Inhibition Of Inward‐Rectifier K+ Channels In Vascular Smooth Muscle Restores Myogenic Tone Development In Mouse Bladder Arterioles

Abstract

The urinary bladder is highly vascularized, and chronic decreases in blood flow are linked to bladder dysfunction. While increases in intraluminal pressure constrict most arterioles (“myogenic tone”), mouse bladder arterioles do not exhibit a myogenic response to pressure. We examined the electrophysiological and vasoactive properties of mouse bladder feed arterioles to determine why myogenic tone is absent. In isolated pressurized bladder arterioles, smooth muscle cell membrane potential was hyperpolarized at 20 mmHg (−72.8±1.4 mV), and did not change significantly when intraluminal pressure was increased to 80 mmHg (−74.3±2.2 mV). However, increasing extracellular K+ from 5.9 mM to 60 mM caused a significant depolarization (−22.7±0.2 mV) at 80 mmHg, which was accompanied by vessel constriction. Given that inward‐rectifier K+ (KIR) channels can have a strong influence on membrane potential in smooth muscle cells, membrane potential was again measured in the presence or absence of the KIR channel blocker BaCl2 (100 μM). In the absence of BaCl2, smooth muscle cell membrane potential remained hyperpolarized at both 20 to 80 mmHg (−70.4±1.9 mV and −72.2±3.1 mV, respectively). In the presence of BaCl2, membrane potential depolarized significantly at both 20 mmHg (−56.2±3.1 mV) and 80 mmHg (−43.3±2.0 mV). To determine if KIR channel inhibition could restore myogenic tone, diameter of isolated pressurized bladder arterioles was measured at increasing pressures (10–80 mmHg) in the presence and absence of 100 μM BaCl2. BaCl2 had no effect on vessel diameter at 20 and 40 mmHg, but resulted in the development of significant myogenic tone at both 60 and 80 mmHg (25.5±9.1% and 41.5±3.9% constriction, respectively). These data support the concept that, in urinary bladder arterioles, KIR channel conductance cannot be overcome by pressure‐induced depolarizing conductances, and thus smooth muscle cell membrane potential remains hyperpolarized and the arterioles do not constrict as intraluminal pressure increases. This represents a novel adaptation to maintain blood flow into the bladder during filling.Support or Funding InformationSupported by NIH R37DK053832 and K01DK103840.