Inhibition of vascular smooth muscle inward-rectifier K+channels restores myogenic tone in mouse urinary bladder arterioles.
Prolonged decreases in urinary bladder blood flow are linked to overactive and underactive bladder pathologies. However, the mechanisms regulating bladder vascular reactivity are largely unknown. To investigate these mechanisms, we examined myogenic and vasoactive properties of mouse bladder feed arterioles (BFAs). Unlike similar-sized arterioles from other vascular beds, BFAs failed to constrict in response to increases in intraluminal pressure (5-80 mmHg). Consistent with this lack of myogenic tone, arteriolar smooth muscle cell membrane potential was hyperpolarized (-72.8 ± 1.4 mV) at 20 mmHg and unaffected by increasing pressure to 80 mmHg (-74.3 ± 2.2 mV). In contrast, BFAs constricted to the thromboxane analog U-46619 (100 nM), the adrenergic agonist phenylephrine (10 µM), and KCl (60 mM). Inhibition of nitric oxide synthase or intermediate- and small-conductance Ca2+-activated K+channels did not alter arteriolar diameter, indicating that the dilated state of BFAs is not attributable to overactive endothelium-dependent dilatory influences. Myocytes isolated from BFAs exhibited BaCl2(100 µM)-sensitive K+currents consistent with strong inward-rectifier K+(KIR) channels. Notably, block of these KIRchannels "restored" pressure-induced constriction and membrane depolarization. This suggests that these channels, in part, account for hyperpolarization and associated absence of tone in BFAs. Furthermore, smooth muscle-specific knockout of KIR2.1 caused significant myogenic tone to develop at physiological pressures. This suggests that1) the regulation of vascular tone in the bladder is independent of pressure, insofar as pressure-induced depolarizing conductances cannot overcome KIR2.1-mediated hyperpolarization; and2) maintenance of bladder blood flow during bladder filling is likely controlled by neurohumoral influences.
Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and nathan.tykocki@uvm.edu.
Nathan R
0000-0001-5432-7656
NR
Tykocki
Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and.
Adrian D
AD
Bonev
Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and.
Thomas A
TA
Longden
Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and.
Thomas J
TJ
Heppner
Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont; and.|Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
Mark T
MT
Nelson
D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure; D005838:Genotype; D066298:In Vitro Techniques; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D001743:Urinary Bladder / Q000098:blood supply*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
C489461:Kir2.1 channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents
myogenic tone; potassium channels; urinary bladder; vasculature