An analysis of the action of phorbol 12, 13-dibutyrate on mechanical activity in rat uterine smooth muscle.
The effects of phorbol 12, 13-dibutyrate (PDB) on mechanical activity in the pregnant rat uterus were investigated in isolated strips. In Ca(++)-containing solution, PDB (2.5 x 10(-8) to 10(-6) M) increased in a concentration-dependent manner the amplitude of the electrically induced contraction, but had no effect on the resting tension. PDB (10(-7) M) had a dual action, stimulatory then inhibitory, on contractions evoked by K(+)-rich (40 mM K+) solution or oxytocin. The inhibitory effect appeared more rapidly and the percentage of inhibition was increased for 10(-6) M PDB, which in addition abolished completely oxytocin-induced contraction after 20 min of application. PDB also reduced the amplitude of transient contraction evoked by oxytocin in Ca(++)-free solution. In saponin-skinned strips, 10(-7) M PDB increased the contraction induced by pCa ranging from 7 to 6, whereas 10(-6) M PDB reduced all Ca(++)-activated contractions from pCa = 7 to pCa = 5. PDB had no significant effect on the Ca(++)-uptake and the Ca(++)-release mechanisms of the intracellular Ca(++)-store. All of the effects of PDB were antagonized by the addition of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (2 x 10(-5) M). In addition, the inactive phorbol 13,20-diacetate (10(-8) to 10(-6) M) had no effect on the mechanical activity in uterus. These results suggest the existence of different sites of action of PDB in rat uterus, via the activation of protein kinase C: 1) contractile machinery; 2) potential-dependent Ca channels; and 3) phospholipase C.
Laboratoire de Physiologie Cellulaire et de Pharmacologie Moléculaire, Institut National de la Santé et de la Recherche Médicale, Université de Bordeaux II, France.
J P
JP
Savineau
J
J
Mironneau
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects*
D007295:Inositol Phosphates; D015240:Phorbol 12,13-Dibutyrate; D010121:Oxytocin; D011188:Potassium; D002118:Calcium