Mibefradil

Mibefradil is calcium channel blocker with moderate selectivity for T-type Ca2+ channels displaying IC50 values of 2.7 μM and 18.6 μM for T-type and L-type channels respectively. Mibefradil is antihypertensive agent for the treatment of hypertension and chronic angina pectoris.

Gating Modulation of the Tumor-Related Kv10.1 Channel by Mibefradil.[Pubmed:27255432]

J Cell Physiol. 2017 Aug;232(8):2019-2032.

Several reports credit Mibefradil with tumor suppressing properties arising from its known inhibition of Ca(2+) currents. Given that Mibefradil (Mb) is also known to inhibit K(+) channels, we decided to study the interaction between this organic compound and the tumor-related Kv10.1 channel. Here we report that Mb modulates the gating of Kv10.1. Mb induces an apparent inactivation from both open and early closed states where the channels dwell at hyperpolarized potentials. Additionally, Mb accelerates the kinetics of current activation, in a manner that depends on initial conditions. Our observations suggest that Mb binds to the voltage sensor domain of Kv10.1 channels, thereby modifying the gating of the channels in a way that in some, but not all, aspects opposes to the gating effects exerted by divalent cations. J. Cell. Physiol. 232: 2019-2032, 2017. (c) 2016 Wiley Periodicals, Inc.

CACNA1H(M1549V) Mutant Calcium Channel Causes Autonomous Aldosterone Production in HAC15 Cells and Is Inhibited by Mibefradil.[Pubmed:27258646]

Endocrinology. 2016 Aug;157(8):3016-22.

We recently demonstrated that a recurrent gain-of-function mutation in a T-type calcium channel, CACNA1H(M1549V), causes a novel Mendelian disorder featuring early-onset primary aldosteronism and hypertension. This variant was found independently in five families. CACNA1H(M1549V) leads to impaired channel inactivation and activation at more hyperpolarized potentials, inferred to cause increased calcium entry. We here aimed to study the effect of this variant on aldosterone production. We heterologously expressed empty vector, CACNA1H(WT) and CACNA1H(M1549V) in the aldosterone-producing adrenocortical cancer cell line H295R and its subclone HAC15. Transfection rates, expression levels, and subcellular distribution of the channel were similar between CACNA1H(WT) and CACNA1H(M1549V). We measured aldosterone production by an ELISA and CYP11B2 (aldosterone synthase) expression by real-time PCR. In unstimulated cells, transfection of CACNA1H(WT) led to a 2-fold increase in aldosterone levels compared with vector-transfected cells. Expression of CACNA1H(M1549V) caused a 7-fold increase in aldosterone levels. Treatment with angiotensin II or increased extracellular potassium levels further stimulated aldosterone production in both CACNA1H(WT)- and CACNA1H(M1549V)-transfected cells. Similar results were obtained for CYP11B2 expression. Inhibition of CACNA1H channels with the T-type calcium channel blocker Mibefradil completely abrogated the effects of CACNA1H(WT) and CACNA1H(M1549V) on CYP11B2 expression. These results directly link CACNA1H(M1549V) to increased aldosterone production. They suggest that calcium channel blockers may be beneficial in the treatment of a subset of patients with primary aldosteronism. Such blockers could target CACNA1H or both CACNA1H and the L-type calcium channel CACNA1D that is also expressed in the adrenal gland and mutated in patients with primary aldosteronism.

Mibefradil suppresses the proliferation of pulmonary artery smooth muscle cells.[Pubmed:26755813]

J Investig Med. 2016 Jan;64(1):45-9.

Intracellular Ca(2+) levels play a critical role in the regulation of vasodilation and vasoconstriction by stimulating pulmonary artery smooth muscle cell (PASMC) proliferation, which is important in the pathogenesis of pulmonary arterial hypertension (PAH); however, L-type Ca(2+) channel antagonists are useful in only few patients with PAH. The present study sought to assess the effect of Mibefradil, which blocks T-type Ca(2+) channels, on PASMC proliferation and Ca(2+) channel profile. Human PASMCs were stimulated with 25 ng/mL platelet-derived growth factor-BB (PDGF-BB) with and without 10 microM Mibefradil or 100 nM sildenafil. After 48 or 72 h, PASMC proliferation and Ca(2+) channel expression were assessed by MTT assays and western blot analysis, respectively. PDGF-BB-induced PASMC proliferation at 72 h (p<0.01), which was inhibited by both sildenafil and Mibefradil (p<0.01). Transient receptor potential Ca(2+) channel 6 (TRPC6) expression was significantly increased with PDGF-BB stimulation (p=0.009); however, no changes in TRPC1, TRPC3, CAV1.2, and CAV3.2 levels were observed. Although both TRPC1 and CAV1.2 expression levels were increased in PDGF-stimulated PASMCs on Mibefradil and sildenafil treatment, it was not statistically significant (p=0.086 and 1.000, respectively). Mibefradil inhibits PDGF-BB-stimulated PASMC proliferation; however, the mechanism through which it functions remains to be determined. Further studies are required to elucidate the full therapeutic value of Mibefradil for PAH.

Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas.[Pubmed:28371832]

Neuro Oncol. 2017 Jun 1;19(6):845-852.

Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG. Methods: Adult patients with rHGG >/=3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB. Results: Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 +/- 287 ng/mL (mean +/- SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB. Conclusions: MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.

Mibefradil (Ro 40-5967) is a calcium channel blocker with moderate selectivity for T-type Ca2+ channels displaying IC50s of 2.7 μM and 18.6 μM for T-type and L-type currents, respectively.

Mibefradil,116644-53-2,Natural Products,Calcium Channel, buy Mibefradil , Mibefradil supplier , purchase Mibefradil , Mibefradil cost , Mibefradil manufacturer , order Mibefradil , high purity Mibefradil