Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart

Guiraudou, P.; Pucheu, Sylvie; Gayraud, R.; Gautier, Patrick; Roccon, Alain; Herbert, Jean Marc; Nisato, Dino

doi:10.1016/j.ejphar.2004.05.046

Cited by 29 publications

(25 citation statements)

References 22 publications

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“…Thus, it is likely that NO is involved in the vasodilation caused by AM and DEA. [6][7][8] The results of the present study provide direct evi-dence that therapeutic concentrations of AM and DEA enhanced eNOS-mediated NO production in human endothelial cells. AM is known to affect mRNA expression including ionic channels.…”

Section: Discussionmentioning

confidence: 61%

“…Previous studies have described the coronary and peripheral vasodilatory effects of AM, DEA, and their analogue, dronedarone, in humans and experimental animals. [6][7][8] Though the cardiovascular protective properties of amiodarone such as vasodilation are, at least in part, attributable to the blockade of calcium channels, another mechanism involving NO is likely to be involved. 6,7) However, the effects of AM and DEA on NO production remain unclarified.…”

Section: Neuronal Nos (Nnos) Inducible Nos (Inos) and Endothelial Nosmentioning

confidence: 99%

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Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells

Kishida

Nakajima

et al. 2006

Int. Heart J.

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SUMMARYAmiodarone (AM) is a potent vasodilator and exhibits diverse cardiovascular protective effects in vivo, but their underlying mechanisms remain unsettled. We investigated the effects of AM and N-desethylamiodarone (DEA), the major metabolite of AM, on endothelial nitric oxide (NO) production using cultured human umbilical vein endothelial cells (HUVECs). The release of NO was evaluated as measured by nitrite, a stable metabolite of NO, using the Griess reaction and also measured directly by a NO-selective electrode. The expression of each nitric oxide synthase (NOS) mRNA was examined by reverse transcriptase-polymerase chain reaction (RT-PCR), and the effects of AM on eNOS mRNA expression were studied by quantitative real-time RT-PCR. AM and DEA(1-30 µM) enhanced NO production in a concentration-dependent manner. DEA was capable of producing more NO than AM. L-NAME, a nonselective NOS inhibitor, EGTA, a Ca 2+ -chelating agent, and nickel, a nonspecific Ca 2+ blocker, all inhibited AM-induced NO production. However, LY294002, an Akt pathway inhibitor and SB202190, a MAP kinase inhibitor, did not significantly suppress the production. In RT-PCR analysis, only eNOS mRNA was detected. Treatment with AM for 4 hours did not show a significant increase in the expression of eNOS mRNA. AM lower than 30 µM did not induce apoptosis, net cell loss, or LDH release from cells. The present study provides the first evidence that therapeutic concentrations of AM and DEA enhance eNOS-mediated NO production without any toxic or apoptotic effects. This mechanism may underlie the cardiovascular protective effects of AM and its metabolite observed in a clinical setting. (Int Heart J 2006; 47: 85-93)

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Section: Discussionmentioning

confidence: 61%

Section: Neuronal Nos (Nnos) Inducible Nos (Inos) and Endothelial Nosmentioning

confidence: 99%

Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells

Kishida

Nakajima

et al. 2006

Int. Heart J.

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“…33 Dronedarone (0.01 to 1 mol/L) induced a concentration-dependent reduction of coronary perfusion pressure in isolated guinea pig hearts, effects that were independent of the nitric oxide synthase pathway and possibly related to its calcium current blockade. 36 The effect of dronedarone on single-cell cardiac action potential is variable, depending on species and the duration of drug administration. The most consistent effect is usedependent inhibition of maximum upstroke velocity, both after acute and sustained administration.…”

Section: Electrophysiological Properties Of Dronedarone In Vitro Expementioning

confidence: 99%

“…33 Dronedarone (0.01 to 1 mol/L) induced a concentration-dependent reduction of coronary perfusion pressure in isolated guinea pig hearts, effects that were independent of the nitric oxide synthase pathway and possibly related to its calcium current blockade. 36 From the Main Line Health Heart Center and Lankenau Hospital (C.P., G.X.Y., P.R.K. ), Wynnewood; Jefferson Medical College, Thomas Jefferson University (G.X.Y., P.R.K.…”

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confidence: 99%

Dronedarone

2009

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Abstract-Amiodarone is the most effective antiarrhythmic drug for maintaining sinus rhythm for patients with atrial fibrillation. Extra-cardiac side effects have been a limiting factor, especially during chronic use, and may offset its benefits. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been developed for the treatment of atrial fibrillation and atrial flutter. Similar to amiodarone, dronedarone is a potent blocker of multiple ion currents, including the rapidly activating delayed-rectifier potassium current, the slowly activating delayed-rectifier potassium current, the inward rectifier potassium current, the acetylcholine activated potassium current, peak sodium current, and L-type calcium current, and exhibits antiadrenergic effects. It has been studied for maintenance of sinus rhythm and control of ventricular response during episodes of atrial fibrillation. Dronedarone reduces mortality and morbidity in patients with high-risk atrial fibrillation, but may be unsafe in those with severe heart failure. This article will review evidence of safety and effectiveness of dronedarone in patients with atrial fibrillation. Key Words: amiodarone Ⅲ arrhythmia Ⅲ atrial fibrillations Ⅲ dronedarone A trial fibrillation (AF) is the most common arrhythmia in clinical practice and a usual cause for hospitalization and consultation. 1,2 It is an epidemic. It is projected that by 2050, more than 15 million people will contract AF in the United States alone. 2,3 Nearly 1 in every 10 persons aged 80 years and older has AF, 1,4,5 predisposing them to stroke, heart failure, and death. 6,7 A recent report from Centers for Medicare and Medicaid Services suggested that AF accounted for 1 765 304 hospitalizations in 1999. 8 The cost of medical care for patients with AF is almost 5 times higher than the care of patients without AF. 9,10 Despite improvements in primary and secondary prevention of ischemic heart disease and hypertension, the US age-adjusted death rate due to AF increased from 27.6 in 1980 to 69.8 per 100 000 in 1998. 2,11 Current therapy for AF is multidimensional and complicated. 12 There is some consensus on the benefits of anticoagulation in patients with AF, but debate continues about the relative value of rate versus rhythm control. Recent clinical trials have failed to demonstrate superiority of sinus rhythm maintenance, 13-18 but antiarrhythmic therapy is important for patients with severe symptoms. Conventional antiarrhythmic drugs have limited efficacy and safety. In fact, data suggest that the benefit of restoring and maintaining sinus rhythm in AF may be offset by significant cardiac and extracardiac side effects of currently used drugs. 19 -21 Improvement in the current approach to AF is clearly necessary. This review focuses on dronedarone, a new antiarrhythmic drug for AF suppression (Figure 1). Electrophysiological Properties of Dronedarone In Vitro ExperimentsIn vitro electrophysiological properties of dronedarone and its comparison with amiodarone are summarized in Table...

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“…8,9) The benzofuran amiodarone (A) and its analogue KB130015 (B) were reported to relax vascular smooth muscle. [10][11][12] A new noniodinated benzofuran derivative dronedarone, SR33589 (C) was recently approved by the Food and Drug Administration (FDA) for treatment of atrial fibrillation and atrial flutter. 13) Khellin (D) and visnagin (E) are the principle active constituents obtained from Ammi visnaga L. and which possess strong vasodilatation and spasmolytic activities.…”

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confidence: 99%

Benzofuran–Morpholinomethyl–Pyrazoline Hybrids as a New Class of Vasorelaxant Agents: Synthesis and Quantitative Structure–Activity Relationship Study

et al. 2014

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The benzofuran-morpholinomethyl-pyrazoline hybrids 4a-e, 5a-e and 6a-j were synthesized via reaction of α,β-unsaturated carbonyl compounds 3a-e with hydrazine hydrate, semicarbazide or thiosemicarbazide. Applying the Mannich reaction to 5-(5-aryl-4,5-dihydro-1H-pyrazol-3-yl)-4-methoxybenzofuran-6-ols 7a-e with morpholine hydrochloride and paraformaldehyde afforded positional isomeric 7-morpholinomethyl derivatives 4a-e and N-morpholinomethyl derivatives 8a-e. All the synthesized compounds showed significant vasodilatation properties in isolated thoracic aortic rings of rats precontracted using the standard norepinephrine hydrochloride technique. Compounds 3d, 3e, 5a-c, 6b, 6c, 6f, 6h and 6i exhibited activity (IC 50 0.3185-0.4577 mM) superior to that of prazocin (IC 50 0.487 mM), while 5d, 6j and 8c showed comparable activity (IC 50 0.4789-0.4951 mM). The quantitative structure-activity relationship study revealed a correlation between the observed vasorelaxant activities of the newly synthesized compounds and their different physicochemical parameters, especially solubility, in addition to structure connectivity and energetic quantities calculated from stored three dimensional (3D) conformations. Absorption, distribution, metabolism and elimination (ADME) evaluation showed good agreement with the biological results obtained.

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Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart

Cited by 29 publications

References 22 publications

Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells

Amiodarone and N-Desethylamiodarone Enhance Endothelial Nitric Oxide Production in Human Endothelial Cells

Dronedarone

Benzofuran–Morpholinomethyl–Pyrazoline Hybrids as a New Class of Vasorelaxant Agents: Synthesis and Quantitative Structure–Activity Relationship Study

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