Dalcetrapib
L-type calcium channels explain how torcetrapib raises aldosterone and blood pressure, an effect dalcetrapib does not share (J Hypertens 2010)
Original title: Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels
The increased mortality seen with the CETP inhibitor torcetrapib was partly attributed to increased aldosterone production and blood pressure. In adrenocarcinoma H295R cells, torcetrapib and angiotensin II, but not dalcetrapib, a structurally different CETP inhibitor, elevated aldosterone synthase mRNA and aldosterone production. Unlike angiotensin II, torcetrapib steroidogenesis was unaffected by angiotensin receptor or T-type calcium channel blockade, but was blocked by several L-type calcium channel antagonists, and torcetrapib specifically upregulated the L-type calcium channel alpha 1C subunit. In spontaneously hypertensive rats, torcetrapib produced a potent hypertensive effect mediated by the L-type calcium channel. The findings link the steroidogenic and hypertensive side effects of torcetrapib to voltage-gated L-type calcium channels, a mechanism not shared by structurally unrelated CETP inhibitors such as dalcetrapib.
Original abstract
Objective: The increased mortality observed with the cholesteryl ester transfer protein inhibitor torcetrapib is partly due to increased aldosterone production and blood pressure. The mechanisms underlying these effects were investigated.
Methods: Cytochrome P450 subunit 11B2 (aldosterone synthase), extracellular signal-regulated kinase (p44/42) and voltage-gated Cachannel alpha subunit mRNA profiling, aldosterone production, cytosolic calcium and RNA interference were assessed in adrenocarcinoma human cells (H295R). Telemetry was conducted in spontaneously hypertensive rats.
Results: Torcetrapib and angiotensin II (Ang II) but not dalcetrapib (a structurally different cholesteryl ester transfer protein inhibitor) elevated both cytochrome P450 subunit 11B2 mRNA and aldosterone production in H295R cells at 6 h. At days 1-5, torcetrapib produced a sustained increase of cytochrome P450 subunit 11B2 mRNA, unlike Ang II. Although torcetrapib and Ang II potentiated the effect of 25-OH cholesterol and raised pregnenolone levels, torcetrapib increased neither cytosolic Ca at 5 min nor extracellular signal-regulated kinase1/2 phosphorylation, suggesting initially divergent pathways. Unlike Ang II, torcetrapib steroidogenesis was not affected by Ang II type 1 receptor antagonism or voltage-gated T-type Ca channel antagonism, but was blocked by several L-type Cachannel antagonists. In unbiased genome-wide screening, Ang II and torcetrapib modulated an overlapping but distinct set of genes in H295R cells. Torcetrapib, but not Ang II, upregulated mRNA levels of the L-type Ca channel alpha 1C subunit. In spontaneously hypertensive rat, torcetrapib had a potent hypertensive effect mediated by the L-type Ca channel.
Conclusion: The unique steroidogenic and hypertensive side effects of torcetrapib may be linked and involve voltage-gated L-type Ca channels. Structurally unrelated cholesteryl ester transfer protein inhibitors such as dalcetrapib do not share this effect.
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Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.