Phorbol ester-induced contractions of mouse detrusor muscle are inhibited by nifedipine.
The effects of phorbol esters on contractions of detrusor strips isolated from mouse urinary bladder were studied. Beta-phorbol-12,13-dibutyrate (beta-PDBu, 10 nM) significantly enhances both the neurogenic and myogenic detrusor contractions to a similar extent. By contrast, an inactive isoform of protein kinase C (PKC) stimulation, alpha-phorbol-12,13-dibutyrate (100 nM) has no such enhancing effect on the muscle contraction. The effect of beta-PDBu was dependent on the extracellular Ca2+ concentration. Nifedipine (0.3 microM, a L-type Ca2+ channel blocker), staurosporine (1 microM) and bisindolylmaleimide I (microM, a selective PKC inhibitor) but not omega-conotoxin GVIA (an N-type Ca2+ channel blocker) abolished the enhancing effect of beta-PDBu. In other words, beta-PDBu failed to augment the nifedipine-insensitive component of the muscle contraction. Moreover, beta-PDBu not only enhances the muscle response induced by exogenous agonists (acetylcholine or ATP) and KCl but also increases the resting tone of detrusor muscle, an effect which is also inhibited by nifedipine and bisindolylmaleimide I. From these findings, it is concluded that the enhancing effect of beta-PDBu is due to activation of the L-type Ca2+ channel through phosphorylation by protein kinase C. This allows more Ca2+ influx from the extracellular medium, leading to an increase in the contractions of the mouse detrusor muscle.
Lin
M J
MJ
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Liu
S H
SH
Lin-Shiau
S Y
SY
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D015240:Phorbol 12,13-Dibutyrate; D013779:Tetrodotoxin; D011493:Protein Kinase C; D009543:Nifedipine