Disease relevance of Mibefradil

• Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension [1].
• Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia [1].
• The novel calcium antagonist Ro 40-5967 limits myocardial infarct size in the dog [2].
• Pretreatment with Ro 40-5967 (n = 17, 1000 micrograms/kg i.v.) significantly (P < 0.001) reduced the incidence of VF (13 of 17 protected) during the exercise plus ischemia test [3].
• Effects of the new calcium antagonist mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: a multicenter, placebo-controlled study. Ro 40-5967 International Study Group [4].

High impact information on Mibefradil

• The present study shows that the chemically novel nondihydropyridine Ca2+ antagonist, Ro 40-5967, blocks T-type divalent ion currents in vascular muscle cells [5].
• Assessment of left ventricular end-systolic pressure-volume relations with an impedance catheter and transient inferior vena cava occlusion: use of this system in the evaluation of the cardiotonic effects of dobutamine, milrinone, Posicor and epinephrine [6].
• Voltage-dependent blockade of diverse types of voltage-gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 40-5967) [7].
• Cyclic GMP content, an indicator of NO release, was not increased in aortas from Ro 40-5967-treated SHR [8].
• Arterial blood pressure was decreased by Ro 40-5967 [8].

Chemical compound and disease context of Mibefradil

• The effects of Ro 40-5967 on the susceptibility to ventricular fibrillation were investigated and compared to diltiazem [3].
• The goals of the present study were to assess the effects of Ro 40-5967 on myocardial function during ischemia, and to compare them to those of verapamil [9].
• Enalapril was more effective than Ro 40-5967 in inducing regression of cardiac hypertrophy [10].

Biological context of Mibefradil

• Ro 40-5967 inhibited reversibly the T- and L-type currents with IC50 values of 2.7 and 18.6 microM, respectively [11].
• 6. In conclusion Ro 40-5967 led to a significant elevation of the plasma concentration-time curve (AUC) of digoxin [12].
• Ro 40-5967 defines an additional and possibly unique antagonist binding site on the L-type voltage-gated Ca2+ channel [13].
• It was found that at a physiological membrane potential (-80 mV) Ro 40-5967 was also less potent than verapamil in inhibiting this current, and that negative inotropy and Ca2+ channel blockade were correlated [14].
• The protective effect of Ro 40-5967 could be partially explained by the decrease of arterial pressure and heart rate induced by Ro 40-5967 [9].

Anatomical context of Mibefradil

• Maximal relaxation to acetylcholine in rings with endothelium was increased by Ro 40-5967 [8].
• The actions of the novel calcium (Ca2+) channel antagonist mibefradil (Ro 40-5967), a selective T-type channel blocker in myocardium, were investigated in embryonic rat spinal motoneurones maintained in culture [15].
• Mibefradil (Ro 40-5967) inhibits several Ca2+ and K+ currents in human fusion-competent myoblasts [16].
• Blocking actions of the novel Ca++ antagonist, Ro 40-5967 ((1S,2S)-2-[2[[3-(2-benzimidazolylpropyl] methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-++naphthyl+ ++ methoxyacetate dihydrochloride), on divalent inward currents were characterized in spontaneously active vascular muscle cells (VMC) of neonatal rat azygos veins [17].
• The concentration of Ro 40-5967 which inhibited the magnitude of peak inward currents by 50% (IC50) was estimated to be 1 microM (n = 5) in muscle cells from coronary artery and 10 microM (n = 4) in saphenous artery [18].

Associations of Mibefradil with other chemical compounds

• The IC50 values at a holding potential of -80 or -40 mV were 4.9 and 1.4 microM for Ro 40-5967 and 250 and 15.5 microM for verapamil [19].
• 3. Ro 40-5967 led to an increase of mean maximum digoxin plasma concentrations (Cmax) and AUC [12].
• Though activation of adhesion molecule expression utilizes PKC and/or calmodulin as second-messenger pathways the investigated calcium channel blockers verapamil (R- and S-enantiomers), diltiazem and Ro 40-5967 failed to inhibit adhesion molecule expression [20].
• For this purpose, two kidney-one clip (2K-1C) hypertensive rats, 6 weeks after renal artery clipping, were either untreated or treated for 5 weeks with equihypotensive doses of enalapril (3 mg/kg/day) and Ro 40-5967 (30 mg/kg/day) [10].
• The effects of Ro 40-5967, a chemically novel Ca2+ channel antagonist, were examined on K(+)- and norepinephrine (NE)-stimulated intracellular free Ca2+ concentrations in dog coronary artery vascular muscle cells (VMC) [21].

Gene context of Mibefradil

• Surprisingly, higher concentrations of verapamil (> 12.5 micrograms/ml) or Ro 40-5967 (5 micrograms/ml) significantly enhanced IL-1-induced expression of ELAM-1 [20].
• These data suggest that there is an important direct PKC inhibitory action of Ro 40-5967 that would at least partially explain relaxation of ET-induced contractions [22].
• Actions of the novel Ca2+ antagonist, Ro 40-5967, which displays unusual efficacy against endothelin (ET)-induced contractions, were studied in isolated vascular muscle cells (VMCs) using the fluorescent protein kinase C (PKC) indicator, BODIPY 12 alpha-phorbol ester 13 beta-acetate (PBA-BODIPY) [22].
• Interaction of Ro 40-5967 and verapamil with the stably expressed alpha 1-subunit of the cardiac L-type calcium channel [19].
• Plasma haptoglobin decreased by 67% after 3.5 h in 2 subjects who received 80 mg Ro 40-5967 in one arm (treatment schedule thereupon discontinued) [23].

References