Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries

Abstract

Lagaud, Guy, Venkateswarlu Karicheti, Harm. J. Knot, George J. Christ, and Ismail Laher. Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries. Am J Physiol Heart Circ Physiol 283: H2177-H2186, 2002; 10.1152/ajpheart. 00605.2001.-The effects of two structurally distinct inhibitors of gap junction communication were studied by using three different forms of vasoconstriction in pressurized rat middle cerebral arteries. The sensitivity of myogenic tone (at 60 mmHg), vasopressin-induced tone (10 nM, at 20 mmHg), and depolarizing solution-induced tone (80 mM K ϩ , at 20 mmHg) to inhibition by heptanol (1.0 M to 3.0 mM) or 18␣-glycyrrhetinic acid (18␣-GA, 1.0 to 50 M) were determined. Pressure-induced myogenic tone was inhibited by heptanol (IC50 ϭ 0.75 Ϯ 0.09 mM) and 18␣-GA (ϳ30 M). Vasopressin-induced vasoconstriction was also inhibited by heptanol (IC 50 ϭ 0.4 Ϯ 0.3 mM) and 18␣-GA (Ͼ1 M). Depolarizing solution-induced vasoconstriction was less sensitive to inhibition by heptanol compared to vasopressin (P Ͻ 0.01) or pressure-induced constriction (P Ͻ 0.05). However, 18␣-GA did not inhibit depolarization-induced constriction. Sharp microelectrode experiments on isolated arteries revealed stable membrane potentials, with no detectable effect of heptanol (1 mM) or 18␣-GA (20-30 M) on the average membrane potential at 20 mmHg. However, Ϸ20% of impaled cells (5 of 28) exhibited uncharacteristic oscillations in membrane potential after pharmacological uncoupling. At 60 mmHg a Ϸ7-to 9-mV hyperpolarization and corresponding vasodilation (Ϸ50%) was observed, and the frequency of membrane potential oscillations doubled (9 of 23 cells). These data indicate that gap junctions play an important role in the maintenance and modulation of membrane potential and tone in cerebral resistance arteries.heptanol; glycyrrhetinic acid; vascular smooth muscle; resistance arteries; vasopressin and depolarization RESISTANCE ARTERIES react to increases and decreases in transmural pressure by constriction and dilation, respectively. This ability to respond to pressure in a manner independent of neurohormonal modulation (15) resides in vascular smooth muscle cells and was therefore termed a "myogenic response" (22). Currently, the mechanisms producing pressure-induced constriction are complex and not fully understood. However, elevations in pressure produce smooth muscle depolarization, which coincides with arterial constriction, and in some studies the production of spontaneous action potentials (20)(21)24). This in turn results in an inward movement of Ca 2ϩ via voltageoperated Ca 2ϩ channels. The net result of Ca 2ϩ influx (associated with membrane depolarization), coupled with enhanced myofilament calcium sensitivity, is an increase in vascular tone (15,24,28). Despite the stable arterial diameter commonly observed in small pressurized cerebral arteries, recent studies in resistance arteries demonstrate great individual variability in Ca 2ϩ -signaling modalities in individual myocytes within the vascular wall, suggesting...

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