Calcium Channel Blocking Properties of Amlodipine in Vascular Smooth Muscle and Cardiac Muscle In Vitro: Evidence for Voltage Modulation of Vascular Dihydropyridine Receptors

Burges, Roger A.; Gardiner, Donald G.; Gwilt, Michael; Higgins, Alan J.; Blackburn, K J; Campbell, Simon F.; Cross, P. E.; Stubbs, J. K.

doi:10.1097/00005344-198701000-00018

Cited by 77 publications

(61 citation statements)

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“…2), it was found that the 50% effective concentrations (EC 50 s) for the stimulation of cefixime transport are in the same range as the K i values for inhibition of the slow-type Ca 2ϩ channels by those blockers (6,11). 14 C]cefixime transport into Caco-2 cells determined in the absence or the presence of 100 M nifedipine revealed that the Ca 2ϩ channel blocker significantly increases V max but that it has no effects on K m (Fig.…”

Section: Effects Of Camentioning

confidence: 97%

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca ²⁺ Channel Blockers

Wenzel

Kuntz

Diestel

et al. 2002

Antimicrob Agents Chemother

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The ␤-lactam antibiotic group encompasses the penicillins, cephalosporins, carbapenems, and monobactams (13). The high intestinal absorption rates of orally active ␤-lactams are mainly explained by the fact that they serve as substrates for the intestinal peptide transporter PEPT1 (10). PEPT1 is located in the apical membranes of intestinal epithelial cells (23) and the Caco-2 human intestinal epithelial cell line (39). The peptide transporter translocates di-and tripeptides (17, 33) as well as a variety of peptidomimetic compounds, including selected immunostimulants (25, 28), angiotensin-converting-enzyme inhibitors (7, 31), and ␤-lactam antibiotics (36, 43), in a proton-coupled electrogenic mode (1).The affinities of ␤-lactams for PEPT1 show large variabilities, depending on the structure of the individual antibiotic (10, 42). Moreover, it was shown that different ␤-lactams can display completely different pH dependencies for transport into Caco-2 cells or into oocytes expressing heterologously cloned mammalian PEPT1. The optimum pH for transport of zwitterionic ␤-lactams such as cefadroxil is 6.5, whereas the dianionic cefixime is effectively transported only at pH values Ͻ6.0 (42). Since the intestinal epithelium has a fairly stable surface pH compartment (microclimate pH) with a pH that is Ͼ6.25 and Ͻ6.75 (22), interactions of ␤-lactams with PEPT1 in the normal gut and thus their in vivo absorption rates may be defined by the pH at the membrane surface. This might explain why cefixime, which is efficiently transported by PEPT1 in vitro at pH values below 6.0, shows a comparably low oral availability in vivo (3, 15). Other factors contributing to the absorption of ␤-lactams via PEPT1 may include regulation of transport capacity by protein kinase C (PKC)-and insulin-dependent pathways (9, 29). Understanding of those mechanisms responsible for alterations in the transport kinetics of PEPT1 could be important for specific enhancement of the absorption of drugs with low oral availabilities, such as cefixime, which is usually used for the treatment of respiratory tract infections (37). As it has been shown that rates of absorption of cefixime are increased by 30% when the Ca 2ϩ channel blocker nifedipine is coadministered with cefixime in humans (14), we were interested in studying the underlying mechanisms responsible for this increase. Although it had been suggested that neurohormonal regulation may be involved in mediating the effects of nifedipine on cefixime transport (18), we hypothesized that the alterations in intracellular free calcium ion (Ca 2ϩ in ) concentrations caused by nifedipine could enhance PEPT1 transport activity for cefixime.We therefore altered the Ca 2ϩ in concentration in Caco-2 cells, a human intestinal epithelial cell line that expresses PEPT1, with either Ca 2ϩ channel blockers or Ca 2ϩ ionophores and measured the effects on the apical influx of [ 14 -C]cefixime. Moreover, by use of intracellular pH (pH in ) measurements, we assessed whether alterations in Ca 2ϩ in levels secondarily ...

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Section: Effects Of Camentioning

confidence: 97%

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca ²⁺ Channel Blockers

Wenzel

Kuntz

Diestel

et al. 2002

Antimicrob Agents Chemother

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“…To examine the pattern of voltage-dependence of propafenone-and quinidine-induced inhibition, in rat aorta and coronary artery the effect of the drugs was studied at different membrane potentials which were controlled by changing the extracellular concentration of KCl (i.e., 'potassium clamp'; Burges et al, 1987;Nelson & Worley,1989;Godfraid & Salomone, 1991;Salomone & Godfraind, 1993). Aortic and coronary rings were incubated for 30 min in Ca2"-free (5 mM KCl) or in Ca2"-free depolarizing (40 mM KCI) PSS (with isotonic replacement of NaCl by KCl).…”

Section: Voltage-dependence Of Drug-induced Inhibitionmentioning

confidence: 99%

“…According to the modulated receptor hypothesis, binding of a drug to a receptor site located within the channel is modulated by the conformational state of the channel (rested, activated, inactivated) which is determined by the membrane potential (Hondeghem & Katzung, 1984). Radioligand binding (Burges et al, 1987;Godfraind & Salomone, '1991;Triggle, 1991;Salomone & Godfraind, 1993) and electrophysiological studies (Uehara & Hume, 1985;Bean et al, 1986;Nelson & Worley, 1989) have found that most CCBs bind with greater affinity under depolarizing conditions. Since depolarization of the membrane potential shifts the conformation of Ca2" channels into the activated and inactivated states, the voltage-dependence has been attributed to a preferential binding to these states of the channel (Uehara & Hume, 1985;Bean et al, 1986;.…”

Section: Inhibition Of'5ca2+ Influxmentioning

confidence: 99%

Voltage‐ and time‐dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine

Pérez-Vizcaíno

Pozo

Zaragozá

et al. 1994

British J Pharmacology

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1 Class I antiarrhythmic drugs (e.g. Na+ channel blockers) such as propafenone and quinidine also inhibit voltage-gated Ca2" and K+ channels. In the present paper the voltage-and time-dependent inhibitory effects of propafenone and quinidine were studied on depolarization-induced vascular contractions and 45Ca2+ uptake in isolated endothelium denuded rat aorta and pig left descending coronary artery.2 Quinidine and propafenone (10-7 M-5 x 10-M) produced a concentration-dependent relaxation of the contractions induced by 80mM KCL. Propafenone was significantly more potent (P<0.05) than quinidine in both rat aorta and pig coronary arteries but both drugs were more potent (P<0.05) in relaxing rat aorta than pig coronary arteries. In rat aortic rings, the relaxant effects of propafenone were unaffected by pretreatment with the Na+ channel blocker, tetrodotoxin. 3 The degree of inhibition produced after prolonged exposure (40 min) to propafenone and quinidine differed as the time of depolarization with 80 mM KCl was increased. Quinidine (3 x 10-6 M, 10-S M and 3 X 10-5M) not only produced an inhibition at the very early stage of contraction, but also a time-dependent inhibition was observed. In contrast, propafenone (10-6 M, 3 X 10-6 M and 10-5 M) produced a more marked concentration-dependent early block but only a mild time-dependent inhibition. 4 The voltage-dependence of propafenone-and quinidine-induced inhibition, was studied in rat aorta and coronary arteries which had been incubated in 5 or 40mM KCl Ca2"-free solution and then contracted by changing the bath solution to 100 mM KCI and 2 mM CaCl2 solution. The inhibitor effects of quinidine were significantly enhanced (P <0.05) when the preparations were preincubated in 40 mM KCl (depolarizing) solution. In contrast, the effects of propafenone were quite similar in 5 or in 40 mM KCI solution.5 Quinidine, 10-5 M, produced a greater inhibition (P<0.05) of 100 mM KCl-stimulated 45Ca2+ uptake in aortic rings preincubated in depolarizing as compared to normal solution. In contrast, the inhibition produced by 3 x 10-6 M propafenone was similar in aortic rings incubated in 5 or 40 mM KCl solution. 6 It is concluded that both quinidine and propafenone inhibited vascular smooth muscle contraction which could be attributed to reduced Ca2+ entry. The voltage-and time-dependent inhibitory effects of quinidine may reflect an increased binding of the drug to Ca2+ channels at depolarized potentials.

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“…These findings contrast with studies of the onset of resistance arteries (Harder & Hermsmeyer, 1983;Cheung, lodipine-induced inhibition of contraction in isolated 1984;Stekiel et al, 1986). Such a state of depolarization will od vessels, where amlodipine-induced inhibition is exmake vascular smooth muscle much more susceptible to nely slow (Burges et al, 1987;Hughes et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Similar vasorelaxant properties have been observed in vitro. In rat isolated aortic strips Burges et al (1987) demonstrated that the onset and offset of amlodipine were much slower than nifedipine, and in radioligand binding studies, Rigby et I Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

The action of amlodipine on voltage‐operated calcium channels in vascular smooth muscle

Hughes

Wijetunge

1993

British J Pharmacology

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1 Amlodipine, a dihydropyridine derivative largely ionized at physiological pH, inhibited calcium channel currents in single vascular smooth muscle cells isolated from rabbit ear artery in a concentration-dependent manner. 2 Amlodipine inhibited the current-voltage relationship for calcium channel currents across the range of test potentials used. However, the effect of amlodipine was more marked on more depolarized test potentials. Amlodipine also shifted the steady-state inactivation curve for calcium channel currents in a hyperpolarized direction. 3 The potency of amlodipine as determined from the steady-state inhibition of calcium channel current induced by the drug was dependent on the holding potential of the cells. Use of a more depolarized holding potential increased the potency of amlodipine. 4 Onset of amlodipine-induced inhibition was relatively rapid at both -60 mV and -40 mV holding potential. The use of a more depolarized holding potential increased the rate of association of amlodipine. No recovery from amlodipine-induced inhibition was seen over a 20 min period following washout of the drug. 5 In addition to voltage-dependence, the action of amlodipine showed use-dependence, in that the effect of amlodipine was more marked when calcium channel currents were evoked frequently. Increasing the frequency of activation of calcium channel currents did not alter the apparent onset rate of amlodipine-induced inhibition, but increased the degree of inhibition achieved by the drug. 6 The electrophysiological properties of amlodipine, particularly its voltage-dependence are probably important determinants of its action in vivo.

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Calcium Channel Blocking Properties of Amlodipine in Vascular Smooth Muscle and Cardiac Muscle In Vitro: Evidence for Voltage Modulation of Vascular Dihydropyridine Receptors

Cited by 77 publications

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PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca ²⁺ Channel Blockers

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca ²⁺ Channel Blockers

Voltage‐ and time‐dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine

The action of amlodipine on voltage‐operated calcium channels in vascular smooth muscle

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Calcium Channel Blocking Properties of Amlodipine in Vascular Smooth Muscle and Cardiac Muscle In Vitro: Evidence for Voltage Modulation of Vascular Dihydropyridine Receptors

Cited by 77 publications

References 0 publications

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers

Voltage‐ and time‐dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine

The action of amlodipine on voltage‐operated calcium channels in vascular smooth muscle

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Product

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PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca ²⁺ Channel Blockers

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca ²⁺ Channel Blockers