beta(1)-subunit of BK channels regulates arterial wall [Ca2+] and diameterin mouse cerebral arteries

Mice with a disrupted beta (1) (BK beta (1))-subunit of the large-conductan ce Ca2+-activated K+ (BK) channel gene develop systemic hypertension and ca rdiac hypertrophy, which is likely caused by uncoupling of Ca2+ sparks to B K channels in arterial smooth muscle cells. However, little is known about the physiological levels of global intracellular Ca2+ concentration ([Ca2+] (i)) and its regulation by Ca2+ sparks and BK channel subunits. We utilized a BK beta (1) knockout C57BL/6 mouse model and studied the effects of inhi bitors of ryanodine receptor and BK channels on the global [Ca2+](i) and di ameter of small cerebral arteries pressurized to 60 mmHg. Ryanodine (10 muM ) or iberiotoxin (100 nM) increased [Ca2+](i) by similar to 75 nM and const ricted +/+ BK beta (1) wildtype arteries (pressurized to 60 mmHg) with myog enic tone by;10 mm. In contrast, ryanodine (10 mM) or iberiotoxin (100 nM) had no significant effect on [Ca2+](i) and diameter of -/- BK beta (1)-pres surized (60 mmHg) arteries. These results are consistent with the idea that Ca2+ sparks in arterial smooth muscle cells limit myogenic tone through ac tivation of BK channels. The activation of BK channels by Ca2+ sparks reduc es the voltage-dependent Ca2+ influx and [Ca2+](i) through tonic hyperpolar ization. Deletion of BK beta (1) disrupts this negative feedback mechanism, leading to increased arterial tone through an increase in global [Ca2+](i) .