Effects of calcium entry blockers on tension development and calcium influx in rat uterus

Granger, Susan E.; Hollingsworth, Michael A.; Weston, A.H.

doi:10.1111/j.1476-5381.1986.tb10166.x

Cited by 58 publications

(35 citation statements)

References 15 publications

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“…Those other cell types include the endometrium which lies inside the myometrial smooth muscle of the uterus, the enteric nervous system which innervates the intestinal smooth muscle of the duodenum, and the urothelium which separates the detrusor smooth muscle of the bladder wall from the urine inside. But while these nonmuscular cells may be able to modulate spontaneous contractility of the adjacent smooth muscle cell layers (Gershon, 1981;Granger et al, 1986;Haynes and Pennefather, 1993;Buckner et al, 2002;Azadzoi et al, 2004;Bulbul et al, 2007;Kanai et al, 2007), they are not likely the primary site for gemfibrozil's relaxant effects. If, for example, gemfibrozil's relaxation of the duodenal contractility seen in Figure 5 were mediated solely by inhibition of enteric neuronal release of contractile neurotransmitters, then we would not expect to see its relaxant influence in uterus and bladder as well.…”

Section: Effects Of Gemfibrozil On Spontaneous Contractions Of Rat Utmentioning

confidence: 99%

“…uterus, duodenum and bladder. These tissues are known for their ability to exhibit spontaneously-occurring phasic rhythmic contractions, which are physiologically relevant and can be observed in vitro without the need to administer contractile agents (Small and Weston, 1971;Gershon, 1981;Granger et al, 1986;Leroy et al, 1991;Haynes and Pennefather, 1993;Buckner et al, 2002;Vedernikov et al, 2003;Azadzoi et al, 2004;Szigeti et al, 2005;Bulbul et al, 2007;Kanai et al, 2007). We determined if gemfibrozil inhibits these spontaneous activities.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Phelps

Peuler

2010

J. Smooth Muscle Res.

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Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPARα may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 μM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 μM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or spontaneously-occurring. These findings are particularly relevant to both the recently renewed concern over the impact of fibrates on hypertension and a new understanding of their gastrointestinal side effects.

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Section: Effects Of Gemfibrozil On Spontaneous Contractions Of Rat Utmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Phelps

Peuler

2010

J. Smooth Muscle Res.

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“…Simultaneous measurement of tension development and extracellular electrical activity was performed as described by Granger et al (1986) and Edwards etal. (1986).…”

Section: Extracellular Electrical Recordingmentioning

confidence: 99%

The relaxant action of BRL 34915 in rat uterus

Hollingsworth

Amédée

Edwards

et al. 1987

British J Pharmacology

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1 BRL 34915 (0.04-1.3 tiM) caused concentration-dependent inhibition of spontaneous phasic spasms of the isolated uterus of the term pregnant rat and this effect was not antagonized by propranolol. Spasms evoked by low concentrations of KC1 (< 20 mM) were inhibited by BRL 34915 but those evoked by higher concentrations ( >40 mM) were unaffected.2 In experiments using extracellular electrical recording, BRL 34915 (1O fM) selectively inhibited oxytocin-induced phasic spasms and the associated spike activity but had little effect on the tonic component of the spasms. BRL 34915, as an inhibitor of phasic spasms to oxytocin (0.2 nM), was antagonized by procaine (0.3 and 1 mM). 3 BRL 34915 (10 EM) did not inhibit Ca2+-induced spasm of saponin-skinned thin myometrial strips.4 Intracellular microelectrode recording from myometrial strips showed that BRL 34915 (10I jM) inhibited action potentials and phasic spasms in the presence of oxytocin (0.2 nM) and produced a hyperpolarization of 5 mV. 5In single myometrial cells under current or voltage clamp, BRL 34915 (0I jAM) had no effect on action potentials and inward current in Ca2+-or Ba2+-containing media in the presence of tetraethylammonium, 4-aminopyridine and .caesium chloride. In the absence of these K+-channel inhibitors, BRL 34915 had no effect on resting membrane potential, membrane resistance, action potentials, inward current or outward current.6 BRL 34915 (1 or 1O IM) had no effect on '8Rb efflux from myometrial strips. 86Rb efflux was increased by oxytocin (0.2 and 20 nM). 7 The relaxant profile of BRL 34915 in the rat uterus is similar to that described for other smooth muscles where an action to open membrane K+-channels has been proposed. BRL 34915 inhibited spike production but produced only a small hyperpolarization without a detectable increase in 86Rb efflux. Membrane resistance and transmembrane currents were unaffected. These results suggest that in the uterus the effects of BRL 34915 may be restricted to K+-channels involved in the production of pacemaker activity.

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“…Myocyte membrane depolarization opens VGCCs, allowing Ca 2ϩ to influx from the extracellular space and elicit concerted periodic contractions (9,12,24,27,31,32). Indeed, inhibition of VGCCs using dihydropyridines, such as nifedipine, is a mainstay of current clinical intervention for preterm labor in the United States.…”

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confidence: 99%

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

Skarra

Cornwell

Solodushko

et al. 2011

American Journal of Physiology-Cell Physiology

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Skarra DV, Cornwell T, Solodushko V, Brown A, Taylor MS. CyPPA, a positive modulator of small-conductance Ca 2ϩ -activated K ϩ channels, inhibits phasic uterine contractions and delays preterm birth in mice. Am J Physiol Cell Physiol 301: C1027-C1035, 2011. First published July 27, 2011; doi:10.1152/ajpcell.00082.2011.-Organized uterine contractions, including those necessary for parturition, are dependent on calcium entry through voltage-gated calcium channels in myometrial smooth muscle cells. Recent evidence suggests that small-conductance Ca 2ϩ -activated potassium channels (K Ca 2), specifically isoforms K Ca2.2 and 2.3, may control these contractions through negative feedback regulation of Ca 2ϩ entry. We tested whether selective pharmacologic activation of K Ca2.2/2.3 channels might depress uterine contractions, providing a new strategy for preterm labor intervention. Western blot analysis and immunofluorescence microscopy revealed expression of both KCa2.2 and KCa2.3 in the myometrium of nonpregnant (NP) and pregnant (gestation day 10 and 16; D10 and D16, respectively) mice. Spontaneous phasic contractions of isolated NP, D10, and D16 uterine strips were all suppressed by the KCa2.2/2.3-selective activator CyPPA in a concentration-dependent manner. This effect was antagonized by the selective KCa2 inhibitor apamin. Whereas CyPPA sensitivity was reduced in D10 and D16 versus NP strips (pIC50 5.33 Ϯ 0.09, 4.64 Ϯ 0.03, 4.72 Ϯ 0.10, respectively), all contractions were abolished between 30 and 60 M. Blunted contractions were associated with CyPPA depression of spontaneous Ca 2ϩ events in myometrial smooth muscle bundles. Augmentation of uterine contractions with oxytocin or prostaglandin F2␣ did not reduce CyPPA sensitivity or efficacy. Finally, in an RU486-induced preterm labor model, CyPPA significantly delayed time to delivery by 3.4 h and caused a 2.5-fold increase in pup retention. These data indicate that pharmacologic stimulation of myometrial KCa2.2/2.3 channels effectively suppresses Ca 2ϩ -mediated uterine contractions and delays preterm birth in mice, supporting the potential utility of this approach in tocolytic therapies.

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Effects of calcium entry blockers on tension development and calcium influx in rat uterus

Cited by 58 publications

References 15 publications

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

The relaxant action of BRL 34915 in rat uterus

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

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Effects of calcium entry blockers on tension development and calcium influx in rat uterus

Cited by 58 publications

References 15 publications

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

The relaxant action of BRL 34915 in rat uterus

CyPPA, a positive modulator of small-conductance Ca2+-activated K+ channels, inhibits phasic uterine contractions and delays preterm birth in mice

Contact Info

Product

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CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice