1. The subcellular mechanisms regulating stimulus-contraction coupling in detrusor remain to be determined. We used Ca2+-free solutions, Ca2+ channel blockers, cyclopiazonic acid (CPA), and RhoA kinase (ROK) inhibitors to test the hypothesis that Ca2+ influx and Ca2+ sensitization play primary roles. 2 In rabbit detrusor, peak bethanechol (BE)-induced force was inhibited 90% by incubation for 3 min in a Ca2+-free solution. By comparison, a 20 min incubation of rabbit femoral artery in a Ca2+-free solution reduced receptor-induced force by only 5%. 3. In detrusor, inhibition of sarcoplasmic reticular (SR) Ca2+ release by 2APB, or depletion of SR Ca2+ by CPA, inhibited BE-induced force by only 27%. The CPA-insensitive force was abolished by LACl3. By comparison, 2APB inhibited receptor-induced force in rabbit femoral artery by 71%. 4. In the presence of the non-selective cation channel (NSCC) inhibitor, LOE-908, BE did not produce an increase in [Ca2+]i but did produce weak increases in myosin phosphorylation and force. 5. Inhibitors of ROK-induced Ca2+ sensitization, HA-1077 and Y-27632, inhibited BE-induced force by ∼50%, and in combination with LOE-908, nearly abolished force. 6. These data suggest that two principal muscarinic receptor-stimulated detrusor contractile mechanisms include NSCC activation, that elevates [Ca2+]i and ROK activation, that sensitizes cross bridges to Ca2+.
CITATION STYLE
Jezior, J. R., Brady, J. D., Rosenstein, D. I., Mccammon, K. A., Miner, A. S., & Ratz, P. H. (2001). Dependency of detrusor contractions on calcium sensitization and calcium entry through LOE-908-sensitive channels. British Journal of Pharmacology, 134(1), 78–87. https://doi.org/10.1038/sj.bjp.0704241
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