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Department of Pharmacology and Therapeutics and McKnight Brain Institute, Vascular Biology and Cell Physiology Group, University of Florida College of Medicine, Gainesville, Florida 32610-0267
Earlier studies have implicated
phospholipase C (PLC) in the development of myogenic tone (MT) based on
pharmacological studies in larger arteries. In the present study, we
further investigated the cellular effects of PLC inhibition using
pharmacological and electrophysiological approaches to provide more
quantitative functional evidence for the involvement of PLC in the
genesis of MT in small cerebral arteries. The
phosphatidylinositol-selective PLC (PI-PLC) inhibitor U-73122 decreased
MT by 87% in posterior cerebral arteries from Sprague-Dawley rats with
pIC50 of 6.2 ± 0.09 (n = 5). Similar potency (pIC50 of 6.2 ± 0.04, n = 5)
was observed in arteries with MT that were further constricted with 30 nM serotonin. The phosphatidylcholine-specific (PC-PLC) inhibitor
D609 had no effect on MT. U-73343, the inactive analog of U-73122, did
not show any relaxant effect, but at higher concentrations (>1 µM)
it reduced MT. In the presence of 125-500 nM U-73122, the
pressure-diameter curves shifted toward that obtained in Ca-free
conditions. U-73122-mediated decrease in MT was accompanied by a
decrease in mean arterial wall calcium (maximum effect: 77 ± 3%
of 16 mM KCl-mediated decrease, n = 4). This was due to
a simultaneous membrane potential hyperpolarization of ~9 mV or from
44 ± 1 to 53 ± 2 mV (10 µM, P < 0.001, n = 8). In summary, this study provides the
first quantitative data suggesting a critical importance of PI-PLC in
the genesis of pressure-induced MT in rat cerebral arteries via
membrane potential depolarization and increased calcium influx.
serotonin; diacylglycerol; myogenic constriction; U-73122; D609
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