Junctional and nonjunctional effects of heptanol and glycyrrhetinic acid derivates in rat mesenteric small arteries

Abstract

1. Heptanol, 18α-glycyrrhetinic acid (18αGA) and 18β-glycyrrhetinic acid (18βGA) are known blockers of gap junctions, and are often used in vascular studies. However, actions unrelated to gap junction block have been repeatedly suggested in the literature for these compounds. We report here the findings from a comprehensive study of these compounds in the arterial wall. 2. Rat isolated mesenteric small arteries were studied with respect to isometric tension (myography), [Ca 2+] i (Ca 2+-sensitive dyes), membrane potential and - as a measure of intercellular coupling - input resistance (sharp intracellular glass electrodes). Also, membrane currents (patch-clamp) were measured in isolated smooth muscle cells (SMCs). Confocal imaging was used for visualisation of [Ca 2+] i events in single SMCs in the arterial wall. 3. Heptanol (150 μM) activated potassium currents, hyperpolarised the membrane, inhibited the Ca 2+ current, and reduced [Ca 2+] i and tension, but had little effect on input resistance. Only at concentrations above 200 μM did heptanol elevate input resistance, desynchronise SMCs and abolish vasomotion. 4. 18βGA (30 μM) not only increased input resistance and desynchronised SMCs but also had nonjunctional effects on membrane currents. 18αGA (100 μM) had no significant effects on tension, [Ca 2+] i, total membrane current and synchronisation in vascular smooth muscle. 5. We conclude that in mesenteric small arteries, heptanol and 18βGA have important nonjunctional effects at concentrations where they have little or no effect on intercellular communication. Thus, the effects of heptanol and 18βGA on vascular function cannot be interpreted as being caused only by effects on gap junctions. 18αGA apparently does not block communication between SMCs in these arteries, although an effect on myoendothelial gap junctions cannot be excluded.