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.
Northover
B J
BJ
School of Applied Sciences, De Montfort University, Gateway, Leicester, U.K.
D015761:4-Aminopyridine / Q000494:pharmacology; D000322:Adrenergic Agonists / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006325:Heart Atria; D066298:In Vitro Techniques; D007211:Indoles; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D013599:Systole
D000322:Adrenergic Agonists; D007211:Indoles; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; D010042:Ouabain; D015761:4-Aminopyridine; D011493:Protein Kinase C; D007545:Isoproterenol; C048960:indo-1; D002118:Calcium