Mefenamic acid as a novel activator of L‐type voltage‐dependent Ca<sup>2+</sup> channels in smooth muscle cells from pig proximal urethra

Teramoto, Noriyoshi; Tomoda, Toshihisa; Ito, Yushi

doi:10.1038/sj.bjp.0706051

Cited by 6 publications

(9 citation statements)

References 17 publications

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“…For example, BAY K8644, which shifts the L-type Ca 2+ channel activation curve to hyperpolarized potentials [33,34], caused an increase of basal Ca 2+ influx and tone (Figure 8, see also [30]). Furthermore, Bay K8644 shifted the [K + -response curve to lower K + concentrations by about 8 mM at midpoint, independent of the presence of levcromakalim, indicating that both the position of the window on the voltage axis and the resting membrane potential determine the window contraction.…”

Section: Discussionmentioning

confidence: 99%

Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta

et al. 2012

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BackgroundElectrophysiological studies of L-type Ca2+ channels in isolated vascular smooth muscle cells revealed that depolarization of these cells evoked a transient and a time-independent Ca2+ current. The sustained, non-inactivating current occurred at voltages where voltage-dependent activation and inactivation overlapped (voltage window) and its contribution to basal tone or active tension in larger multicellular blood vessel preparations is unknown at present. This study investigated whether window Ca2+ influx affects isometric contraction of multicellular C57Bl6 mouse aortic segments.ResultsIntracellular Ca2+ (Cai2+, Fura-2), membrane potential and isometric force were measured in aortic segments, which were clamped at fixed membrane potentials by increasing extracellular K+ concentrations. K+ above 20 mM evoked biphasic contractions, which were not affected by inhibition of IP3- or Ca2+ induced Ca2+ release with 2-aminoethoxydiphenyl borate or ryanodine, respectively, ruling out the contribution of intracellular Ca2+ release. The fast force component paralleled Cai2+ increase, but the slow contraction coincided with Cai2+ decrease. In the absence of extracellular Ca2+, basal tension and Cai2+ declined, and depolarization failed to evoke Cai2+ signals or contraction. Subsequent re-introduction of external Ca2+ elicited only slow contractions, which were now matched by Cai2+ increase. After Cai2+ attained steady-state, isometric force kept increasing due to Ca2+- sensitization of the contractile elements. The slow force responses displayed a bell-shaped voltage-dependence, were suppressed by hyperpolarization with levcromakalim, and enhanced by an agonist of L-type Ca2+ channels (BAY K8644).ConclusionThe isometric response of mouse aortic segments to depolarization consists of a fast, transient contraction paralleled by a transient Ca2+ influx via Ca2+ channels which completely inactivate. Ca2+ channels, which did not completely inactivate during the depolarization, initiated a second, sustained phase of contraction, which was matched by a sustained non-inactivating window Ca2+ influx. Together with sensitization, this window L-type Ca2+ influx is a major determinant of basal and active tension of mouse aortic smooth muscle.

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Section: Discussionmentioning

confidence: 99%

Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta

et al. 2012

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“…Patch-clamp experiments were performed at room temperature (21-23°C), as described previously (Teramoto et al, 2005). Junction potentials between bath and pipette solutions were measured with a 3 M KCl reference electrode and were < 2 mV, so that correction of these potentials was not necessary.…”

Section: Methodsmentioning

confidence: 99%

Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca²⁺ Currents and Ca²⁺ Transients in Murine Urinary Bladder Myocytes

Zhu

Brain

Aishima

et al. 2007

J Pharmacol Exp Ther

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The anticholinergic propiverine (1-methyl-4-piperidyl diphenylpropoxyacetate), which is used for the treatment of overactive bladder syndrome, has functionally active metabolites [M-1 (1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide) and M-2 (1-methyl-4-piperidyl benzilate N-oxide)], but the site of actions of these metabolites is uncertain. Propiverine is rapidly absorbed after oral administration and is extensively biotransformed in the liver, giving rise to several active metabolites (M-1 and M-2). This study determines the effect of M-1 and M-2 on voltage-dependent nifedipine-sensitive inward Ca 2ϩ currents (I Ca ) using patch-clamp techniques and fluorescent Ca 2ϩ imaging [after electrical field stimulation (EFS) and acetylcholine (ACh)] in the murine urinary bladder. In conventional whole-cell recording, propiverine and M-1 but not M-2 inhibited the peak amplitude of I Ca in a concentration-dependent manner at a holding potential of Ϫ60 mV (propiverine, K i ϭ 10 M; M-1, K i ϭ 118 M). M-1 shifted the steady-state inactivation curve of I Ca to the left at Ϫ90 mV by 7 mV. Carbachol (CCh) reversibly inhibited I Ca . This inhibition probably occurred through muscarinic type 3 receptors, coupling with G-proteins, because nanomolar concentrations of 4-diphenylacetoxy-N-methyl-piperidine greatly reduced this inhibition, whereas pirenzepine or ,4]benzodiazepine-6-one (AF-DX 116) at concentrations up to 1 M was almost ineffective. In the presence of M-2, the CCh-induced inhibition of I Ca was blocked. In fluorescent Ca 2ϩ imaging, M-2 inhibited EFS-induced and ACh-induced Ca 2ϩ transients. These results suggest that M-1 acts, at least in part, as a Ca 2ϩ channel antagonist (as it inhibited I Ca ), whereas M-2 has more direct antimuscarinic actions.

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“…Patch‐clamp experiments were performed at room temperature (21–23°C), as described previously (Teramoto et al ., 2005). Junction potentials between bath and pipette solutions were measured with a 3 M KCl reference electrode and were <2 mV, so that correction for these potentials was not necessary.…”

Section: Methodsmentioning

confidence: 99%

“…Data are expressed as mean with the standard deviation (s.d.). In order to obtain precise components of I Ba , the method for subtraction of the leak and capacitive currents was performed to subtract I Ba in the presence of 100 μ M Cd 2+ from I Ba (Teramoto et al ., 2005).…”

Section: Methodsmentioning

confidence: 99%

The actions of azelnidipine, a dihydropyridine‐derivative Ca antagonist, on voltage‐dependent Ba²⁺ currents in guinea‐pig vascular smooth muscle

Hl¹,

Tomoda²,

Aishima³

et al. 2006

British J Pharmacology

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Background and purpose: Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca 2 þ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltagedependent L-type Ca 2 þ channels were investigated in guinea-pig portal vein. Experimental approach: The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba 2 þ currents (I Ba ) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique. Key results: Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, K i ¼ 153 nM; amlodipine, K i ¼ 16 nM; nifedipine, K i ¼ 7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of I Ba in a concentration-and voltage-dependent manner (-60 mV, K i ¼ 282 nM; À90 mV, K i ¼ 2 mM) and shifted the steady-state inactivation curve of I Ba to the left at À90 mV by 16 mV. The inhibitory effects of azelnidipine on I Ba persisted after 7 min washout at À60 mV. In contrast, I Ba gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of I Ba at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644. Conclusions and implications: These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca 2 þ channels in vascular smooth muscle.

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Mefenamic acid as a novel activator of L‐type voltage‐dependent Ca²⁺ channels in smooth muscle cells from pig proximal urethra

Cited by 6 publications

References 17 publications

Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta

Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta

Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca²⁺ Currents and Ca²⁺ Transients in Murine Urinary Bladder Myocytes

The actions of azelnidipine, a dihydropyridine‐derivative Ca antagonist, on voltage‐dependent Ba²⁺ currents in guinea‐pig vascular smooth muscle

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Mefenamic acid as a novel activator of L‐type voltage‐dependent Ca2+ channels in smooth muscle cells from pig proximal urethra

Cited by 6 publications

References 17 publications

Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta

Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta

Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca2+ Currents and Ca2+ Transients in Murine Urinary Bladder Myocytes

The actions of azelnidipine, a dihydropyridine‐derivative Ca antagonist, on voltage‐dependent Ba2+ currents in guinea‐pig vascular smooth muscle

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Mefenamic acid as a novel activator of L‐type voltage‐dependent Ca²⁺ channels in smooth muscle cells from pig proximal urethra

Actions of Two Main Metabolites of Propiverine (M-1 and M-2) on Voltage-Dependent L-Type Ca²⁺ Currents and Ca²⁺ Transients in Murine Urinary Bladder Myocytes

The actions of azelnidipine, a dihydropyridine‐derivative Ca antagonist, on voltage‐dependent Ba²⁺ currents in guinea‐pig vascular smooth muscle