β1-subunit of BK channels regulates arterial wall [Ca2+] and diameter in mouse cerebral arteries

Abstract

Mice with a disrupted β1(BKβ1)-subunit of the large-conductance Ca2+-activated K+ (BK) channel gene develop systemic hypertension and cardiac hypertrophy, which is likely caused by uncoupling of Ca2+ sparks to BK 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 BKβ1 knockout C57BL/6 mouse model and studied the effects of inhibitors of ryanodine receptor and BK channels on the global [Ca2+]i and diameter of small cerebral arteries pressurized to 60 mmHg. Ryanodine (10 μM) or iberiotoxin (100 nM) increased [Ca2+]i by ∼75 nM and constricted +/+ BKβ1 wild-type arteries (pressurized to 60 mmHg) with myogenic tone by ∼10 μm. In contrast, ryanodine (10 μM) or iberiotoxin (100 nM) had no significant effect on [Ca2+]i and diameter of −/− BKβ1-pressurized (60 mmHg) arteries. These results are consistent with the idea that Ca2+ sparks in arterial smooth muscle cells limit myogenic tone through activation of BK channels. The activation of BK channels by Ca2+ sparks reduces the voltage-dependent Ca2+ influx and [Ca2+]i through tonic hyperpolarization. Deletion of BKβ1 disrupts this negative feedback mechanism, leading to increased arterial tone through an increase in global [Ca2+]i.