Effect of extracellular Ca2+ on cholinergic, KCl and phorbol ester-mediated phosphoinositide turnover and guinea pig urinary bladder contraction.
The effect of extracellular Ca2+ ([Ca2+]o) on cholinergic, KCl and phorbol ester-mediated detrusor contractions was related to phosphoinositide (PI) breakdown in guinea pig urinary bladder. Carbachol (1.0 mM) elicited a 20-fold increase in inositol phosphate (IP) accumulation both in presence and absence of [Ca2+]o yielding the same EC50 value (approximately 12 microM). In contrast, carbachol-induced detrusor contractions were reduced by 35% without [Ca2+]o, but maximal efficacy was restored with Ca2+ replenishment. In absence of [Ca2+]o, repeated cholinergic stimulation yielded contractions only if tissues were intermittently equilibrated in [Ca2+]o. High K+ and PDBu evoked [Ca2+]o-dependent contractions. Ca2+ channel antagonists and divalent metal cations inhibited high K+ more potently than carbachol-mediated contractions. Together, these findings suggest multiple sources of Ca2+ for urinary bladder contraction, where voltage-sensitive responses depend primarily on [Ca2+]o and PI-linked muscarinic responses involved Ca2+ mobilization from intracellular stores as well. Clinical agents used for the treatment of urinary incontinence inhibited both carbachol-induced PI turnover and muscle contraction with the same rank order of potency both in presence and absence of [Ca2+]o. These findings suggest that the cholinergic mechanism of action of these agents involves the PI-Ca2+ effector system.
Lowe
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Nova Pharmaceutical Corporation, Baltimore, MD 21224.
Noronha-Blob
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D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
D010703:Phorbol Esters; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D015240:Phorbol 12,13-Dibutyrate; D011189:Potassium Chloride; D002217:Carbachol; D011493:Protein Kinase C; D002118:Calcium