Inhibition of smooth muscle cell calcium mobilization and aortic ring contraction by lactone vastatins

Escobales, Nelson; Crespo, Marı́a J.; Altieri, Pablo I.; Furilla, Robert A.

doi:10.1097/00004872-199601000-00015

Cited by 12 publications

(17 citation statements)

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“…Although we did not investigate intracellular signaling mechanisms within the vascular smooth muscle that could contribute to AICAR-mediated endothelium-independent relaxation in the present study, previous in vitro biochemical experiments demonstrate that AMPK is able to phosphorylate and desensitize MLCK and thus could presumably induce relaxation in the context of an intact vascular system (31). Endothelium-independent relaxation to AICAR may also occur due to effects of AMPK on HMG-CoA reductase (10,16,33,44), which could involve modulation of Rho-kinase and L-type channel extracellular calcium entry (45), thus potentially exerting influence over vascular smooth muscle mechanisms of calcium sensitization and calcium-mediated contraction. As indicated, however, we did not undertake to study these mechanisms in the current study, and additional cellular and physiological studies will be required to elucidate mechanisms of AMPK-mediated relaxation in vascular smooth muscle.…”

Section: Discussionmentioning

confidence: 89%

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Ford

Rush

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Ford RJ, Rush JW. Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent. Am J Physiol Heart Circ Physiol 300: H64 -H75, 2011. First published October 22, 2010 doi:10.1152/ajpheart.00597.2010.-Activation of AMP-activated protein kinase (AMPK) induces vasorelaxation in arteries from healthy animals, but the mechanisms coordinating this effect are unclear and the integrity of this response has not been investigated in dysfunctional arteries of hypertensive animals. Here we investigate the mechanisms of relaxation to the AMPK activator 5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside (AICAR) in isolated thoracic aorta rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Although AICAR generated dose-dependent (10 Ϫ6 -10 Ϫ2 M) relaxation in precontracted WKY and SHR aortic rings with (E ϩ ) or without (E Ϫ ) endothelium, relaxation was enhanced in E ϩ rings. Relaxation in SHR E ϩ rings was also enhanced at low [AICAR] (10 Ϫ6 M) compared with that of WKY (57 Ϯ 8% vs. 3 Ϯ 2% relaxation in SHR vs. WKY E ϩ ), but was similar and near 100% in both groups at high [AICAR]. Pharmacological dissection showed that the mechanisms responsible for the endothelium-dependent component of relaxation across the dose range of AICAR are exclusively nitric oxide (NO) mediated in WKY rings, but partly NO dependent and partly cyclooxygenase (COX) dependent in SHR vessels. Further investigation revealed that AChstimulated COX-endothelium-derived contracting factors (EDCF)-mediated contractions were suppressed by AICAR, and this effect was reversed in the presence of the AMPK inhibitor Compound C in quiescent E ϩ SHR aortic rings. Western blots demonstrated that P(Thr 172 )-AMPK and P(Ser 79 )-acetyl-CoA carboxylase (indexes of AMPK activation) were elevated in SHR versus WKY E ϩ rings at low AICAR (ϳ2-fold). Together these findings suggest that AMPKmediated inhibition of EDCF-dependent contraction and elevated AMPK activation may contribute to the enhanced sensitivity of SHR E ϩ rings to AICAR. These results demonstrate AMPK-mediated vasorelaxation is present and enhanced in arteries of SHR and suggest that activation of AMPK may be a potential strategy to improve vasomotor dysfunction by suppressing enhanced endoperoxidemediated contraction and enhancing NO-mediated relaxation.spontaneously hypertensive rats; Wistar-Kyoto rats; nitric oxide; adenosine 5=-monophosphate-activated protein kinase; 5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside; endothelium-derived contracting factors AMP-ACTIVATED PROTEIN KINASE (AMPK) is emerging as a potential regulator of vascular function. Although recognized primarily as a modulator of cellular energy status and metabolism (28, 57), the identification of its existence in vascular cells and of its ability to be stimulated by numerous physical (8,20,59), energetic (17), hormonal (5, 8, 43), and chemical (8, 9, 11, 12, 29, 35, 40, 53) mediators of vasomotor function suggest a p...

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Section: Discussionmentioning

confidence: 89%

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Ford

Rush

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…The effects of simvastatin on Ca 2+ current through Ltype channels were not dependent of the presence of mevalonate [22,23] . On the other hand, other described effects of statins on Ca 2+ homeostasis related to release of Ca 2+ from intracellular stores are inhibited in the presence of mevalonate [7,8,24] . The direct effect of simvastatin on vascular smooth muscle cells from normotensive rats has been related to both blockade of calcium entry and to release of Ca 2+ from the sarcoplasmic reticulum [11] .…”

Section: +mentioning

confidence: 97%

“…Thus, the anti-atherosclerotic effect of simvastatin might in part result from its inhibitory effect on the synthesis of isoprenoids, independent of its hypocholesterolemic properties [5,6] . These actions of HMG-CoA reductase inhibitors on the proliferation and migration of vascular smooth muscle cells are related to Ca 2+ signaling, which is affected by isoprenoids [7,8] . Statins inhibit Ras and Rho isoprenylation.…”

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confidence: 99%

Regulation of Vascular Tone from Spontaneously Hypertensive Rats by the HMG-CoA Reductase Inhibitor, Simvastatin

Pérez‐Guerrero

Márquez-Martín²,

Herrera³

et al. 2005

Pharmacology

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The acute effect of simvastatin on aortic rings from spontaneously hypertensive rats (SHRs) was identified. Simvastatin-evoked relaxations of both depolarized and phenylephrine-precontracted arteries were independent of the presence of endothelium. This effect was inhibited by diltiazem and mevalonate, but not by the Rho-kinase inhibitor, Y-27632. Simvastatin prevented contraction induced by phenylephrine, calcium ionophore A-23187 and CaCl₂ in Ca²⁺-free medium. Y-27632 decreased the effect of simvastatin. On the contrary, contraction induced by noradrenaline in Ca²⁺-free medium was not affected. These results suggest that simvastatin elicited an effect on vascular smooth muscle cells from SHRs that may involve blockade of extracellular calcium entry and decrease vascular contraction by affecting Rho-kinase.

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“…These drugs also reduce blood pressure [13][14][15] , decrease oxidative stress [16] , improve endothelial function in diabetic patients [17] , and decrease smooth muscle cell proliferation and migration [18] . In addition, statins partially inhibit the agonist-induced contraction of aortic rings from rats [19,20] and decrease norepinephrine-induced vascular contraction [21] . The reduced incidence of ischemic events and myocardial infarction observed after statin treatment can be attributed to a combination of factors, including decreased cholesterol levels, improved endothelial function, and possibly reduced vascular tone in the coronary vasculature.…”

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confidence: 99%

Statins Decrease Serotonin-Induced Contractions in Coronary Arteries of Swine in vitro

Crespo

Quidgley²

2006

Pharmacology

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Recent evidence suggests that statins improve the status of patients with coronary artery disease not only by reducing cholesterol levels, but also by acting at the level of the endothelium-smooth muscle unit. Previous results from our laboratory showed that these drugs interact with the vascular wall by partially inhibiting calcium-dependent, agonist-induced contractions in rat aortas. To evaluate whether this effect is also extended to the coronary vasculature, we assessed the effect of statins on serotonin (5-HT) induced contractions of left and right coronary arteries of swine. Concentration-response curves for the 5-HT-induced contractions (from 0.1 nmol/l to 100 µmol/l) were calculated on rings from both coronaries in the presence and absence of either (5 µmol/l) pravastatin, mevastatin, simvastatin, lovastatin, or atorvastatin. After a 45-min incubation period, all statins significantly reduced the E_max for the 5-HT-induced contractions, ranging from 51.9 ± 1.9% (simvastatin) to 15.9 ± 2.0% (pravastatin) in the left coronary artery and from 48.8 ± 2.0% (simvastatin) to 17.8 ± 2.5% (pravastatin) in the right coronary artery. The EC₅₀ values for the 5-HT-induced contractions were 0.150 ± 0.005 µmol/l for the left coronary artery and 0.171 ± 0.010 µmol/l for the right coronary artery. These values significantly changed after incubation with statins, ranging from 1.240 ± 0.101 µmol/l (for simvastatin) to 0.081± 0.008 µmol/l (for pravastatin) in the left coronary artery and from 1.410 ± 0.075 µmol/l (for simvastatin) to 0.084 ± 0.008 µmol/l (for pravastatin) in the right coronary artery. This evidence supports the possibility that, beyond their lipid-lowering properties, statins may provide a beneficial effect in atherosclerotic patients by reducing the tone in the coronary vasculature, facilitating blood flow to the myocardium.

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Inhibition of smooth muscle cell calcium mobilization and aortic ring contraction by lactone vastatins

Cited by 12 publications

References 0 publications

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Regulation of Vascular Tone from Spontaneously Hypertensive Rats by the HMG-CoA Reductase Inhibitor, Simvastatin

Statins Decrease Serotonin-Induced Contractions in Coronary Arteries of Swine in vitro

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