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Articles in PresS, published online ahead of print August 29, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00624.2002
Submitted on July 23, 2002
Accepted on August 19, 2002
1 Pharmacology & Therapeutics, University of Florida, Gainesville, Florida, USA
* To whom correspondence should be addressed. E-mail: hknot{at}college.med.ufl.edu.
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 myogenic tone 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 myogenic tone that were further constricted with 30 nM Serotonin. The Phosphatidylcholine-selective PLC inhibitor D609 had no effect on myogenic tone. U-73343, the inactive analogue 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 towards that obtained in Ca free conditions. U-73122-mediated decrease in myogenic tone was accompanied by a decrease in the 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 myogenic tone in rat cerebral arteries via membrane potential depolarization and increased calcium influx.
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