/m2(p<0.01), as well as a decreased pulmonary wedge pressure from 26 ± 2 to 14 ± 4 mm Hg (p<0.01). The norepinephrine levels were significantly reduced after one month (from 1,496 ± 185 to 678 ± 95 pg/ml; p<0.01), whereas the plasma renin activity was not. One patient died suddenly during the one-month follow-up period. With the exception of one case, which was also treated with heparin, a transient cutaneous rash and a drop in the level of blood platelets were observed, pimobendane was well tolerated. This new inotropic and vasodilating drug thus seems to have promise for the treatment of chronic congestive heart failure.