Decreased expression of maxi-K+ channel beta1-subunit and altered vasoregulation in hypoxia.
BACKGROUND
Hypertension, a major cause of cardiovascular morbidity and mortality, can result from chronic hypoxia; however, the pathogenesis of this disorder is unknown. We hypothesized that downregulation of the maxi-K+ channel beta1-subunit by hypoxia decreases the ability of these channels to hyperpolarize arterial smooth muscle cells, thus favoring vasoconstriction and hypertension.


RESULTS
Lowering O2 tension produced a decrease of maxi-K+ beta1-subunit mRNA levels in rat (aortic and basilar) and human (mammary) arterial myocytes. This was paralleled by a reduction of the beta1-subunit protein level as determined by immunocytochemistry and flow cytometry. Exposure to hypoxia also produced a decrease of open probability, mean open time, and sensitivity to the xenoestrogen tamoxifen of single maxi-K+ channels recorded from patch-clamped dispersed myocytes. The number of channels per patch and the single-channel conductance were not altered. The vasorelaxing force of maxi-K+ channels was diminished in rat and human arterial rings exposed to low oxygen tension.


CONCLUSIONS
These results indicate that a decrease of the maxi-K+ channel beta1-subunit expression in arterial myocytes is a key factor in the vasomotor alterations induced by hypoxia.
Navarro-Antolín
Javier
J
Laboratorio de Investigaciones Biomédicas, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, Spain.
Levitsky
Konstantin L
KL
Calderón
Eva
E
Ordóñez
Antonio
A
López-Barneo
José
J
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000209:etiology; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species; D014664:Vasodilation / Q000187:drug effects
D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D017382:Reactive Oxygen Species; D010656:Phenylephrine