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Key points Large conductance voltage- and Ca2+-activated K+ channels (BK channels) require the ancillary subunit BKβ1 for normal function in smooth muscle, renal and adrenal tissues., BK channels influence vascular tone and blood pressure in mice, and a gain-of-function BKβ1 polymorphism has been associated with low prevalence of diastolic hypertension in human population studies., In this study, we genetically removed the BKβ1 gene in three different strains of mice and then restored BKβ1 expression selectively in smooth muscle to determine its tissue-specific contribution to blood pressure., We show that loss of BKβ1 in smooth muscle cells robustly increases vascular tone, but blood pressure of mice lacking BKβ1 was increased, unaltered or decreased depending on the genetic background., The results clarify the contested view that BK channel activity influences blood pressure by setting vascular tone and they shed light on the relative contribution of vascular and renal/adrenal BK channel activity to blood pressure levels., Abstract The large conductance voltage- and Ca2+-activated K+ (BK) channel is an important determinant of vascular tone and contributes to blood pressure regulation. Both activities depend on the ancillary BKβ1 subunit. To determine the significance of smooth muscle BK channel activity for blood pressure regulation, we investigated the potential link between changes in arterial tone and altered blood pressure in BKβ1 knockout (BKβ1−/−) mice from three different genetically defined strains. While vascular tone was consistently increased in all BKβ1−/− mice independent of genetic background, BKβ1−/− strains exhibited increased (strain A), unaltered (strain B) or decreased (strain C) mean arterial blood pressures compared to their corresponding BKβ1+/+ controls. In agreement with previous data on aldosterone regulation by renal/adrenal BK channel function, BKβ1−/− strain A mice have increased plasma aldosterone and increased blood pressure. Consistently, blockade of mineralocorticoid receptors by spironolactone treatment reversibly restored the elevated blood pressure to the BKβ1+/+ strain A level. In contrast, loss of BKβ1 did not affect plasma aldosterone in strain C mice. Smooth muscle-restricted restoration of BKβ1 expression increased blood pressure in BKβ1−/− strain C mice, implying that impaired smooth muscle BK channel activity lowers blood pressure in these animals. We conclude that BK channel activity directly affects vascular tone but influences blood pressure independent of this effect via different pathways. [ABSTRACT FROM AUTHOR]