Inhibition and Facilitation by Pimobendan, a Calcium Sensitizer, of Catecholamine Secretion From Bovine Adrenal Chromaffin Cells

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The effects of pimobendan, a Ca2+ sensitizer with inhibitory action against cyclic-GMP-inhibited phosphodiesterase (PDE-III), on catecholamine (CA) secretion were studied in bovine adrenal chromaffin cells. In intact cells, pimobendan (10 – 100 μM) inhibited CA secretion stimulated by acetylcholine (10 and 30 μM) and 1,1-dimethyl-4-phenyl-piperazinium (DMPP) (3 and 10 μM), but facilitated CA secretion stimulated by high K+ (30 mM), histamine (3 μM), and angiotensin-II (3 μM). Histamine and angiotensin-II had no effect on CA secretion in Ca2+-free medium. The inhibition or facilitation by pimobendan of the stimulation-evoked CA secretion was not affected by H-89 (1 μM) and H-8 (30 μM), inhibitors of cyclic-AMP-dependent protein kinase. Milrinone (10 and 30 μM) and amrinone (100 and 300 μM), inhibitors of PDE-III, did not affect the stimulation-evoked CA secretion. In β-escin-permeabilized cells, pimobendan (10 – 100 μM) did not affect CA secretion stimulated by Ca2+ (0.1 – 10 μM) in the presence and absence of MgATP (2 mM). These results indicate that pimobendan has dual effects, inhibition and facilitation, on CA secretion. The inhibition may be due to an inhibitory action on nicotinic receptors and the facilitation may be due to a facilitatory action on stimulation-induced Ca2+ influx. Neither Ca2+ sensitizing nor PDE-III inhibiting actions seem to be related to these effects.
2003-03-01