Positive inotropic responses upon administration of milrinone, an inhibitor of the phosphodiesterase enzyme (PDE), involve a well-pronounced positive chronotropic effect. Here we tested whether milrinone evokes this chronotropic response solely by PDE inhibition or by a concerted action that involve additional pharmacological targets. Milrinone stimulated increases in heart rate were studied in right atrial preparations of guinea pig in the presence or absence of inhibitors of putative ancillary molecular pathways or ion channels: i.e. β receptor blockers with distinct selectivities (propranolol, metoprolol, and carvedilol), α1 receptor blocker (prazosin), inhibitor of the small conductance Ca2+ activated K+ (SK) channels (apamin), L-type Ca2+ channel blockers (verapamil and diltiazem), and different Na+ channel blockers (lidocaine, tetrodotoxin, and quinidine). Carvedilol, which inhibits β1, β2, α1 and 5-HT receptors, limited the positive chronotropic effects of milrinone to about 40%, (p<0.01). In the presence of another non-selective blocker of the β receptors, propranolol, and blockers of the L-type Ca2+ channels, only non-significant trends towards reductions of the milrinone effects were seen. The α1 receptor blocker prazosin did not limit the milrinone evoked positive chronotropy. Blockers of Na+ channels, SK channels, or the β1 receptor blocker, metoprolol also did not affect the positive chronotropy evoked by milrinone. We conclude that milrinone increases heart rate in response to adrenergic signaling, that besides PDE inhibition, may involve a 5-HT-receptor-dependent component. Our exploratory approach paves the way to more focused experiments with the use of selective 5-HT-receptor antagonists to confirm or reject the involvement of a specific 5-HT-receptor dependent pathway.
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