Bethanechol activates a post-receptor negative feedback mechanism in rabbit urinary bladder smooth muscle.
OBJECTIVE
Recent studies using vascular and gut smooth muscles indicate that contractile receptor agonists may activate post-receptor down-regulatory mechanisms causing a temporary reduction in the strength of subsequent contractions. Our data indicate a similar mechanism exists in detrusor smooth muscle of the urinary bladder.


METHODS
Each isolated strip of female rabbit detrusor was placed in a tissue bath, secured to an isometric force transducer, and length-adjusted until depolarization with 110 mM KCl produced a maximum contraction (S0). Subsequent contractions were normalized to S0 (S/S0) or to a first stimulus with 30 mM KCl or caffeine (S/S1). Tissues were pretreated with the muscarinic receptor agonist, bethanechol (BE), then stimulated with KCl, caffeine, or Bay k 8644 to identify potential post-receptor down-regulation.


RESULTS
Contractions induced by 30 mM KCl had three phases labeled fast peak (FP), slow peak (SP) and steady-state (SS). In tissues exposed for 30 min. to a maximum BE concentration then washed for 5 min., the KCl-induced FP and SP, but not SS, responses were reduced by approximately 40%. Smaller reductions in peak KCl-induced contractions occurred in tissues pretreated for a shorter duration or with a 100-fold lower BE concentration. This down-regulation induced by bethanechol pretreatment was reversible, lasting approximately 1-2 h. Not only were KCl-induced contractions reduced by BE pretreatment, but also those produced by the intracellular Ca(2+)-mobilizer, caffeine, and the L-type Ca2+ channel agonist, Bay k 8644.


CONCLUSIONS
Pretreatment of isolated strips of rabbit detrusor with a muscarinic receptor agonist produced short-term down-regulation of KCl-induced peak contractions that may have involved inhibition of both influx of extracellular Ca2+ and release of intracellular Ca2+. Reductions in the degree of this novel modulatory response during disease conditions and aging could enhance contractile activity, possibly causing detrusor instability.
Shenfeld
O Z
OZ
Department of Urology, Eastern Virginia Medical School, Norfolk 23501, USA.
Morgan
C W
CW
Ratz
P H
PH
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D018723:Bethanechol / Q000494:pharmacology*; D002110:Caffeine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005246:Feedback / Q000187:drug effects; D005260:Female; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D013552:Swine; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
D018721:Muscarinic Agonists; D018723:Bethanechol; D002110:Caffeine; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester