Down-regulation of  -adrenergic receptors on mononuclear leukocytes induced by dobutamine treatment in patients with congestive heart failure

Teng, Jeng Kai; Kwan, C. M.; Liu, Lin; Tsai, L.-M.; Chang, Wei‐Ting; Chen, J. H.

doi:10.1093/eurheartj/14.10.1349

Cited by 10 publications

(8 citation statements)

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“…In line with the present findings, a 24 h levosimendan infusion has previously been shown to maintain the haemodynamic effects at a similar level at 24 and 48 h,10 with the effects lasting for about 7 days 14. The haemodynamic effects of dobutamine may diminish owing to tachyphylaxis,15,16 but in the present study this was not seen, and cardiac index and PCWP were at similar levels at 24 and 48 h in the dobutamine group.…”

Section: Discussionsupporting

confidence: 89%

Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta‐blockers

Bergh

Andersson

Dahlström

et al. 2010

European J of Heart Fail

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AimsThe aim of this study is to compare the effects of a 24 h intravenous infusion of levosimendan and a 48 h infusion of dobutamine on invasive haemodynamics in patients with acutely decompensated chronic NYHA class III–IV heart failure. All patients were receiving optimal oral therapy including a β-blocker.Methods and resultsThis was a multinational, randomized, double-blind, phase IV study in 60 patients; follow-up was 1 month. There was a significant increase in cardiac index and a significant decrease in pulmonary capillary wedge pressure (PCWP) at 24 and 48 h for both dobutamine and levosimendan. The improvement in cardiac index with levosimendan was not significantly different from dobutamine at 24 h (P = 0.07), but became significant at 48 h (0.44 ± 0.56 vs. 0.66 ± 0.63 L/min/m2; P = 0.04). At 24 h, the reduction in the mean change in PCWP from baseline was similar for levosimendan and dobutamine, however, at 48 h the difference was more marked for levosimendan (−3.6 ± 7.6 vs. −8.3 ± 6.7 mmHg; P = 0.02). No difference was observed between the groups for change in NYHA class, β-blocker use, hospitalizations, treatment discontinuations or rescue medication use. Reduction in B-type natriuretic peptide (BNP) was significantly greater with levosimendan at 48 h (P = 0.03). According to physician's assessment, the improvement in fatigue (P = 0.01) and dyspnoea (P = 0.04) was in favour of dobutamine treatment, and hypotension was significantly more frequent with levosimendan (P = 0.007). No increase in atrial fibrillation or ventricular tachycardia was seen in either group.ConclusionA 24 h levosimendan infusion achieved haemodynamic and neurohormonal improvement that was at least comparable at 24 h and superior at 48 h to a 48 h dobutamine infusion.

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Section: Discussionsupporting

confidence: 89%

Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta‐blockers

Bergh

Andersson

Dahlström

et al. 2010

European J of Heart Fail

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“…However, a notable exception to the correlation between agonist strength and rate of down-regulation is evidenced by the data from dobutamine treatments that show a slightly greater rate of down-regulation of ␤-ARs than the coupling efficiency would predict. Consistent with our results, dobutamine has been shown to be a potent down-regulator of ␤-ARs in leukocytes when administered for treatment of congestive heart failure (Teng et al, 1993). Furthermore, Blevins et al (2000) have shown that dobutamine displays unusual properties with regard to a quantitative analysis of GTP shifts relative to the other agonists.…”

Section: Agonistsupporting

confidence: 91%

Kinetic Analysis of Agonist-Induced Down-Regulation of the β₂-Adrenergic Receptor in BEAS-2B Cells Reveals High- and Low-Affinity Components

2000

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We examined the interrelationships of internalization and down-regulation of the beta(2)-adrenergic receptor in response to treatment of the BEAS-2B human epithelial cell line with both a series of agonists at high occupancy and with various concentrations of fenoterol that gave occupancies from 0.93 to 0.001. We found that the extent of internalization measured after a 30-min treatment increased as a function of coupling efficiency, with ephedrine, dobutamine, albuterol, fenoterol, and epinephrine giving 0, 7, 17, 48, and 55% internalization, respectively. With the exception of dobutamine, the rates of down-regulation (k(deg)) also showed a dependence on agonist coupling efficiency, giving (in terms of fraction of receptors lost/h) 0.082 with ephedrine, 0.250 with dobutamine, 0.148 with albuterol, 0.194 with fenoterol, and 0.212 with epinephrine. Comparison of down-regulation to internalization showed that weak agonists caused down-regulation in the absence of significant internalization. The extent of internalization caused by fenoterol over a 1000-fold range of occupancy was proportional to agonist occupancy. However, although no internalization was observed with the low concentrations (0.2 and 2 nM fenoterol), these concentrations did cause significant down-regulation. Thus, as with partial agonists, it was clear that down-regulation occurred in the absence of measurable internalization. The kinetics of agonist-induced down-regulation are consistent with a scheme in which down-regulation proceeds by two pathways; a high-affinity, low-capacity component (EC(50) = 0.5 nM) clearly dissociated from internalization and a low-affinity, high-capacity component (EC(50) = 160 nM) closely correlated with internalization.

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“…Also, the down-regulation of beta-adrenergic receptors with prolonged dobutamine infusion [88] has clinical implications leading to development of tolerance [89]. Dobutamine is not hemodynamically as effective in patients receiving beta-blockers as those who are not.…”

Section: Dobutaminementioning

confidence: 99%

Levosimendan: A New Inodilatory Drug for the Treatment of Decompensated Heart Failure

Kivikko¹,

Lehtonen²

2005

CPD

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Levosimendan is a new calcium sensitizer developed for the treatment of congestive heart failure. Experimental studies indicate that levosimendan increases myocardial contractility and dilates both the peripheral and coronary vessels. Its positive inotropic effect is based on calcium-dependent binding of the drug to cardiac troponin C. It also acts as an opener of ATP-dependent potassium channels in vascular smooth muscle, thus inducing vasodilation. Although levosimendan acts preferentially as a calcium sensitizer it has also demonstrated selective phosphodiesterase III inhibitory effects in vitro. However, this selective inhibition does not seem to contribute to the positive action at pharmacologically relevant concentrations. Levosimendan has an active metabolite, OR-1896. Similarly to levosimendan, the metabolite exerts its positive inotropic and vasodilatory effects on myocardium and vasculature. The elimination half-life of levosimendan is about 1 hour. Thus, with intravenous administration, the parent drug rapidly disappears from the circulation after the infusion is stopped. The active metabolite, however, has a half-life of approximately 80 hours, and can be detected in circulation up to 2 weeks after stopping a 24-hour infusion of levosimendan. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure. Both patients with ischemic and non-ischemic etiology have participated in the studies. Levosimendan produces significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in PCWP, mean blood pressure, mean pulmonary artery pressure, mean right atrial pressure and total peripheral resistance. With a loading dose, the effects on PCWP and cardiac ouput are seen within few minutes. There is no sign of development of tolerance even with a prolonged infusion up to 48 hours. Cardiac performance is improved with no significant increases in oxygen consumption or potentially malignant rhythm disorders. Due to the formation of an active metabolite, the hemodynamic effects are maintained up to several days after stopping levosimendan infusion. Compared to dobutamine, levosimendan produces similar increase in cardiac output but profoundly greater decrease in pulmonary capillary wedge pressure. On the contrary to dobutamine, the hemodynamic effects are not attenuated with concomitant beta-blocker use. Levosimendan has been shown to have favourable effects on symptoms of heart failure superior to placebo and at least comparable to dobutamine. Mortality and morbidity in levosimendan treated patients has been shown to be significantly lower when compared to dobutamine or placebo treated patients. The most common adverse events associated with levosimendan treatment are headache and hypotension, as a likely consequence of the vasodilating properties of the compound. In conclusion, levosimendan offers a new effective option for the treatment of acutely decompensated heart failure. Unlike traditio...

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Down-regulation of -adrenergic receptors on mononuclear leukocytes induced by dobutamine treatment in patients with congestive heart failure

Cited by 10 publications

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Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta‐blockers

Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta‐blockers

Kinetic Analysis of Agonist-Induced Down-Regulation of the β₂-Adrenergic Receptor in BEAS-2B Cells Reveals High- and Low-Affinity Components

Levosimendan: A New Inodilatory Drug for the Treatment of Decompensated Heart Failure

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Down-regulation of -adrenergic receptors on mononuclear leukocytes induced by dobutamine treatment in patients with congestive heart failure

Cited by 10 publications

References 0 publications

Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta‐blockers

Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta‐blockers

Kinetic Analysis of Agonist-Induced Down-Regulation of the β2-Adrenergic Receptor in BEAS-2B Cells Reveals High- and Low-Affinity Components

Levosimendan: A New Inodilatory Drug for the Treatment of Decompensated Heart Failure

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Kinetic Analysis of Agonist-Induced Down-Regulation of the β₂-Adrenergic Receptor in BEAS-2B Cells Reveals High- and Low-Affinity Components