An analysis of the action of phorbol 12, 13-dibutyrate on mechanical activity in rat uterine smooth muscle

JP Savineau and J Mironneau

Laboratoire de Physiologie Cellulaire et de Pharmacologie Moleculaire, Institut National de la Sante et de la Recherche Medicale, Universite de Bordeaux II, France.

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.

Volume 255, Issue 1, pp. 133-139, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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