Chronotropic Effects of Milrinone in a Guinea Pig Ex Vivo Model: A Pilot Study to Screen for New Mechanisms of Action

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: ie, β receptor blockers with distinct selectivities (propranolol, metoprolol, and carvedilol), α1 receptor blocker (prazosin), inhibitor of the small conductance Ca 2+ activated K + (SK) channels (apamin), L-type Ca 2+ 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 nonselective blocker of the β receptors, propranolol, and blockers of the l -type Ca 2+ channels, only nonsignificant trends toward 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, which 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.