Phorbol 12,13-dibutyrate produces negative inotropism and selective antagonism of responses to adrenoceptor agonists in rat atria.

Rat atria loaded in vitro with the dye INDO-1 produced fluorescence signals indicative of changes in cytoplasmic calcium ion concentration ([Ca2+]c). Such atria showed systolic/diastolic fluctuations indicative of a systolic rise and a diastolic fall in both tension and [Ca2+]c. Positively inotropic responses of the atria to isoprenaline, phenylephrine, ouabain or 4-aminopyridine were associated with fluorescence changes indicative of increased systolic increments in [Ca2+]c. Treatment of atria with phorbol dibutyrate, on the other hand, produced negative inotropism and fluorescence changes indicative of declining systolic increments in [Ca2+]c. Pretreating atria with phorbol dibutyrate diminished both the inotropic and fluorescence responses to subsequent treatment with phenylephrine or isoprenaline, although responses to ouabain or 4-aminopyridine were unchanged. Exposure of atria to a selective inhibitor of protein kinase C mitigated the effects of pretreatment with phorbol dibutyrate, but failed to modify responses to phenylephrine or isoprenaline that were produced in the absence of phorbol dibutyrate.