Drug Discov Ther. 2009;3(6):272-277.

Positive inotropic effect of PHR0007 (2-(4-(4-(Benzyloxy)-3-methoxybenzyl)piperazin-1-)-N-(1-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide) on atrial dynamics in beating rabbit atria.

Lan Y, Piao HR, Cui X


The aim of the present study was to examine the positive inotropic effects and mechanism of action of PHR0007 (2-(4-(4-(Benzyloxy)-3-methoxybenzyl)piperazin-1-)-N-(1-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide) on beating rabbit atria. Atria were obtained from New Zealand white rabbits, and experiments performed using a perfused beating atrial model. The effects of PHR0007 (1, 30, or 100 μmol/L), and of the protein kinase inhibitors, staurosporine (1.0 μmol/L) or H-89 (10 μmol/L), plus PHR0007 (30 μmol/L), on atrial pulse pressure and stroke volume were analyzed. PHR0007 significantly increased atrial pulse pressure and atrial stroke volume in beating rabbit atria compared with control baseline levels. These effects of PHR0007 were completely blocked by pretreatment with either staurosporine (a nonspecific protein kinase inhibitor) or H-89 (a cAMP-dependent protein kinase A inhibitor). In addition, 3-isobutyl-1-methylxanthine (IBMX), a non-specific inhibitor of phosphodiesterases (PDEs), completely blocked the positive inotropic effect of PHR0007 on atrial dynamics, but forskolin, an activator of adenylyl cyclases (AC), failed to modulate PHR0007-induced increases in atrial pulse pressure and stroke volume. In conclusion, these data suggest that PHR0007 produces a positive inotropic effect in rabbit atria via the PDE-cAMP-PKA signaling pathway.

KEYWORDS: Inotropic effect, PHR0007, milrinone, protein kinase A (PKA), cAMP, PDE

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