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1Microvascular Biology Group, School of Medical Sciences, RMIT University, Bundoora, Victoria; and 2Department of Physiology and Pharmacology, University of New South Wales, Kensington, New South Wales, Australia
Submitted 31 March 2005 ; accepted in final form 27 April 2005
The present studies examined relationships between intraluminal pressure, membrane potential (Em), and myogenic tone in skeletal muscle arterioles. Using pharmacological interventions targeting Ca2+ entry/release mechanisms, these studies also determined the role of Ca2+ pathways and Em in determining steady-state myogenic constriction. Studies were conducted in isolated and cannulated arterioles under zero flow. Increasing intraluminal pressure (0–150 mmHg) resulted in progressive membrane depolarization (–55.3 ± 4.1 to –29.4 ± 0.7 mV) that exhibited a sigmoidal relationship between extent of myogenic constriction and Em. Thus, despite further depolarization, at pressures >70 mmHg, little additional vasoconstriction occurred. This was not due to an inability of voltage-operated Ca2+ channels to be activated as KCl (75 mM) evoked depolarization and vasoconstriction at 120 mmHg. Nifedipine (1 µM) and cyclopiazonic acid (30 µM) significantly attenuated established myogenic tone, whereas inhibition of inositol 1,4,5-trisphosphate-mediated Ca2+ release/entry by 2-aminoethoxydiphenylborate (50 µM) had little effect. Combinations of the Ca2+ entry blockers with the sarcoplasmic reticulum (SR) inhibitor caused a total loss of tone, suggesting that while depolarization-mediated Ca2+ entry makes a significant contribution to myogenic tone, an interaction between Ca2+ entry and SR Ca2+ release is necessary for maintenance of myogenic constriction. In contrast, none of the agents, in combination or alone, altered Em, demonstrating the downstream role of Ca2+ mobilization relative to changes in Em. Large-conductance Ca2+-activated K+ channels modulated Em to exert a small effect on myogenic tone, and consistent with this, skeletal muscle arterioles appeared to show an inherently steep relationship between Em and extent of myogenic tone. Collectively, skeletal muscle arterioles exhibit complex relationships between Em, Ca2+ availability, and myogenic constriction that impact on the tissue's physiological function.
voltage-operated calcium channels; large-conductance calcium-activated potassium channels
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