Muscarinic down-regulation of cAMP-stimulated potassium ion secretion by rabbit distal colon.
The sustained effects of the cholinergic agonist carbachol (CCh) on electrolyte transport across the isolated, short-circuited rabbit distal colon were examined in the absence and presence of secretagogue (di-butyryl cyclic-adenosine monophosphate, dB-cAMP). Steady-state, basal absorption of 22Na+, 42K+ (86Rb+), and 36Cl- were not significantly altered by addition of the CCh (10(-4) mmol/l) to the serosal reservoir. Stimulation with dB-cAMP (1.0 mmol/l, serosal) promoted K+ (or Rb+) and Cl- secretion across the colon, without significantly affecting the unidirectional or net fluxes of Na+. Serosal (but not mucosal) addition of CCh to dB-cAMP-stimulated tissues reduced the serosal to mucosal flux of Rb+ (J(Rb)SM) in a concentration-dependent manner with a half-maximum concentration approximately equal 5 micromol/l. Pretreatment with CCh (100 micromol/l, serosal) inhibited dB-cAMP-induced K+ secretion, but had no significant effect on the steady-state unidirectional fluxes of Na+ or Cl-. Serosal histamine (20 micromol/l) also inhibited J(Rb)SM in dB-cAMP-stimulated tissues. Serosal epinephrine (10 micromol/l) promoted a decrease in short-circuit current (Isc) and transepithelial potential (VT) that was mirrored by increases in J(Rb)SM. Both Isc, and VT became more positive and J(Rb)SM was reduced when CCh was added to the epinephrine-stimulated tissues. Serosal muscarine (50 micromol/l) mimicked the CCh-induced inhibition of J(Rb)SM, but serosal nicotine (50 micromol/l) had no effect. In atropine-treated tissues (1 micromol/l, serosal), CCh failed to block dB-cAMP-stimulated increases in J(Rb)SM. The inhibitory action of CCh was observed in tissues that had been pretreated with 50 micromol/l serosal hexamethonium (a ganglionic transmission blocker) or 2 micromol/l serosal tetrodotoxin (a voltage-gated Na+ channel blocker), indicating that the inhibitory action of this cholinergic agonist does not depend on remnant enteric neural pathways. Rubidium ion transport across confluent monolayers of T84 cells was similarly affected by dB-cAMP and CCh, supporting the notion that enteric neural pathways are not required. Serosal charybdotoxin (20 nmol/l) mitigated the inhibitory action of CCh on J(Rb)SM in dB-cAMP-stimulated tissues, suggesting a role for basolateral, Ca2+-dependent K+ channels in the actions of CCh. It is concluded that basolateral muscarinic receptors (and possibly other Ca2+-dependent receptor pathways) of secretory colonocytes mediate the down-regulation of potassium ion secretion by rabbit distal colon, possibly by increasing basolateral membrane K+ conductance.
Freel
R W
RW
Department of Medicine, University of California at Irvine, 92697, USA. rfreel@uci.edu
Vaziri
N D
ND
Hatch
M
M
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology*; D004573:Electrolytes / Q000378:metabolism; D004594:Electrophysiology; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007477:Ions; D008297:Male; D011188:Potassium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000502:physiology*; D012413:Rubidium / Q000037:antagonists & inhibitors / Q000378:metabolism
D018679:Cholinergic Agonists; D004573:Electrolytes; D007477:Ions; D011976:Receptors, Muscarinic; D003994:Bucladesine; D006632:Histamine; D002217:Carbachol; D000242:Cyclic AMP; D012413:Rubidium; D011188:Potassium; D004837:Epinephrine