Effects of phorbol-12,13-dibutyrate and protein kinase C inhibitors on Mn(2+)-dependent norepinephrine-induced contractions involving increase in Mn2+ sensitivity in Ca(2+)-depleted vas deferens of the guinea pig.
1. In Ca(2+)-depleted Mn(2+)-loaded vas deferens from the guinea pig (Mn-loaded preparations), norepinephrine (NE) induced a tonic contraction dose dependently without extracellular Ca2+ and Mn2+. 2. In the beta-escin skinned vas deferens, Mn2+ as well as Ca2+ induced contractions. Guanosine triphosphate and NE increased the sensitivity of contractile mechanisms to these divalent cations. 3. Phorbol-12,13-dibutyrate (PDBu) did not induce contractions in normal (Mn(2+)-unloaded Ca(2+)-contained) preparations, whereas it induced slow sustained contractions dose dependently in Mn-loaded preparations. Although cumulative applications of PDBu desensitized the preparations to this phorbol ester, the desensitization did not affect Mn(2+)-dependent NE-induced contractions. PDBu did not affect the dose-response relation of NE in Mn-loaded preparations. 4. Staurosporine (10-100 nM) preferentially inhibited NE-induced contractions in normal and in Mn-loaded preparations to that induced by K+ in normal preparations. However, bisindolylmaleimide I (1 microM) did not inhibit NE-induced contractions in normal and Mn-loaded preparations but abolished PDBu-induced contractions. 5. These results suggest that the NE-induced increase in the Mn2+ sensitivity of contractile mechanisms contributes to Mn(2+)-dependent NE-induced contractions, which may not involve the activation of protein kinase C.
Tsunobuchi-Ushijima
H
H
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Gomi
Y
Y
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004928:Escin / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D015240:Phorbol 12,13-Dibutyrate; D004928:Escin; D006160:Guanosine Triphosphate; D011493:Protein Kinase C; D019311:Staurosporine; D008274:Magnesium; C088060:bisindolylmaleimide; D002118:Calcium; D009638:Norepinephrine