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Open Access

Analysis of BKCa channel deficient mice

  • Peter Ruth1Email author,
  • Iancu Bucurenciu1,
  • Hong Zhao1,
  • Xiao-Bo Zhou2,
  • Ulrike Sausbier1,
  • Claudia Arntz1,
  • Susi Feil3,
  • Kyrill Essin4,
  • Robert Feil3,
  • Franz Hofmann3,
  • Hans-Günther Knaus5,
  • Michael J Shipston6,
  • Johan Storm7,
  • Michael Korth2,
  • Rudolf Schubert8,
  • Maik Gollasch4 and
  • Matthias Sausbier1
BMC Pharmacology20055(Suppl 1):S39

https://doi.org/10.1186/1471-2210-5-S1-S39

Published: 16 June 2005

The large-conductance, voltage and Ca2+-dependent K+ (BK) channel links membrane depolarization and local increases in cytosolic Ca2+ to hyperpolarizing K+ outward currents and has been proposed as an important effector of the cGMP/cGMP kinase pathway in the control of vascular and smooth muscle tone.

Deletion of the pore-forming BK channel α subunit leads to a significant blood pressure elevation. In smooth muscle from small arteries, deletion of the BK channel leads to a depolarized membrane potential, a complete lack of membrane hyperpolarizing spontaneous K+ outward currents, and an attenuated cGMP vasorelaxation associated with a reduced suppression of Ca2+ transients by cGMP. However, the BK-/- mice also exhibit a hyperaldosteronism accompanied with decreased serum K+ levels as well as increased vascular tone in small arteries. The high level of BK channel expression observed in wild-type adrenal glomerulosa cells, together with unaltered serum renin activities and corticotropin levels in mutant mice, suggests that the hyperaldosteronism results from abnormal adrenal cortical function in BK-/- mice. The urinary bladder phenotype in BK-/- comprises an overactive bladder associated with an increased intravesical pressure and frequent micturitions. This phenotype was traced back to hyperactivity of the detrusor muscle caused by depolarized membrane potential, as well as disruption of cGMP-dependent modulation of the frequency of rhythmic contractions. In BK-/- detrusor, however, cGMP efficiently reduced the contractility of the muscle, while cGMP did not affect the contractility of wild-type detrusor. It appears that the BK channel deficiency activates or up-regulates cGMP-sensitive mechanisms that are responsible for the inhibitory effect of cGMP on muscle contractility in the BK-/- genotype.

These results identify previously unknown roles of BK channels in blood pressure regulation and raise the possibility that BK channel dysfunction may underlie specific forms of hyperaldosteronism. Further, the results identify BK channels as predominant regulator of urinary bladder smooth muscle contractility. The modulatory role of cGMP for urinary bladder rhythmic contractions switches from frequency control in wild-type towards contractility regulation in BK-/- detrusor.

Authors’ Affiliations

(1)
Pharmakologie und Toxikologie, Pharmazeutisches Institut der Universität Tübingen
(2)
Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf
(3)
Institut für Pharmakologie und Toxikologie der Technischen Universität München
(4)
Helios Franz-Volhard-Klinik, Med. Klinik für Nephrologie und Intensivmedizin, MDC für Molekulare Medizin, Humboldt Universität Berlin
(5)
Institut für Biochemische Pharmakologie, Universität Innsbruck
(6)
Membrane Biology Group, Division of Biomedical Science, University of Edinburgh
(7)
Dept. of Physiology, and Centre for Molecul, Biology & Neuroscience, University of Oslo
(8)
Institut für Physiologie der Universität Rostock

Copyright

© BioMed Central Ltd 2005

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