Methionine and its derivatives increase bladder excitability by inhibiting stretch-dependent K(+) channels.
OBJECTIVE
During the bladder filling phase, the volume of the urinary bladder increases dramatically, with only minimal increases in intravesical pressure. To accomplish this, the smooth muscle of the bladder wall must remain relaxed during bladder filling. However, the mechanisms responsible for the stabilization of bladder excitability during stretch are unclear. We hypothesized that stretch-dependent K(+) (TREK) channels in bladder smooth muscle cells may inhibit contraction in response to stretch.


METHODS
Bladder tissues from mouse, guinea pig and monkey were used for molecular, patch clamp, mechanical, electrical, Ca(2+) imaging and cystometric responses to methionine and its derivatives, which are putative blockers of stretch-dependent K(+) (SDK) channels.


RESULTS
SDK channels are functionally expressed in bladder myocytes. The single channel conductance of SDK channels is 89pS in symmetrical K(+) conditions and is blocked by L-methionine. Expressed TREK-1 currents are also inhibited by L-methioninol. All three types of bladder smooth muscle cells from mouse, guinea pig and monkey expressed TREK-1 genes. L-methionine, methioninol and methionine methyl ester but not D-methionine increased contractility in concentration-dependent manner. Methioninol further increased contractility and depolarized the membrane in the presence of blockers of Ca(2+)-activated K(+) conductance. L-methionine induced Ca(2+) waves that spread long distances through the tissue under stretched conditions and were associated with strong contractions. In cystometric assays, methioninol injection increased bladder excitability mimicking overactive bladder activity.


CONCLUSIONS
Methioninol-sensitive K(+) (SDK, TREK-1) channels appear to be important to prevent spread of excitation through the syncitium during bladder filling.
Baker
S A
SA
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Hennig
G W
GW
Han
J
J
Britton
F C
FC
Smith
T K
TK
Koh
S D
SD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D006168:Guinea Pigs; D008252:Macaca fascicularis; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; C014656:methioninol; D008715:Methionine; C038344:methionine methyl ester; D002118:Calcium