Effects of intrathecal injection of a hyperpolarization-activated channel (Ih) inhibitor ZD7288 on bladder function in urethane-anesthetized rats.
OBJECTIVE
The role of I(h) channels at the spinal level in the control of bladder function was examined in urethane anesthetized female rats.


METHODS
Bladder activity was recorded via a transurethral catheter under isovolumetric conditions or via an intravesical catheter during continuous infusion cystometry. ZD7288, a selective I(h) channel inhibitor, was administered intrathecally at L6-S1 segmental levels of the spinal cord.


RESULTS
Under isovolumetric conditions, intrathecal 0.3 microg of ZD7288 was inactive, whereas 1 and 3 microg abolished bladder activity for 5.6 +/- 1.8 and 20.7 +/- 3.9 min, respectively. Three micrograms also tended to decrease the amplitude of the contractions when they reappeared. During continuous cystometry, an intrathecal injection of ZD7288 at 0.3-3 microg dose-dependently increased the intercontraction intervals by 7.5%, 33.1%, and 57.5% from pre-drug values. A higher dose of ZD7288 (3 microg) tended to increase the pressure threshold for inducing micturition by 16.6% and the maximum voiding pressure by 11.1%. On the other hand, cardiovascular parameters such as heart rate and mean blood pressure were not affected by 0.3-3 microg of intrathecal ZD7288.


CONCLUSIONS
These results indicate that I(h) channels play an important role in the control of micturition. Because I(h) channel inhibition in the lumbosacral spinal cord reduced the frequency of the micturition reflex without significantly affecting the amplitude of reflex bladder contraction, I(h) channels might preferentially be involved in afferent processing in the spinal cord to control the micturition reflex.
Masuda
Noriyuki
N
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Masuda
Hitoshi
H
Matsuyoshi
Hiroko
H
Chancellor
Michael B
MB
de Groat
William C
WC
Yoshimura
Naoki
N
D018686:Anesthetics, Intravenous; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007278:Injections, Spinal; D009119:Muscle Contraction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D015221:Potassium Channels / Q000378:metabolism; D011312:Pressure; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D014520:Urethane; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D014554:Urination / Q000187:drug effects; D014563:Urodynamics / Q000187:drug effects
D018686:Anesthetics, Intravenous; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788; D014520:Urethane