Dihydropyridine calcium channel antagonists as antidepressant drugs in mice and rats

A pharmacological profile of the effects of nimodipine, nifedipine and nitrendipine (2.5-20 mg/kg p.o.) in several models which are indicative of possible antidepressant activity, was tested in mice and rats. These compounds, as well as verapamil (short-lasting effect), but not diltiazem, reduced the hypothermia induced by a large dose of apomorphine in mice. Nimodipine and nifedipine slightly increased the behavioural action of L-DOPA in mice, and nimodipine facilitated the action of imipramine in the L-DOPA test. Nimodipine, nifedipine, verapamil and diltiazem slightly reduced the clonidine-induced hypoactivity in rats. The hypothermia induced by reserpine or clonidine in mice was not changed by these drugs. Various antidepressants (imipramine, amitriptyline, citalopram, mianserin) used in the behavioural despair test in mice, in doses which were not effective by themselves, increased the immobility-reducing effect when given jointly with 1,4-dihydropyridine calcium channel antagonists (5 mg/kg). The above results indicate that the psychopharmacological profile of nimodipine, nifedipine and nitrendipine resembles that of antidepressants in some tests only; moreover, these results support the assumption that concomitant administration of antidepressants and 1,4-dihydropyridine calcium channel antagonists may result in a greater antidepressant efficacy.     

Uptake of calcium antagonistic drugs into muscles as related to their lipid solubilities

Calcium antagonists, e.g. bepridil and verapamil, block the Ca2+-dependent slow action potentials in frog skeletal muscle [L.M. Kerr and N. Sperelakis, J. Pharmac. exp. Ther. 222, 80 (1982)]. To determine whether the calcium antagonistic drugs may enter the fibers and exert an internal action as well, uptake of tritiated bepridil, verapamil, nitredipine, nifedipine, and diltiazem into rat extensor digitorum longus (EDL) muscles was examined. It was found that the uptake values of verapamil, nitrendipine, and bepridil were much higher than those of nifedipine and diltiazem. The order of uptake was: bepridil greater than nitrendipine greater than verapamil much greater than nifedipine greater than diltiazem. The small uptake values of nifedipine and diltiazem may represent primarily binding to the surface membrane. In frog skeletal muscle (sartorius) also, the uptake of bepridil was greater than that of verapamil, and disruption of the T-tubules by the glycerol method did not change them. The same order of drug uptake values was found for monolayer cultures of vascular smooth muscle cells (rat aorta). The order of uptake in isolated sarcoplasmic reticulum (SR) from rat skeletal muscles was: verapamil greater than nitrendipine greater than bepridil greater than nifedipine greater than diltiazem. The lipid solubility values of the calcium antagonists were measured by their partition coefficients in oil/Ringer, octanol/Ringer, and chloroform/Ringer systems. The order of lipid solubility was: bepridil greater than verapamil greater than nitrendipine greater than nifedipine much greater than diltiazem. Thus, the calcium antagonists with the highest lipid solubilities were taken up more by the muscle cells and SR. It is concluded that verapamil, bepridil, and nitrendipine enter and accumulate inside the muscle cells, whereas nifedipine and diltiazem do not permeate readily.     

Influence of extracellular calcium and calcium antagonists on contractions induced by potassium and prostaglandin F2 alpha in isolated cerebral and mesenteric arteries of the cat.

1 The effects of a number of calcium antagonists (diltiazem, nifedipine, nimodipine and verapamil) have been studied on feline isolated pial arteries contracted by potassium (127 mM) or prostaglandin F2 alpha (PGF2 alpha, 2.5 microM) and mesenteric arteries contracted by potassium (127 mM). 2 Withdrawal of Ca2+ from the extracellular medium for 30 min reduced the contractile response to potassium in cerebral vessels by 92% and in mesenteric vessels by 96%. Subsequent addition of Ca2+ caused reproducible contractions which were inhibited by both nifedipine and nimodipine. 3 The four calcium antagonists relaxed the isolated middle cerebral artery contracted either by potassium or PGF2 alpha, and mesenteric arteries contracted by potassium, in the following order of potency: nimodipine greater than nifedipine greater than verapamil greater than diltiazem. 4 Nimodipine was more potent than nifedipine in cerebral arteries, and more potent in cerebral than in mesenteric arteries. Otherwise, the potassium-contracted cerebral and mesenteric vessels showed no major differences in sensitivity to calcium antagonists.     

Effects of Bay k 8644 on the coronary vascular selectivity of the dihydropyridine Ca antagonists in the canine isolated, blood-perfused papillary muscle preparation

Antagonism by Bay k 8644 of the coronary vasodilator and negative inotropic effects of Ca antagonists was simultaneously investigated in the canine isolated, blood-perfused papillary muscle electrically driven at 2 Hz. Drugs were given intraarterially. Continuously infused intraarterially, Bay k 8644 inhibited more predominantly the coronary vasodilator effects of the dihydropyridine Ca antagonists (nifedipine, nitrendipine, and nicardipine) than those of diltiazem and verapamil, or the negative inotropic effects of nifedipine and nitrendipine. The negative inotropic effects of nicardipine, diltiazem, and verapamil were not significantly affected by Bay k 8644. The dose ratio for producing a 50% decrease in developed tension of the papillary muscle over the dose for producing a 50% increase in coronary blood flow (which reflects vascular selectivity) were 41 for nitrendipine, 25 for nifedipine, 21 for nicardipine, 9 for diltiazem, and 7 for verapamil. During infusion by Bay k 8644, the ratio was small (2 to 6) and almost similar among all five Ca antagonists. These results indicate that Bay k 8644 antagonizes more effectively the coronary vasodilating effects of the dihydropyridine Ca antagonists, suggesting that there is a specific type of Ca channel on coronary vascular smooth muscles, through which the dihydropyridine Ca antagonists act.     

Some behavioral effects of repeated administration of calcium channel antagonists

The effect of the calcium channel antagonists nifedipine, nimodipine, and diltiazem (10 mg/kg PO) was studied after single and repeated administration to rats. All the compounds administered repeatedly reduced significantly the duration of immobility in the forced swimming test. At the same time the locomotor activity of rats was reduced (nifedipine, nimodipine) or unchanged (diltiazem). All the calcium channel antagonists studied did not modify the behavior of normal or phenylephrine-stimulated rats in the open field test. Only nimodipine, given repeatedly, was able to antagonize the clonidine-induced behavioral inhibition in the latter test. The results indicate that, like antidepressants, calcium channel antagonists given repeatedly to rats reduce the immobility time in the forced swimming test, but do not change the responsiveness of alpha 1- and alpha 2-adrenoceptors to their agonists.     

Clinical efficacy of nifedipine and other calcium antagonists in patients with primary esophageal motor dysfunctions

In this paper the pharmacodynamic effects of calcium channel blockers (verapamil, nifedipine, diltiazem, fendiline, nitrendipine, nimodipine, and nisoldipine) on esophageal motility in man and their clinical effects in patients with various forms of primary esophageal motility disorders are critically analysed and summarized. The evaluation of efficacy and safety is mainly focused on nifedipine (Bay a 1040, Adalat; CAS 21829-25-4), since it has been best documented clinical pharmacologically and therapeutically in this field. Nifedipine and--with varying potency--the other calcium antagonists reduce effectively the increased lower esophageal sphincter pressure (LESP) and abnormally high and prolonged peristaltic and nonperistaltic contractions in the esophageal body in patients with achalasia, diffuse esophageal spasm (DES), and other disorders which may cause angina-like chest pain and/or dysphagia. Pharmacodynamic effects on esophageal motility are closely correlated with the plasma concentration of nifedipine in healthy volunteers and in patients. However, a final judgement on the therapeutic value of these compounds in esophageal motor abnormalities cannot be given due to conflicting results from clinical studies with fairly small numbers of patients and varying study designs. Among the different calcium antagonists investigated nifedipine represents the best investigated and the most suitable compound for the treatment of primary hypertensive esophageal motor disorders.     

Haloperidol-induced catalepsy is influenced by calcium channel antagonists

The effect of pretreatment of some voltage-dependent calcium channel antagonists was studied on haloperidol-induced catalepsy in male Wistar rats. Cataleptogenic effect of haloperidol (0.25 mg/kg, i.p.) was enhanced dose-dependently by nitrendipine (5, 10 and 20 mg/kg, i.p.) and the highest dose of nimodipine (20 mg/kg, i.p.). Neither verapamil (10 and 20 mg/kg, i.p.) nor diltiazem (10 and 20 mg/kg, i.p.) influenced the score of haloperidol-induced catalepsy in rats. These results suggest the involvement of calcium-dependent mechanisms in the generation of haloperidol-induced catalepsy. The possible involvement of dopaminergic mechanisms and modification by calcium channel antagonists are discussed.     

Comparison of negative inotropic potency, reversibility, and effects on calcium influx of six calcium channel antagonists in cultured myocardial cells.

The negative inotropic effects of calcium channel antagonists on the myocardium were used as a standard for the definition and determination of potency of this group of drugs. The effects of six calcium channel antagonists (verapamil, methoxyverapamil (D600), nifedipine, lidoflazine, perhexiline and diltiazem) were compared on cultured chick embryo ventricular cells. Drug concentrations producing 50% inhibition of contractile amplitude, derived from linearized concentration-response curves, varied from 2.8 X 10(-8)M for nifedipine to 8.3 X 10(-7)M for perhexiline. Equipotent negative inotropic concentrations of verapamil, D600, perhexiline, diltiazem and lidoflazine produced a similar inhibitory effect on 45Ca uptake into cultured cells. Nifedipine produced no significant inhibition of 45Ca uptake. The time required for recovery of contractility after cessation of drug superfusion varied in the order lidoflazine greater than perhexiline greater than D600 greater than verapamil greater than nifedipine greater than diltiazem. This relative order accords closely with the reported in vivo half-lives of these drugs. It is concluded that while some inhibition of 45Ca2+ uptake into cardiac cells can be demonstrated with five of the six calcium channel blockers studied, the relationship between the degree of inhibition of calcium influx and negative inotropic effects may not be uniform for all calcium channel antagonists.     

Comparative cardiovascular actions of clentiazem, diltiazem, verapamil, nifedipine, and nimodipine in isolated rabbit tissues.

Clentiazem is an 8-chloro-substituted derivative of diltiazem. We compared the relative potency of clentiazem with that of diltiazem, verapamil, nifedipine, and nimodipine in isolated rabbit right atria and vascular smooth muscle removed from various arterial beds. In experiments with isolated right atria, calcium channel blockers were added cumulatively to study relative cardiodepressive potencies (as compared with vascular effects) with the following results: verapamil greater than or equal to diltiazem greater than clentiazem greater than or equal to nimodipine much greater than nifedipine. The aorta, pulmonary, renal, mesenteric, coronary, and basilar arteries were removed, cut helically in strips, and mounted in isolated tissue baths to measure isometric force. Vessels were contracted with either 40 mM KCl (opening voltage-operated calcium channels) or 1 x 10(-5) M norepinephrine (NE, opening receptor-operated calcium channels). Cumulative dose-response curves were generated for relaxation with each calcium channel blocker. All compounds were more potent at relaxing potassium-induced contractions than NE-induced contractions. In vessels precontracted with KCl, neither diltiazem, verapamil, or nifedipine showed selectivity for basilar artery as compared with the mesenteric artery. Both clentiazem and nimodipine were selective (6- and 30-fold, respectively) for basilar artery in blocking potassium-induced contractions. When NE was used to contract the arteries, clentiazem (12-fold), diltiazem (8-fold), verapamil (8-fold), and nifedipine (153-fold) were all more potent in relaxing the contraction in basilar artery than in mesenteric artery. Nimodipine failed to demonstrate selectivity for basilar artery as compared with mesenteric artery contracted with NE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of calcium antagonists on KCl-evoked calcium uptake by rat cortical synaptosomes

A series of calcium antagonists were used to study their blocking effect on high potassium-induced calcium uptake into rat cortical synaptosomes; these antagonists were classified into five groups: dihydropyridine group (i.e. nifedipine and nitrendipine), benzothiazepine group (i.e. diltiazem), phenylalkylamine group (i.e. verapamil and D600), phenothiazine group (i.e. trifluoperazine) and diphenylpiperazine group (i.e. flunarizine and cinnarizine). Voltage-dependent 45Ca2+-uptake into this fraction was measured after 20 sec KCl-induced depolarization. The ID30 values of the above-mentioned antagonists affecting 45Ca2+-uptake were calculated to be nitrendipine (80 microM), nifedipine (100 microM), verapamil (50 microM), D600 (15 microM), diltiazem (70 microM), trifluoperazine (7 microM), cinnarizine (1.2 microM) and flunarizine (0.7 microM). Our results reveal that in rat brain synaptosomal fractions, calcium influx via the voltage-gated calcium channel appears to be more sensitive to diphenylpiperazine and phenothiazine groups; whereas, phenylalkylamine, benzothiazepine and dihydropyridine groups were relatively insensitive. This contrasts with the well known data obtained from vascular smooth muscle, in which the dihydropyridine group is the most sensitive of all the groups studied. Our results suggest that calcium channels in neuronal tissue are most likely different from those in non-neuronal tissue.     

Studies of [3H]nitrendipine binding and KCl-induced calcium uptake in rat cortical synaptosomes

Rat cortical synaptosomal fraction was used to study whether there is a direct link between [3H]nitrendipine binding and KCl-induced calcium uptake. [3H]Nitrendipine exhibited reversible and saturable binding to this preparation. The equilibrium dissociation constant Kd was 0.6 nM and the maximal binding capacity, Bmax, was 120 fmol/mg of protein. The binding could be displaced by certain calcium channel antagonists, the potency of which was in the order: nitrendipine greater than nifedipine greater than D600 greater than verapamil greater than flunarizine. Voltage-dependent 45Ca2+-uptake into this fraction was measured after 20 sec KCl-induced depolarization. Nitrendipine at high concentration (10 microM) had little effect on 45Ca2+-uptake into brain synaptosomes. The order of the above-mentioned calcium antagonists affecting 45Ca2+-uptake was flunarizine greater than D600 greater than verapamil greater than nifedipine greater than nitrendipine. Our results suggest that high-affinity binding of [3H]nitrendipine is not directly linked to voltage-dependent calcium uptake in brain.     

Cardiovascular and renal actions of calcium channel blocker chemical subgroups: a search for renal specificity

The diuretic and natriuretic responses to structurally distinct classes of Ca2+ channel blockers have been compared, to determine whether any agent provoked K+-sparing natriuresis, and to assess the relation of such responses with drug effects on blood pressure. Conscious normotensive Sprague-Dawley rats received vehicle or one of the following drugs in an oral saline load (40 mL kg-1) nifedipine, nimodipine, nitrendipine, prenylamine, cinnarizine, flunarizine, diltiazem, verapamil, hydrochlorothiazide, amiloride, or hydralazine, at doses from 0.316 to 100 mg kg-1. Urine was collected for 6h. Blood pressure was monitored directly in parallel studies. Diltiazem (31.6, 100 mg kg-1) and flunarizine (100 mg.kg-1) enhanced urine and electrolyte excretion in spite of marked hypotension; diltiazem was the only drug to produce dose-related renal responses. In contrast, equihypotensive doses of hydralazine and nifedipine produced overt urine and electrolyte retention. Nitrendipine and prenylamine (0.316 mg kg-1 each) produced slight diuresis or natriuresis without altering blood pressure; higher doses had no effect. The 31.6 mg kg-1 doses of verapamil, nitrendipine, and nimodipine markedly reduced blood pressure, but neither enhanced nor limited urine and electrolyte excretion. Cinnarizine failed to produce any cardiovascular or renal effects. Diuretic responses evoked by the Ca2+ channel blockers were not class-specific, showed no tendency towards sparing K+, were generally weaker than those produced by low doses of amiloride or hydrochlorothiazide, and were dissociable from drug-induced changes in blood pressure.     

Differential potentiation by depolarization of the effects of calcium antagonists on contraction and Ca2+ current in guinea-pig heart.

1. The effects of elevation of extracellular K+ concentration ([K+]o) on the negative inotropic potencies of three representative calcium antagonists, diltiazem, verapamil and nifedipine, were investigated in guinea-pig papillary muscle preparations. 2. The negative inotropic effect of diltiazem was potentiated 110 fold when [K+]o was raised from 2.7 mM to 12.7 mM. The effect of verapamil was also potentiated to a lesser extent, but that of nifedipine was not affected. 3. Resting membrane potentials in ventricular muscles were about -80 mV and -60 mV in 2.7 mM K+ and 12.7 mM K+, respectively. 4. To clarify the mechanism responsible for the differential potentiation of the negative inotropic effects, the blocking actions of the three calcium antagonists on the L-type Ca2+ channel current (ICa(L)) were compared at the holding potentials of -80 mV and -60 mV by the whole-cell patch-clamp technique. 5. The use-dependent blocking effect of diltiazem on ICa(L) was enhanced markedly by the change in the holding potential from -80 mV to -60 mV. The effect of verapamil was also enhanced to a lesser extent but that of nifedipine was not affected in this range of depolarization. 6. The differential effects of the [K+]o elevation on the negative inotropic potencies of the three calcium antagonists are explained by the differences in voltage-dependency of their use-dependent blocking effects on ICa(L). 7. The properties of diltiazem and verapamil observed in this study may contribute to their protective effects on the ischaemic myocardium, without affecting the normal myocardium.     

The activity of nifedipine,diltiazem, verapamil,and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity

A characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazem, verapamil, and lidoflazine. All drugs produced relaxation of K⁺ depolarized guinea pig ileal longitudinal muscle strips and K⁺ depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration-response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA₂ estimates: nifedipine 9.5, diltiazem 7.65, verapamil 7.8, and lidoflazine 7.0. Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine-contracted rabbit aortae while weak effects were observed with verapamil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazem displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this regard.     

Inhibitory effects of L- and T-type calcium antagonists on contractions of human detrusor muscle

The inhibitory and relaxant effects of the L-type calcium antagonists nifedipine, nimodipine, verapamil and diltiazem, and of the T-type calcium antagonist mibefradil, on contractions of isolated human detrusor muscle were investigated. The tissue was obtained from 10 patients undergoing cystectomy due to bladder cancer. Effects of the calcium antagonists at different concentrations on the concentration-response curves for carbachol were investigated. Furthermore, concentration-relaxation curves were performed using potassium-precontracted muscle strips. All L-type calcium antagonists suppressed the mean concentration-response curve of carbachol significantly at a concentration of 10⁻⁶ M. Mibefradil up to 10⁻⁵ M did not significantly suppress it. Nifedipine significantly reduced the carbachol-induced maximum contraction to 75% and 44%, verapamil to 75% and 67% of the appropriate control value at concentrations of 10⁻⁷ and 10⁻⁶ M, respectively. Diltiazem reduced it insignificantly to 96% and 71% at the above-mentioned concentrations. The concentration-relaxation experiments revealed following pD2-values and maximum relaxations of nifedipine, nimodipine, verapamil and diltiazem, respectively: 6.23, 6.37, 5.66, 5.81 and 85%, 83%, 82%, 90%. Maximum relaxations and pD2-values were not significantly different from each other. The lowest concentration, for which a significant effect compared to control in Student`s t-test was found, amounted to 10⁻¹⁰ M, 10⁻⁹ M, 10⁻⁷ M, 10^−6.5 M and 10⁻⁴ M for nimodipine, nifedipine, diltiazem, verapamil and mibefradil, respectively. L-type calcium antagonists are very potent relaxant agents of the human detrusor muscle in vitro.     

Effects of hypoxia, elevated K+ and acidosis on the potency of verapamil, diltiazem and nifedipine in the guinea-pig isolated papillary muscle.

1 The effects of the structurally diverse calcium channel blockers verapamil, nifedipine and diltiazem were investigated on the force of contraction of guinea-pig, electrically stimulated papillary muscles in vitro. 2 Calcium channel blocking potency was assessed either as a direct negative inotropic effect or as the ability of the drugs to antagonise the positive inotropic effects of added calcium (Ca2+). By either method, the rank order of potency was found to be nifedipine greater than verapamil greater than diltiazem. 3 Various factors which mimic some of the consequences of acute ischaemia in vivo, namely low pH, hypoxia and elevated K+, in combination, but not singly, enhanced the negative inotropic potency of verapamil and to lesser extent that of diltiazem, but not that of nifedipine. 4 Whilst the various interventions, especially in combination, produced a profound negative inotropic effect themselves, this was not responsible per se for the potentiation of the negative inotropic effects of verapamil and diltiazem, since the negative inotropic effects of nifedipine and dinitrophenol were not potentiated under the 'ischaemic' conditions. 5 By use of antagonism of the positive inotropic action of exogenous Ca2+ as an alternative measure of potency, the differential influence of 'ischaemia' on calcium channel blocker potency was confirmed. The effect of verapamil was potentiated some 9 fold, that of diltiazem about 2 fold, and that of nifedipine was unchanged. 6 The differential effect of 'ischaemia' on the potencies of the calcium channel blockers was unexpected. Verapamil (but not nifedipine) is thought to bind to the calcium channel at a specific site not easily accessible from the extracellular space. 'Ischaemic' conditions may cause membranal perturbations which allow verapamil easier access to its binding site thus increasing its negative inotropic potency.     

Frequency- and Potential-Dependency of the Negative Inotropic Action of Various Dihydropyridine and Non-Dihydropyridine Calcium Antagonists

Abstract: Transmembrane voltage and beat frequency are important determinants of the action of several organic calcium antagonists. This is well-known for the cationic amphiphilic calcium antagonists. We intended to assess the functional impact of these phenomena in cardiac muscle with special regard to dihydropyridines. Therefore, concentration-response curves were constructed in isolated guinea-pig left atria for the negative inotropic effect of various compounds. The dihydropyridines nifedipine, racemic nitrendipine, nisoldipine, and felodipine, and the enantiomers of isradipine were investigated at different stimulation frequencies (1 Hz, 2.5 Hz, 4.5 Hz), and at different extracellular K⁺ concentrations (2.7 mM, 5.4 mM, 10.8 mM). These drugs were compared with the cationic amphiphilic compounds gallopamil, verapamil and diltiazem. The potency of some dihydropyridines, particularly nitrendipine, could be modulated to a remarkable extent, covering several orders of magnitude. The potential-dependency of the drugs depended on stimulus frequency and ranged from less than a half to two orders of magnitude. At 2.5 Hz, the rank order of extent of potential-dependency was gallopamil > nitrendipine > diltiazem > verapamil = (+)-isradipine > (-)-isradipine ≥ nisoldipine ≥ felodipine = nifedipine. Based on data obtained from binding studies in intact atria and from patch-clamp measurements of calcium current blockade, a mathematical model was used which describes the observed potency changes. The model was based on the assumptions that 1) binding takes place at a site with a time-varying affinity, and that 2) alteration of experimental condition (frequency, membrane potential) changes the proportion of time the calcium channels display the high-affinity or the low-affinity state.     

3H]diltiazem binding to calcium channel antagonists recognition sites in rat cerebral cortex

The presence of a diltiazem recognition site within the macromolecular complex of the calcium channel in the brain had been hypothesized on the basis of binding studies with [3H]dihydropyridine calcium channel antagonists. In the present study, we therefore characterized [3H]diltiazem binding sites in the rat cerebral cortex. Saturable high affinity (Kd = 50-170 nM) [3H]diltiazem binding to the rat cerebral cortex was stereospecifically inhibited by the enantiomers of diltiazem according to their activity as calcium channel antagonists and modulators of [3H]dihydropyridine binding. An association between the [3H]diltiazem binding site and the calcium channel was further corroborated by the effects of chemically heterogeneous calcium channel antagonists on [3H]diltiazem binding. Dihydropyridines appeared to allosterically affect [3H]diltiazem binding according to their pharmacological effects; e.g. at 37 degrees C nitrendipine enhanced whereas the calcium agonist Bay K 8644 failed to affect [3H]diltiazem binding at concentrations fully inhibiting [3H]nitrendipine binding. The effect of nitrendipine may, at least in part, be explained by an increase in the affinity of [3H]diltiazem.     

Nifedipine, diltiazem, bepridil and verapamil uptakes into cardiac and smooth muscles

Vogel et al. (1979; J. Pharmacol. Exp. Ther. 210, 378) reported that one calcium antagonist, bepridil, exerted an effect internally as well as its effect on blocking Ca2+ entry in cardiac muscle. Therefore, the uptakes of tritiated nifedipine, diltiazem, bepridil, and verapamil by cat ileal smooth muscle, chick embryonic ventricular muscle, and rabbit papillary muscle were investigated. It was found that the uptakes of verapamil and bepridil by the muscles were much higher than those of nifedipine and diltiazem. The uptake of bepridil was substantially greater than that of verapamil; thus, the order of uptake was: bepridil greater than verapamil much greater than nifedipine greater than diltiazem. The cardiac muscles accumulated at least 2-fold greater amount of calcium antagonists than the smooth muscle. The amount of a given calcium antagonist accumulated by a muscle was not a function of the ability of that calcium antagonist to inhibit Ca2+ uptake into the muscle, since nifedipine and diltiazem were more potent in depressing Ca2+ uptake, but had the smallest uptakes. The calcium antagonists were more effective in depressing Ca2+ uptake into smooth muscle than into cardiac muscle. Calculation indicates that internal drug concentration at steady state for both cardiac and smooth muscles was either equal to (diltiazem) or much higher than the drug concentration in the medium (bepridil and verapamil). It is concluded that bepridil and verapamil enter and accumulate in the muscle cells, whereas nifedipine and diltiazem permeate more slowly into the muscles. The ability of all four drugs to enter the muscle cells confers the possibility that these calcium antagonists may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum.     

Effect of the calcium antagonists nifedipine,nitrendipine, nimodipine and nisoldipine on oesophageal motility in man

Summary Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies.Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (–15 min) and in parallel with the manometric measurements.Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r=0.92, nitrendipine r=0.80 and nisoldipine r=0.79. Nimodipine showed no such correlation.It is concluded that among the calcium antagonists studied, nifedipine exerted the strongest effect on oesophageal smooth muscle function, so it appears to be the most suitable compound for the treatment of primary motor abnormalities of the oesophagus.