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- Drvota, V, et al.
(författare)
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The effect of amiodarone on the beta-adrenergic receptor is due to a downregulation of receptor protein and not to a receptor-ligand interaction.
- 1999
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 255:2, s. 515-20
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Tidskriftsartikel (refereegranskat)abstract
- Downregulation of beta adrenergic receptors (beta-AR) by amiodarone (Am) have been reported in several studies both in vivo and in vitro. The mechanism underlying the antiadrenergic effect of Am is, however, still unclear. The aim of this study was to characterize whether the antiadrenergic effect of amiodarone is due to binding to the beta-AR or to downregulation of the beta-AR receptor protein. All experiments were performed on confluent mouse AT-1 cardiomyocytes cultured for 6 days. In acute experiments, equilibrium binding with [3H]-CGP-12177 to beta-AR was not directly inhibited by Am and the equilibrium binding constant did not change during prolonged exposure up to 72 hours. After Am exposure for 48 hours beta-AR density was decreased by 26% (p<0.005). T3 partially prevented the downregulation elicited by Am (p<0.05). A Western blot analysis with beta1-AR antibodies revealed a decreased signal intensity in cells treated with Am for 48 h as compared to control (p<0.05). Isoproterenol-provoked cAMP response did not change after acute exposure to Am. After incubation for 48 hours with Am there was, however, a 20% decrease in cAMP response as compared to control (p<0.05). This study shows that the effect of Am on beta-AR is due to a downregulation of the beta-AR protein and not to a competitive or non-competitive receptor-ligand interaction. This indicates a new pharmacological mechanism for modulation of beta-AR, which probably is transcriptionally regulated.
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- Sarkar, N., et al.
(författare)
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Effects of intramyocardial injection of phVEGF-A(165) as sole therapy in patients with refractory coronary artery disease - 12-month follow-up : Angiogenic gene therapy
- 2001
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 250:5, s. 373-381
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To test the safety and bioactivity of phVEGF-A(165) after intramyocardial injection during 12-month follow-up. Design. Open-labelled study. Subjects. Inclusion criteria were angina pectoris, Canadian Cardiovascular Society (CCS) class III-IV, unamenable to further revascularization, ejection fraction (EF) >30%, perfusion defects extending over >10% of the anterolateral left ventricle wall detectable with adenosine single photon emission computerized tomography (SPECT) and at least one patent vessel visible by coronary angiography. Seven of 39 patients referred for gene therapy were included. Intervention. Via a mini-thoracotomy under general anaesthesia, phVEGF-A(165) was injected directly into the myocardium at four sites in the anterolateral region of the left ventricle. Results. Operative procedures were uneventful. Perioperative release of myocardial markers and electrocardiogram (ECG) changes were detected in two patients. There were no perioperative deaths but one patient died 7 months postoperatively because of myocardial infarction. Plasma vascular endothelial growth factor (VEGF)-A levels increased two to threefold peaking 6 days postoperatively (P<0.004) and returning to baseline by day 30. A significant reduction in angina pectoris was reported. The CCS class improved from 3.30.2 to 1.9 +/-0.3 (P<0.01) and nitroglycerine intake decreased from 3915 to 12 +/-5 tablets week(-1) (P<0.001) 2 months after gene transfer. Improvements remained after 12 months when nitroglycerine consumption approached zero. Improved myocardial function in the phVEGF-A(165) injection region was documented in all patients (P<0.016) by tissue velocity imaging (TVI). Reduced reversible ischaemia was detected by adenosine SPECT in four patients. Improved collateralization was detected in four patients with coronary angiography. Conclusion. Intramyocardial injection of phVEGF-A(165) is safe and may lead to improved myocardial perfusion and function with longstanding symptomatic relief in end-stage angina pectoris. Based on these results this therapeutic potential is being tested in a double-blind placebo controlled multicentre trial, EUROINJECT ONE.
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