Sclareol and cinnarizine are non-selective inhibitors of voltage-gated Cav1.3 L-type Ca ²⁺ channels

A growing body of preclinical evidence indicates that the inhibition of voltage-gated Cav1.3 L-type Ca²⁺ channels could be a therapeutic concept for the therapy of treatment-resistant hypertension, spinal injury and for neuroprotection in early Parkinson's disease (PD). However, available Ca²⁺-channel blockers are potent inhibitors of vascular Cav1.2 L-type channels which can cause low blood pressure as an adverse drug reaction. Therefore, Cav1.3-selective inhibitors are needed to further investigate the therapeutic potential of Cav1.3 as drug target in vivo. The bicyclic diterpene alcohol sclareol has recently been reported to exert neuroprotective properties in a mouse PD model by blocking Cav1.3 L-type channels. This study investigates the proposed Cav1.3-selectivity of sclareol compared to Cav1.2 and to other voltage-gated Ca²⁺ channels in whole-cell patch-clamp experiments. Various stimulation protocols, including dopamine neuron-like firing patterns show that sclareol is neither a subtype-selective nor a potent blocker of heterologously expressed Cav1.3 and inhibits also Cav2.3 channels. Therefore, the contribution of Cav1.3 channel inhibition for the previously reported neuroprotective effects of sclareol in a mouse PD model remains unclear. In addition, cinnarizine, a vertigo therapeutic also under investigation for inhibition of Cav1.3-mediated aldosterone-secretion, inhibits Cav1.3 channels in a frequency-dependent manner, but also without relevant selectivity with respect to Cav1.3.