Hyperforin, an acylphloroglucinol derivative, is a major constituent of St. John's wort extract (Hypericum perforatum L.), which is used in treating
depressive disorders.
Hyperforin has been demonstrated as a modulator of several neuronal
ion channels, and inhibits smooth-muscle contraction induced by various
neurotransmitters. To evaluate the
spasmolytic properties of
hyperforin in more detail, we performed studies on the hamster vas deferens smooth muscle cell line DDT1-MF2. In a first series of experiments, we determined the effect of
hyperforin on intracellular Ca2+ concentration ([Ca2+]i) using the
fluorochrome fura-2. These investigations were supplemented in a second series of assays, where the effects on cellular metabolism were analysed by measuring the rate of extracellular release of acidic metabolites with the help of a microphysiometer.
Hyperforin (0.3-10 microg/ml) caused a concentration-dependent elevation of [Ca2+]i and extracellular acidification rate (ECAR). Both of these effects were independent of extracellular Ca2+. To elucidate whether the increase of [Ca2+]i by
hyperforin causes or results from its ECAR-stimulating properties, we used various pharmacological tools to reveal the sequence of events and the molecular mechanisms involved. Our results suggest that
hyperforin induces release of Ca2+ from as yet unidentified sources. Since the ECAR stimulation was inhibited to a different extent by the intracellular Ca2+
chelator BAPTA as well as by inhibitors of plasmalemmal and mitochondrial Na+/Ca2+ exchange, but not by inhibitors of Na+/H+ antiport, the intracellular Ca2+ increase seems to be essential for this
hyperforin effect. However, further studies are needed to establish the exact mode of action, and to deduce whether this aspect of
hyperforin activity contributes to its
antidepressant and
neuroprotective effects.