Abstract
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 pIC(50) of 6.2 +/- 0.09 (n = 5). Similar potency (pIC(50) 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 microM) 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 approximately 9 mV or from -44 +/- 1 to -53 +/- 2 mV (10 microM, 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.
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