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Biomedical subjects

A M Dart

Publications and source records attributed to A M Dart.

At least 37 records · Page 2Linked to original sources
PubMed2000

Kinins in humans.

The kinin peptide system in humans is complex. Whereas plasma kallikrein generates bradykinin peptides, glandular kallikrein generates kallidin peptides. Moreover, a proportion of kinin peptides is hydroxylated on proline(3) of the bradykinin sequence. We established HPLC-based radioimmunoassays for nonhydroxylated and hydroxylated bradykinin and kallidin peptides and their metabolites in blood and urine. Both nonhydroxylated and hydroxylated bradykinin and kallidin peptides were identified in human blood and urine, although the levels in blood were often below the assay detection limit. Whereas kallidin peptides were more abundant than bradykinin peptides in urine, bradykinin peptides were more abundant in blood. Bradykinin and kallidin peptide levels were higher in venous than arterial blood. Angiotensin-converting enzyme inhibition increased blood levels of bradykinin, but not kallidin, peptides. Reactive hyperemia had no effect on antecubital venous levels of bradykinin or kallidin peptide levels. These studies demonstrate differential regulation of the bradykinin and kallidin peptide systems, and indicate that blood levels of bradykinin peptides are more responsive to angiotensin-converting enzyme inhibition than blood levels of kallidin peptides.

Adult↗
PubMed1999

Lipids and the endothelium.

The normal endothelium is characterised by the production of a number of molecules which affect the contractile state of adjacent myocytes and the behavior of formed elements within the blood stream, and by the absence of cell surface adhesion molecules. In addition, endothelial cells are important modulators of coagulation and fibrinolysis. Whilst effects of lipids have been documented on many of these endothelial processes, there is particularly strong evidence for effects on the vasodilatation mediated by endothelium derived nitric oxide and on the interaction between leukocytes and the endothelial surface. Both LDL cholesterol and triglyceride rich lipoproteins impair endothelium dependent vasodilatation. The effects of LDL cholesterol are primarily evident for lipoprotein particles that have been oxidised with evidence for effects of specific constituents of oxidised LDL, such as lysophosphatidylcholine (LPC). LDL effects have been demonstrated at numerous sites of the nitric oxide signaling pathway including receptor-G protein coupling, nitric oxide synthase and NO bioactivity, with evidence for enhanced superoxide formation and the consequent production of the less potent dilator peroxynitrite. The effects of lipids on endothelium dependent vasodilatation can be reversed not only by reducing the level of elevated lipids levels but also by provision of the NOS substrate, L-arginine and by the provision of antioxidants, although the mechanism for these effects are not fully elucidated. The adhesion of leukocytes to the endothelial surface is stimulated by low density and triglyceride rich lipoproteins. As with endothelium dependent vasodilatation, the effects of LDL cholesterol are primarily evident for low-density lipoprotein particles that have been oxidised, and many of the effects of oxidised LDL can be mimicked by LPC. HDL can overcome pro-adhesive effects of oxidised LDL. The effects of LDL on leukocyte adhesion are secondary to the expression of adhesion molecules on the luminal surfaces of endothelial cells. In addition to the likely deleterious effects of lipids on endothelium-mediated vasodilatation and leukocyte-endothelial cell interaction, lipids have been shown to affect a number of other endothelial processes and function. Thus, oxidised LDL affects endothelial ET1 and PGI2 release. Although effects have been shown on endothelial cell growth and apoptosis and on endothelial processes related to thrombosis and fibrinolysis, these effects have been less extensively studied than endothelial dependent vasodilatation and leukocyte-endothelial cell interaction. Many of the effects of elevated or modified low density and TG rich lipoproteins on endothelial cells and endothelial cell processes could be expected to contribute to the development of atherosclerosis and therefore, to the association between lipids and atherosclerotic, particularly coronary, vascular disease. However, the extent to which "endothelial dysfunction" accounts for the known relationships between serum lipid concentrations and CHD is yet to be established.

Animals↗
PubMed1999

Sympathetic activation triggers ventricular arrhythmias in rat heart with chronic infarction and failure.

OBJECTIVE: To seek direct evidence for a cause-effect relation between sympathetic activation and arrhythmogenesis. METHODS: Rats underwent open-chest surgery with either coronary artery occlusion or sham operation, and were studied 8 weeks later using in situ heart perfusion and nerve stimulation methods. RESULTS: Infarcted rats showed cardiac functional impairment and increased heart and lung weight. The extent of these changes correlated well with infarct size (IS). In in situ perfused hearts, sympathetic nerve stimulation (2 and 4 Hz, 45 s duration) induced a frequency-dependent release of norepinephrine (NE). NE release was lower in MI than that in control groups. In hearts with large IS (> or = 40%, n = 19) ventricular arrhythmias were rare at baseline, but nerve stimulation evoked the onset of ventricular premature beats (95%), tachycardia (37%) and fibrillation (26%), IS and stimulation frequency were key determinants for the inducibility of arrhythmias. Lower K- concentration enhanced arrhythmia inducibility. beta-blockade inhibited the frequency of arrhythmias produced by nerve stimulation. CONCLUSION: In infarcted rat hearts sympathetic activation is a potent trigger for the onset of ventricular tachyarrhythmias.

Adrenergic Uptake Inhibitors↗
PubMed1999

Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol.

OBJECTIVES: Patients with high triglyceride (of which very low density lipoproteins [VLDL] are the main carriers), but with normal low density lipoprotein (LDL) cholesterol levels, were examined for in vivo endothelium function status. BACKGROUND: Very low density lipoproteins inhibit endothelium-dependent, but not -independent, vasorelaxation in vitro. METHODS: Three groups were studied: 1) healthy volunteers (n = 10; triglyceride 1.24+/-0.14 mmol/liter, LDL cholesterol 2.99+/-0.24 mmol/liter); 2) hypertriglyceridemic (n = 11; triglyceride 6.97+/-1.19 mmol/liter, LDL cholesterol 2.17+/-0.2 mmol/liter, p < 0.05); and 3) hypercholesterolemic (n = 10; triglyceride 2.25+/-0.29 mmol/liter, LDL cholesterol 5.61+/-0.54 mmol/liter; p < 0.05) patients. Vasoactive responses to acetylcholine, sodium nitroprusside, noradrenaline, N(G)-monomethyl-L-arginine and postischemic hyperemia were determined using forearm venous occlusion plethysmography. RESULTS: Responses to acetylcholine (37 microg/min) were significantly dampened both in hypercholesterolemic (% increase in forearm blood flow: 268.2+/-62) and hypertriglyceridemic patients (232.6+/-45.2) when compared with controls (547.8+/-108.9; ANOVA p < 0.05). Responses to sodium nitroprusside (at 1.6 microg/min: controls vs. hypercholesterolemics vs. hypertriglyceridemic: 168.7+/- 25.1 vs. 140.6+/-38.9 vs. 178.5+/-54.5% increase), noradrenaline, N(G)-monomethyl-L-arginine and postischemic hyperemic responses were not different among the groups examined. CONCLUSIONS: Acetylcholine responses are impaired in patients with pathophysiologic levels of plasma triglycerides but normal plasma levels of LDL cholesterol. The impairment observed was comparable to that obtained in hypercholesterolemic patients. We conclude that impaired responses to acetylcholine normally associated with hypercholesterolemia also occur in hypertriglyceridemia. These findings identify a potential mechanism by which high plasma triglyceride levels may be atherogenic independent of LDL cholesterol levels.

Acetylcholine↗
PubMed1999

Antiadrenergic effect of chronic amiodarone therapy in human heart failure.

OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.

Adrenergic Antagonists↗
PubMed1999

Effects of heart rate on arterial compliance in men.

1. Arterial compliance is a major determinant of left ventricular afterload. In keeping with earlier experimental data obtained in isolated arterial segments, it has recently been shown in the rat that arterial compliance decreases with an increase in heart rate (HR) induced by atrial pacing. 2. To elucidate the potential relevance of this effect in humans, we investigated nine male volunteers (age 20-30 years; mean 26 years). Systemic arterial compliance (SAC) was measured with the diastolic area method and carotid-to-femoral and femoral-to-dorsalis pedis pulse wave velocities (PWV) were measured to determine regional changes in compliance. Heart rate was first lowered with intravenous metoprolol to 56 +/- 2 b.p.m. and then increased by transoesophageal atrial pacing to 80 and 100 b.p.m. 3. Increasing HR from 56 +/- 2 to 80 b.p.m. by pacing increased mean arterial pressure (MAP) from 78 +/- 2 to 98 +/- 1 mmHg (P < 0.001) and then to 102 +/- 2 mmHg (P = NS). Systemic arterial compliance fell from 0.48 +/- 0.06 to 0.33 +/- 0.04 arbitrary compliance units (ACU; P < 0.01), carotid-to-femoral PWV increased from 6.1 +/- 0.3 to 6.8 +/- 0.4 m/s (P < 0.001) and femoral-to-dorsalis pedis PWV increased from 8.9 +/- 0.4 to 10.1 +/- 0.5 m/s (P < 0.001). Pacing at 100 b.p.m did not change MAP, but did lead to a further decrease in SAC (to 0.24 +/- 0.03 ACU; P < 0.05) and further increases in carotid-to-femoral (7.3 +/- 0.4 m/s; P = NS) and femoral-to-dorsalis pedis PWV (11.3 +/- 0.4 m/s; P < 0.001). 4. We conclude that systemic, central and peripheral compliances decrease in vivo with an increase in HR induced by atrial pacing.

Adrenergic beta-Antagonists↗
PubMed1999

Left ventricular mass and microalbuminuria: relation to ambulatory blood pressure. Hypertension Diagnostic Service Investigators.

1. Both microalbuminuria and left ventricular hypertrophy may reflect target organ damage in essential hypertension. Both are related to the prevailing level of blood pressure and both are associated with an increase in morbidity and mortality. 2. The database of the Hypertension Diagnostic Service, a multicentre secondary referral clinic for patients with essential hypertension, was analysed in order to clarify the level of association between microalbuminuria and left ventricular hypertrophy, which might explain the observed increase in morbidity and mortality in patients with microalbuminuria. Microalbuminuria was measured semiquantitatively by urine dip-stix. After the exclusion of patients with potential secondary hypertension, renal disease and diabetes mellitus, patients with complete data for microalbuminuria, left ventricular mass (LVM) and 24 h blood pressure monitoring were selected. 3. Data were complete for 704 patients (47% male, age 51 +/- 12 years) and 42% tested positive for microalbuminuria. Microalbuminuria was positively related to 24 h systolic blood pressure and weight and was negatively related to age. Left ventricular mass was higher in patients with microalbuminuria (men, 265 +/- 69 g; women, 207 +/- 61 g) than in those without (men, 250 +/- 64 g, P < 0.05; women, 185 +/- 50 g, P < 0.001). After correction for the effects of gender, body mass index and 24 h systolic blood pressure, the presence of microalbuminuria was associated with an increase in LVM of 10 g (P < 0.05, 95% confidence interval, 2-19 g).

Adult↗
PubMed1999

Withdrawal of hormonal therapy for 4 weeks decreases arterial compliance in postmenopausal women.

BACKGROUND: We demonstrated in a previous cross-sectional study that arterial compliance is elevated in postmenopausal women taking estrogen-containing hormonal therapy, which may partially account for the reduction in cardiovascular risk observed. OBJECTIVE: To investigate the effects of withdrawal and recommencement of hormonal therapy, each for 4 weeks, on arterial compliance. METHODS: Seventeen postmenopausal women [aged 56 +/- 4 years (mean +/- SD)] taking long-term hormonal therapy (+HT group) were studied at baseline, 4 weeks after withdrawal of hormonal therapy and again 4 weeks after recommencement. Systemic arterial compliance (SAC), pulse wave velocity (PWV) in the aorto-femoral and femoral-dorsalis pedis regions, and hemodynamic variables were measured at baseline, and at the end of each study intervention. As a time-control, seventeen postmenopausal women (aged 63 +/- 7 years) not taking hormonal therapy (-HT group) were also investigated. RESULTS: SAC significantly decreased from 0.47 +/- 0.06 to 0.40 +/- 0.05 arbitrary compliance units (mean +/- SEM; P < 0.05) after 4 weeks withdrawal from hormonal therapy. PWV in the femoral-dorsalis pedis region was elevated significantly by the withdrawal of hormonal therapy (8.4 +/- 0.4 to 9.4 +/- 0.5 m/s; P < 0.05), but PWV in the aortofemoral region did not change. After therapy had been recommenced for 4 weeks, SAC and PWV in the femoral-dorsalis pedis region were restored to baseline values. The -HT group showed no difference in SAC or PWV, and mean arterial pressure did not change in either group throughout the study period. CONCLUSION: These data suggest that hormonal modulation of distal arterial vascular tone may account for short-term changes in arterial compliance associated with estrogen-containing hormonal therapy.

Aorta, Thoracic↗
PubMed1999

Presynaptic antisympathetic action of amiodarone and its metabolite desethylamiodarone.

Amiodarone has a "reserpine-like" sympatholytic action in the heart. The aims of this study were to test whether desethylamiodarone (DEA), the in vivo bioactive metabolite of amiodarone, has this action and whether this action could be demonstrated in a neuronal preparation. Experiments were performed in intact rats, perfused hearts, or brain synaptosomes treated with DEA and amiodarone, and concentrations of norepinephrine (NE) and dihydroxyphenylglycol (DHPG), the intraneuronal metabolite of NE, were assayed in plasma, coronary effluent, and synaptosomes. In perfused hearts, DEA at 1, 3, and 10 microM increased DHPG overflow by threefold, sixfold, and ninefold, respectively (all p < 0.01 vs. control). DEA at 1 microM was more potent than amiodarone in increasing DHPG overflow. DEA at 1 and 3 microM also inhibited NE release evoked by sympathetic nerve stimulation (p < 0.05). In intact rats, intravenous DEA at 15 mg/kg elicited onefold increase in plasma DHPG level, and oral pretreatment with amiodarone did not interfere with the sympatholytic action of intravenous amiodarone. In synaptosomes, 40-min incubation with amiodarone, DEA (both 10 microM), and reserpine reduced synaptosomal NE content by 42, 45, and 60%, respectively. Thus similar to its parent drug, DEA exerts a presynaptic sympatholytic action in rat hearts in vivo and in vitro. This action of amiodarone and DEA also was observed in synaptosomes.

Amiodarone↗
PubMed1999

Higher systemic arterial compliance is associated with greater exercise time and lower blood pressure in a young older population.

OBJECTIVES: Arterial compliance is an important therapeutic target in older individuals in whom stiffening of the proximal arterial circulation is thought to underlie systolic hypertension and increased cardiac work. We have shown previously that arterial compliance is related to aerobic fitness and that it is increased in young (20 to 35 years old), previously sedentary individuals by a 4-week period of moderate aerobic training. The extent to which compliance relates to exercise performance in a random selection of young older patients has not been reported previously. Therefore, we examined the interrelationship between systemic arterial compliance (SAC) and time to cessation of exercise during a standard treadmill exercise test in an older population. DESIGN: A cross-sectional survey. METHODS: SAC was estimated at rest using simultaneous recordings of ascending aortic flow and carotid applanation tonometry in 43 subjects aged 67 +/- 7 years (mean +/- SD; 24 men and 19 women). Treadmill exercise testing was performed using a modified Bruce protocol. Aerobic capacity was assessed as Heart Rate-Blood Pressure product and exercise tolerance as total treadmill time. RESULTS: SAC and exercise tolerance were related to gender, with men exhibiting greater exercise reserve and higher SAC than women. There was a significant positive correlation between SAC and time to cessation of exercise (r = .34; P = .03), with a negative correlation between SAC and resting heart rate-blood pressure product (r = -.66; P < .001). SAC was correlated with height and blood pressure. Exercise tolerance was related to height (P < .02). CONCLUSIONS: These data indicate a positive association between SAC and fitness level in healthy older people and an inverse association between SAC and systolic blood pressure. Our findings are consistent with either (1) acquisition of a more compliant circulation and lower blood pressure through more physical activity or (2) that a more compliant arterial circulation and lower blood pressure permit greater athletic performance.

Aged↗
PubMed1999

Independent effects of Apo E phenotype and plasma triglyceride on lipoprotein particle sizes in the fasting and postprandial states.

LDL particle sizes and Apo E phenotypes were determined in 212 subjects of whom 51 had angina. LDL diameter was significantly less in subjects with an epsilon2 allele (24.76+/-0.08 vs 24.94+/-0.02 nm, P=0.02), and this was evident for both E2/E3 (24.77+/-0.09 nm) and E2/E4 (24.69+/-0.08 nm) phenotypes. Although there was a negative relation between LDL diameter and plasma triglyceride, the effect of apo E2 was still evident with adjustment for triglyceride. In multiple regression analysis, the significant determinants of LDL diameter were gender (with females having larger particles than males), body mass index, and the presence (or absence) of E2. HDL particle sizes and compositions were determined on fasting samples and, additionally, 5 and 8 hours after a fat-rich meal for 48 coronary heart disease cases and 49 control subjects. Fasting HDL particle sizes were not related to the presence of E2 but were significantly smaller for subjects possessing an epsilon4 allele (8. 09+/-0.08 vs 8.39+/-0.05 nm, P=0.003) and were negatively related to plasma triglyceride. However, the effect of E4 persisted after adjustment for triglyceride. In a multiple regression analysis, the only significant determinant of fasting HDL diameter was the presence (or absence) of E4 with fasting plasma triglyceride just failing to reach significance (P=0.06). There was a postprandial increase in HDL diameter that was less marked in subjects with coronary heart disease. The postprandial increase in HDL diameter was of sufficient magnitude to result in size reclassification of HDL particles. The influence of E4 was also evident at both postprandial time points. Compositional analysis demonstrated that the increase in HDL diameters postprandially could be attributed to triglyceride enrichment, with an accompanying fall in cholesterol ester content. Phospholipid changes postprandially were biphasic with an initial fall followed by a rise in concentration. The increase in triglyceride content was significantly less in those subjects with angina despite an equivalent rise in plasma triglyceride. The present study demonstrates significant, but different, effects of variation in apo E phenotype on the particle sizes of both HDL and LDL. Such effects were still evident with adjustment for differences in plasma triglyceride and suggests that variation in apo E phenotype exerts effects on lipoprotein particle sizes by mechanisms additional to those dependent on change in plasma triglyceride.

Alleles↗
PubMed1999

Exercise training increases basal nitric oxide production from the forearm in hypercholesterolemic patients.

The objective of this study was to investigate the effects of cycle training on basal nitric oxide (NO) production and endothelium-dependent dilator capacity in hypercholesterolemic patients in whom acetylcholine responsiveness is impaired. Nine sedentary hypercholesterolemic volunteers (total plasma cholesterol >6.0 mmol/L; 2 female) aged 44+/-3 years (mean+/-SEM) participated in the study. Subjects remained sedentary for 4 weeks and performed 4 weeks of home-based cycle training (3 x 30 minutes/week at 65% maximum oxygen consumption [VO(2)max]) in a randomized order. Arteriovenous nitrate/nitrite (NO(x)) gradient was assessed and plethysmography was used to measure the forearm blood flow responses to arterial infusions of acetylcholine, sodium nitroprusside, and N(G)mono methyl L-arginine. Training increased VO(2)max from 30.4+/-1.9 to 34.3+/-1.4 mL x kg(-1) x min(-1) (P=0.01). Intrabrachial diastolic blood pressure was reduced from 70+/-3 to 68+/-3 mm Hg (P=0.02) with training, whereas systolic pressure did not change. Plasma triglycerides and total, LDL, and HDL cholesterol were not different between interventions. In the sedentary state, there was a positive forearm arteriovenous difference in plasma NO(x) indicating net extraction (6.8+/-4.0 nmol x 100 mL(-1) x min(-1)), whereas in the trained state this difference was negative, indicating net production (-5.8+/-5.8 nmol x 100 mL(-1) x min(-1); P=0.03). N(G)mono methyl L-arginine, at a dose of 4 micromol/min, caused a greater vasoconstriction after training (79.6+/-3.4% versus 69.9+/-6.8%; P=0.05). Acetylcholine and sodium nitroprusside induced dose-dependent elevations in forearm blood flow that were unaffected by training. These data suggest that basal release of endothelium-derived NO is increased with 4 weeks of home based training in hypercholesterolemic patients, independently of lipid profile modification. This may contribute to the cardiovascular protective effects of exercise training, including reduced blood pressure.

Acetylcholine↗
PubMed1999

Muscular strength training is associated with low arterial compliance and high pulse pressure.

Aerobic exercise training increases arterial compliance and reduces systolic blood pressure, but the effects of muscular strength training on arterial mechanical properties are unknown. We compared blood pressure, whole body arterial compliance, aortic impedance, aortic stiffness (measured by beta-index and carotid pulse pressure divided by normalized systolic expansion [Ep]), pulse wave velocity, and left ventricular parameters in 19 muscular strength-trained athletes (mean+/-SD age, 26+/-4 years) and 19 sedentary controls (26+/-5 years). Subjects were healthy, non-steroid-using, nonsmoking males, and athletes had been engaged in a strength-training program with no aerobic component for a minimum of 12 months. There was no difference in maximum oxygen consumption between groups, but handgrip strength (mean+/-SEM, 44+/-2 versus 56+/-2 kg; P<0.01) and left ventricular mass (168+/-8 versus 190+/-8 g; P<0.05) were greater in athletes. Arterial stiffness was higher in athletes, as evidenced by lower whole body arterial compliance (0.40+/-0.04 versus 0.54+/-0.04 arbitrary compliance units; P=0.01), higher aortic characteristic impedance (1.55+/-0.13 versus 1.18+/-0.08 mm Hg. s. cm-1; P<0.05), beta-index (4.6+/-0.2 versus 3.8+/-0.4; P<0. 05), and ln Ep (10.86+/-0.06 versus 10.60+/-0.08; P<0.01). Femoral-dorsalis pedis pulse wave velocity was also higher in the athletes, but carotid-femoral pulse wave velocity was not different. Furthermore, both carotid (56+/-3 versus 44+/-2 mm Hg; P<0.001) and brachial (60+/-3 versus 50+/-2 mm Hg; P<0.01) pulse pressures were higher in the athletes, but mean arterial pressure and resting heart rate did not differ between groups. These data indicate that both the proximal aorta and the leg arteries are stiffer in strength-trained individuals and contribute to a higher cardiac afterload.

Adult↗
PubMed1999

Identification of a novel, inhibitory action of amiodarone on vesicular monoamine transport.

The benzofuran antiarrhythmic drug, amiodarone, exhibits a wide range of pharmacological properties. Recent in vivo biochemical studies suggest that amiodarone may exert an antiadrenergic action in the heart, which resembles the effects of reserpine. To investigate the cellular basis for this apparent presynaptic, sympatholytic action we used Chinese hamster ovary (CHO) cells expressing the type 2 vesicular monoamine transporter (VMAT2) as a synaptic vesicular model. Amiodarone inhibited the uptake of [3H]norepinephrine in VMAT2-transfected CHO cells in a concentration-dependent manner, with a -log EC50 of 6.44 +/- 0.32. To further identify the site at which amiodarone suppressed vesicular monoamine transport, we examined the ability of amiodarone to displace [3H]reserpine from its binding site in membrane fractions prepared from CHO cells expressing VMAT2. [3H]Reserpine binding was inhibited in a concentration-dependent manner by amiodarone, with an -log EC50 of 6.76 +/- 0.03, reaching 84 +/- 5% inhibition of reserpine binding at 10 microM. A pH-dependent mechanism for this action of amiodarone was excluded in studies using the pH-sensitive fluorescent indicator 2',7'-bis (carboxyethyl)-5,6-carboxyfluorescein (BCECF). These data indicate that amiodarone inhibits the uptake of monoamine into the axoplasmic storage vesicle by inhibiting VMAT. Furthermore, amiodarone competes specifically with reserpine for binding to VMAT. These findings suggest a novel presynaptic site of action for amiodarone.

Adrenergic Uptake Inhibitors↗