Spironolactone inhibition of contraction and calcium channels in rat portal vein

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Abstract
1 The effects of spironolactone have been studied on the mechanical activity of rat portal vein strips and the calcium channel currents of isolated cells using the patch clamp technique (whole-cell configuration). 2 Spironolactone (50 nm to 0.1 mm) depressed both K+-induced and twitch contractions within 5–6 min. This inhibitory effect was overcome by elevating the calcium concentration in the perfusing solution. 3 Spironolactone (60 μm) depressed the transient contractions induced in a Ca2+-free, EGTA-containing solution by either acetylcholine (0.1 mm) or noradrenaline (10 μm). The effect of spironolactone was dependent on a reduction in the filling of the internal calcium store. 4 Rapidly inactivating calcium channel current was maintained in the presence of spironolactone (60 μm), while slowly inactivating calcium channel current was blocked in a concentration-dependent manner. Half-inhibition of slow calcium channel current was obtained at concentrations between 5–7 μm. 5 Administration of spironolactone (10 μm) at rest reduced calcium channel current by about 70% (tonic inhibition). Repetitive depolarizations (300 ms long pulses to zero mV, applied between 0.05 and 0.5 Hz) had no further inhibitory effect on the inward current (absence of use-dependence). 6 When cells were held at depolarized membrane potentials at which slow calcium current was inactivated by about 80%, the inhibitory effect of spironolactone (10 μm) was similar to that obtained with cells normally polarized. Spironolactone (10 μm) had no effect on the voltage-dependence of inactivation of the calcium channel current. 7 Our results suggest that spironolactone acts primarily on the plasma membrane by depressing inward current through slow calcium channels. This effect may be explained by a preferential binding of the drug to the resting state of the slow calcium channel. In addition, spironolactone may depress contractions dependent on the release of calcium from the sarcoplasmic reticulum.

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