Neurogenic mechanisms contribute to hypertension in mice with disruption of the K-Cl cotransporter KCC3.
The neurodegenerative disorder Andermann syndrome is caused by mutations of the K-Cl cotransporter KCC3. Mice with a targeted disruption of the corresponding gene, Slc12a6, reproduce neurodegeneration of the peripheral and central nervous system (CNS) and display arterial hypertension. Kcc3 is expressed in numerous tissues, including the CNS and vascular smooth muscle cells. As the intracellular chloride concentration may influence myogenic tone and hence blood pressure, we measured the chloride concentration in vascular smooth muscle cells. It was indeed increased in superficial brain arteries and saphenous arteries of Kcc3(-/-) mice. Isolated saphenous arteries and their third-order branches, however, reacted indistinguishably to changes in intravascular pressure, stimulation of alpha1-adrenoreceptors, exogenous nitric oxide, or blockade of calcium-activated chloride channels. Likewise, the responses to alpha1-adrenergic stimulation or exogenous nitric oxide in vivo were identical in both genotypes. These results argue against a major vascular-intrinsic component of arterial hypertension in Kcc3(-/-) mice. In contrast, either alpha1-adrenergic blockade or inhibition of ganglionic transmission abolished the difference in arterial blood pressure between both genotypes. This demonstrates a neurogenic component in the maintenance of this phenotype, which is further supported by an increase of urinary norepinephrine and epinephrine excretion in Kcc3(-/-) mice. Our data indicate that local control of myogenic tone does not require KCC3 and that hypertension in Kcc3(-/-) mice depends on an elevated sympathetic tone.
Rust
Marco B
MB
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Faulhaber
Jörg
J
Budack
Mareike K
MK
Pfeffer
Carsten
C
Maritzen
Tanja
T
Didié
Michael
M
Beck
Franz-Xaver
FX
Boettger
Thomas
T
Schubert
Rudolf
R
Ehmke
Heimo
H
Jentsch
Thomas J
TJ
Hübner
Christian A
CA
D000450:Aldosterone / Q000097:blood; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D027981:Symporters / Q000502:physiology*; D014661:Vasoconstriction; D000096922:K Cl- Cotransporters
D000450:Aldosterone; D002118:Calcium; D002712:Chlorides; D027981:Symporters; C492280:Slc12a6 protein, mouse; D000096922:K Cl- Cotransporters