Large-conductance Ca²⁺-activated K⁺channel β₁-subunit knockout mice are not hypertensive

Abstract

Large-conductance Ca2+-activated K+ (BK) channels are composed of pore-forming α-subunits and accessory β1-subunits that modulate Ca2+ sensitivity. BK channels regulate arterial myogenic tone and renal Na+ clearance/K+ reabsorption. Previous studies using indirect or short-term blood pressure measurements found that BK channel β1-subunit knockout (BK β1-KO) mice were hypertensive. We evaluated 24-h mean arterial pressure (MAP) and heart rate in BK β1-KO mice using radiotelemetry. BK β1-KO mice did not have a higher 24-h average MAP when compared with wild-type (WT) mice, although MAP was ∼10 mmHg higher at night. The dose-dependent peak declines in MAP by nifedipine were only slightly larger in BK β1-KO mice. In BK β1-KO mice, giving 1% NaCl to mice to drink for 7 days caused a transient (5 days) elevation of MAP (∼5 mmHg); MAP returned to pre-saline levels by day 6. BK β1-KO mesenteric arteries in vitro demonstrated diminished contractile responses to paxilline, increased reactivity to Bay K 8644 and norepinephrine (NE), and maintained relaxation to isoproterenol. Paxilline and Bay K 8644 did not constrict WT or BK β1-KO mesenteric veins (MV). BK β1-subunits are not expressed in MV. The results indicate that BK β1-KO mice are not hypertensive on normal or high-salt intake. BK channel deficiency increases arterial reactivity to NE and L-type Ca2+ channel function in vitro, but the L-type Ca2+ channel modulation of MAP is not altered in BK β1-KO mice. BK and L-type Ca(2+) channels do not modulate murine venous tone. It appears that selective loss of BK channel function in arteries only is not sufficient to cause sustained hypertension.

High-fat diet-induced obesity alters nitric oxide-mediated neuromuscular transmission and smooth muscle excitability in the mouse distal colon

“…After weaning, these mice were fed either a CD (10 kcal% fat; D12450B) or an isocaloric HFD (60 kcal% fat; D12492, Research Diets, New Brunswick, NJ) (http://jaxmice.jax.org/diomice/diets.html). Founder BK␤1 Ϫ/Ϫ mice were obtained as a gift from Dr. Robert Brenner (University of Texas Health Science Center, San Antonio, TX) and maintained as a homozygous line at Michigan State University (19,64,65,66). BK␤ 1 Ϫ/Ϫ mice were weaned at 3 wk and placed either on the CD or the HFD.…”

IRAG and novel PKG targeting in the cardiovascular system

“…In the vasculature, BK Ca regulates basal blood pressure since the deletion of the pore-forming BK Ca ␣-subunit in mice leads to a significant basal blood pressure elevation (69). However, knockout mice of the accessory calcium-sensitive ␤ 1 -subunit were not hypertensive (96). Interestingly, the BK Ca ␣-subunit deletion enhanced the expression of cGMP signaling proteins (PKG1 and IRAG) in tracheal smooth muscle and led to cholinergic bronchoconstriction in the airways (71).…”

Penitrem A as a Tool for Understanding the Role of Large Conductance Ca2+/Voltage-Sensitive K+Channels in Vascular Function

“…Such changes may explain variable observations regarding blood pressure in BK channel subunit knockout mice. For instance, BK ␤1 subunit knockout mice were originally reported as hypertensive (Brenner et al, 2000;Plü ger et al, 2000), but a recent study contradicted that (Xu et al, 2011). The earlier studies included acute measurements of blood pressure in conscious mice with arterial catheters, whereas the later study used radiotelemetry to monitor blood pressure continuously for 1 week.…”

“…Genetic deletion of ␣ or ␤1 subunits produces hypertension; however, in addition to presumed changes in total peripheral resistance, the role of adrenal BK channels to regulate aldosterone production must be considered (Sausbier et al, 2005;Grimm et al, 2009). In contrast to the original report (Brenner et al, 2000), a recent study indicated that ␤1 knockout mice are normotensive (Xu et al, 2011). Thus, much remains to be determined about the physiological roles of BK channels and/or compensations in response to BK channel gene deletion.…”