Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Ca _v 1.2

Abstract

Abstract-The role of T-type Ca 2ϩ channels for cardiovascular physiology, in particular blood pressure regulation, is controversial. Selective blockade of T-type Ca 2ϩ channels in resistance arteries has been proposed to explain the effect of the antihypertensive drug mibefradil. In the present study, we used a third generation, time-and tissue-specific conditional knockout model of the L-type Ca 2ϩ channel Ca v 1.2 (Ca v 1.2 SMAKO mice) to genetically dissect the effects of mibefradil on T-and L-type Ca 2ϩ channels. Myogenic tone and phenylephrine-induced contraction in hindlimb perfusion experiments were sensitive to mibefradil in control mice, whereas the drug showed no effect in Ca v 1.2-deficient animals. Mean arterial blood pressure in awake, freely moving control mice was reduced by 38Ϯ2.5 mm Hg at a dose of 1.25 mg/kg bodyweight mibefradil, but not changed in

Functional expression of smooth muscle-specific ion channels in TGF-β1-treated human adipose-derived mesenchymal stem cells

“…Among the L-type Ca 2ϩ channels, the Ca v 1.2 (CACNA1C) channel is the dominant isoform in vascular smooth muscle and therefore appears to play an important role in regulating vascular tone and arterial constriction (2,45). Currently, the major targets of dihydropyridine Ca 2ϩ channel blockers as antihypertensive drugs are the Ca v 1.2 channels expressed in vascular smooth muscle (43,66). Therefore, the specific expression of Ca v 1.2 is an important characteristic of vascular smooth muscle.…”

Heterogeneity of L- and T-Channels in the Vasculature

“…This later experiment endeavored to "pharmacologically reproduce" the L-channel conditional knockout model established by Moosmang et al 7 and to shed light on the use of combined L-and T-channel blockade in patients on existing CCB therapy.…”

“…Recently, Moosmang et al, 7 using a conditional L-channel knockout mouse model, demonstrated a loss of mibefradil's vasomotor effects, including impairment of its blood pressurelowering effect and a reduction in its inhibition of vasoconstrictor effects in a hindlimb perfusion model. Appropriately, these researchers concluded that, in their mouse model, vasomotor effects of mibefradil were mediated exclusively via the L-channel.…”

T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells

“…The anti-proliferative and cytotoxic actions of pimozide may be mediated via other complex mechanisms and may not involve T-type channel blockade (17). Mibefradil has also been reported to inhibit cell proliferation through an association with cell swelling and the inhibition of volume-sensitive Cl -channels (27,28) or several other ion channels (29)(30)(31), in addition to a mechanism via the inhibition of T-type channels. Flunarizine, which has been reported to be a T-type antagonist (32), also produces its anti-apoptotic action via the direct inhibition of lipid peroxidation and mitochondrial permeability transition (33).…”