Inhibitors of gap junctions attenuate myogenic tone in cerebral arteries.
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(+), at 20 mmHg) to inhibition by heptanol (1.0 microM to 3.0 mM) or 18alpha-glycyrrhetinic acid (18alpha-GA, 1.0 to 50 microM) were determined. Pressure-induced myogenic tone was inhibited by heptanol (IC(50) = 0.75 +/- 0.09 mM) and 18alpha-GA ( approximately 30 microM). Vasopressin-induced vasoconstriction was also inhibited by heptanol (IC(50) = 0.4 +/- 0.3 mM) and 18alpha-GA (>1 microM). Depolarizing solution-induced vasoconstriction was less sensitive to inhibition by heptanol compared to vasopressin (P < 0.01) or pressure-induced constriction (P < 0.05). However, 18alpha-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 18alpha-GA (20-30 microM) on the average membrane potential at 20 mmHg. However, approximately 20% of impaled cells (5 of 28) exhibited uncharacteristic oscillations in membrane potential after pharmacological uncoupling. At 60 mmHg a approximately 7- to 9-mV hyperpolarization and corresponding vasodilation (approximately 50%) 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.
Lagaud
Guy
G
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Karicheti
Venkateswarlu
V
Knot
Harm J
HJ
Christ
George J
GJ
Laher
Ismail
I
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019850:Heptanol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008839:Microelectrodes; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000502:physiology*; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014667:Vasopressins / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D014667:Vasopressins; C119129:18alpha-glycyrrhetinic acid; D019850:Heptanol; D006034:Glycyrrhetinic Acid