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Excitability of skeletal muscle arterioles

by
Alexandra Uliyanova
Pharmacology and Physiology

B.S. 1999, Moscow Institute of Physics and Technology, Russia
M.S. 2001, Moscow Institute of Physics and Technology, Russia

Thesis advisor: Roman Shirokov, Ph.D.
Assistant Professor
Department of Pharmacology and Physiology

Department of Pharmacology and Physiology
MSB H-609b
Conference Room

Tuesday, February 3, 2009
10:00 a.m.


Abstract

Blood flow to skeletal muscle can increase several times to meet the demands of exercise. Blood flow is actively controlled by contraction or relaxation of arteriolar smooth muscle cells. It is well established that Ca2+ influx through L-type voltage-gated Ca2+ channels is a key step in the arteriolar constriction. However, little is known about ionic mechanisms underlying the smooth muscle excitability.
We developed a method that allowed us to isolate skeletal muscle arterioles of fourth order (wl20 m) and to record from the intact vessels. Smooth muscle cells were electrically uncoupled from each other by peptides, which inhibit the formation of gap junctions. Although currents through L-type Ca2+ channels (15 A/F in 20 mM Ca2+) were expected to be dominant, action potentials were not eliminated by removal of extracellular Ca2+ (<10 M) or by addition of L-type Ca2+ channel blocker nifedipine (10 M). Instead, we found that Na+ channels blocker tetrodotoxin (TTX, 1 M) abolished the upstroke at low, but not at normal (2 mM), extracellular Ca2+. Using whole-cell voltage-clamp we recorded TTX-sensitive Na+ currents (about 20 A/F) at normal (2 mM) extracellular Ca2+. The currents were decreased five-fold when extracellular [Ca2+] was 10 mM. TTX-sensitive Na+ currents were also decreased about three-fold in the presence of 10 mM caffeine, indicating that intracellular Ca2+ regulates voltage-gated Na+ channels. We also found Ca2+ currents that are resistant to 10 M nifedipine (5 A/F in 20 mM Ca2+). Based on their biophysical properties, they are likely to be through voltage-gated T-type Ca2+ channels.
Our results indicate that Na+ and at least two types (T- and L-) of Ca2+ voltage-gated channels contribute to depolarization and voltage-dependent Ca2+ signaling of smooth muscle cells in skeletal muscle arterioles. Voltage-gated Na+ channels appear to be under tight control by intracellular Ca2+.


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