Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension

Schmitt, Rita; Kleinbloesem, C. H.; Belz, G. G.; Schroeter, Volkmar; Feifel, Ulrich; Pozenel, H; Kirch, Wilhelm; Halabi, Atef; Woittiez, Arend-Jan; Welker, H. A.; Brummelen, P. Van

doi:10.1038/clpt.1992.147

Cited by 81 publications

(37 citation statements)

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“…This observation coupled with the lower expression of T-type channels in working myocytes indicates that they do not play a major role in excitationcontraction coupling. Consistent with this notion, mibefradil has little effect on cardiac inotropy at doses that lower blood pressure (356). In contrast, T-type channels may be localized near SR in atrial pacemaker cells of the cat (180).…”

Section: Properties Of T-type Currents In Peripheral Tissuessupporting

confidence: 64%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,488

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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Section: Properties Of T-type Currents In Peripheral Tissuessupporting

confidence: 64%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,488

1,446

View full text Add to dashboard Cite

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“…Increasing doses of the calcium antagonist led to a stepwise rise of PQ-time in the ECG. The latter effect may be due mainly to administration of the calcium antagonist itself as Ro 40-5967 causes a prolongation of the AV conduction time [20].…”

Section: Haemodynamic Functionmentioning

confidence: 99%

“…It leads to vasodilation of peripheral arterial and coronary vessels without reflex tachycardia, causes prolongation of AV-conduction time, but seems to be devoid of negative inotropic effects [17][18][19][20]. The aim of the present study was to clarify a pharmacokinetic and haemodynamic interaction between Ro 40-5967 and digoxin.…”

Section: Introductionmentioning

confidence: 99%

The interaction of the calcium antagonist RO 40‐5967 with digoxin.

Siepmann

Kleinbloesem

Kirch

1995

Brit J Clinical Pharma

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1. The interaction of the newer calcium antagonist Ro 40‐5967 with digoxin was investigated in 42 healthy subjects under steady state conditions. 2. After an adequate loading dose digoxin 0.375 mg once daily was given alone for 1 week. Afterwards three different doses (50, 100, 150 mg daily) of the calcium antagonist Ro 40‐5967 were administered to three groups of 14 subjects each for 1 week concurrently with digoxin 0.375 mg daily. 3. Ro 40‐5967 led to an increase of mean maximum digoxin plasma concentrations (Cmax) and AUC. For AUC this effect was significantly dose‐dependent. 4. Increasing doses of the calcium antagonist led to a stepwise rise of the PQ‐time in ECG. 5. A slight fall of heart rate was seen after a 7 day treatment of digoxin alone. This effect was more pronounced when Ro 40‐5967 was added to the medication. No significant changes of stroke volume and blood pressure were noted. 6. In conclusion Ro 40‐5967 led to a significant elevation of the plasma concentration‐time curve (AUC) of digoxin. This effect was dose‐dependent.

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“…4 mibefradil is effective in the treatment of hypertenMibefradil (Ro 40-5967) is a novel CA that belongs sion 9 and chronic stable angina pectoris, 10 and like to a new structural class of benzimidazolyl-substiamlodipine, mibefradil is not associated with a reflex increase in neurohormones or negative inotropic effects. [11][12][13][14] However, unlike amlodipine, decrease in heart rate.…”

Section: Introductionmentioning

confidence: 99%

A randomised, double-blind trial comparing mibefradil and amlodipine: two long-acting calcium antagonists with similar efficacy but different tolerability profiles

et al. 1997

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Objective: To compare the efficacy and tolerability of mibefradil (−11.5 ± 8.2 mm Hg) and 5/10 mg amlodipine (−13.2 ± 7.9 mm Hg). The number of patients with normibefradil and amlodipine in patients with uncomplicated mild-to-moderate essential hypertension. malised SDBP (р90 mm Hg) increased 23.3% in the mibefradil group and 19.5% in the amlodipine group Design: A double-blind, randomised, parallel group multicentre trial.(approximately 74% in both groups). Patients on mibefradil or amlodipine during the withdrawal period had Methods: 239 patients received 50 mg mibefradil or 5 mg amlodipine for 4 weeks, followed by a forced significantly larger decreases in SDBP than those on placebo. Patients on mibefradil had a decrease in heart titration to 100 mg mibefradil or 10 mg amlodipine for an additional 8 weeks. Patients then entered a 4-week rate of 5.5 bpm. Patients on amlodipine had no change in heart rate; however, cessation of amlodipine was withdrawal period either on therapy or switched to placebo.associated with a decrease in heart rate. Conclusions: Mibefradil was as effective as amlodiResults: Statistically equivalent reductions in trough sitting diastolic blood pressure (SDBP) were observed pine in reducing BP; both compounds were effective treatments of hypertension. after 12 weeks of once-daily treatment with 50/100 mg

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Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension

Cited by 81 publications

References 0 publications

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

The interaction of the calcium antagonist RO 40‐5967 with digoxin.

A randomised, double-blind trial comparing mibefradil and amlodipine: two long-acting calcium antagonists with similar efficacy but different tolerability profiles

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