Agonist-induced desensitization of beta-adrenoceptor function in humans. Subtype-selective reduction in beta 1- or beta 2-adrenoceptor-mediated physiological effects by xamoterol or procaterol.

Brodde, Otto‐Erich; Daul, A; Michel-Reher, Martina B.; Boomsma, Frans; Veld, A. J. Man In 'T; Schlieper, P.; Michel, Martin C.

doi:10.1161/01.cir.81.3.914

Cited by 41 publications

(9 citation statements)

References 32 publications

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“…In our data, a similar result was obtained [8], although the beta-receptor assay was carried out using peripheral lymphocytes [34]. However, since the changes in receptor density may occur in a week [9,32], such a beneficial long-term effect cannot be explained by upregulation only. Thus, we have recently studied the changes in cyclic AMP production of the peripheral lymphocyte by in-vitro isopreterenol or forskolin loading before and after the administration [8] and withdrawal [10] of metoprolol.…”

Section: Fig 4 a Comparison Of Groups I (Beta-blocker Group) And Grsupporting

confidence: 82%

“…What kind of beta blocker can produce a favorable effect in dilated cardiomyopathy? We employed a cardioselective beta blocker without intrinsic sympathetic activity (ISA), metoprolol, in this study, since beta-adrenoceptor antagonists subtypes selectively regulate cardiac beta-receptor subtypes [31][32][33]. Ikram et al [15] employed acebutolol, which has ISA, and reported an adverse effect.…”

Section: Fig 4 a Comparison Of Groups I (Beta-blocker Group) And Grmentioning

confidence: 99%

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Effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy—echocardiographical follow-up

Fukunami

Hashimura

Ohmori

et al. 1991

Cardiovasc Drug Ther

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To evaluate the effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy (DCM), two groups (Group I: 18 patients, Group II: 17 patients) with DCM divided by the order at the entry were followed echocardiographically for 16.9 +/- 3.0 months in Group I and 21.4 +/- 3.9 months in Group II. Metoprolol (final dose: 60 mg/day) was administered in Group I, but not in Group II (the control), although the conventional treatment for heart failure was continued. The left ventricular end-systolic dimension and ejection fraction assessed by echocardiography improved significantly after 6 months in Group I, but not in Group II, even after 48 months, although there were no significant differences in baseline data between the two groups. The end-diastolic dimension decreased significantly after 12 months in Group I only. It was estimated, using the point count method on a left ventricular endomyocardial biopsy specimen taken at entry, that the improvement (delta EF) of the ejection fraction 12 months after metoprolol administration inversely correlated (r = -0.677, p less than 0.01) with percent fibrosis, indicating that the more myocardium remains, the more improvement is expected. These findings suggested a favorable effect of beta blockade in DCM, especially in cases with less fibrosis, showing that the endomyocardial biopsy could be of clinical use in selecting candidates for chronic beta-blocker therapy in DCM.

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Section: Fig 4 a Comparison Of Groups I (Beta-blocker Group) And Grsupporting

confidence: 82%

Section: Fig 4 a Comparison Of Groups I (Beta-blocker Group) And Grmentioning

confidence: 99%

Effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy—echocardiographical follow-up

Fukunami

Hashimura

Ohmori

et al. 1991

Cardiovasc Drug Ther

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“…Over a longer time period24, the vagolytic influence of EPI may dampen the peripheral capability of cholinergic anti-inflammatory pathways. A persistent EPI induced vagolytic effect would potentially heighten pro-inflammatory activity as β-2 receptor activity decreases70 and may permit an exaggerated immune response to additional inflammatory stimuli. A longer EPI infusion may be revealing since it is yet unknown whether the vagolytic effect of EPI persists or attenuates over time.…”

Section: Discussionmentioning

confidence: 99%

Influence of Acute Epinephrine Infusion on Endotoxin-Induced Parameters of Heart Rate Variability

Jan¹,

Coyle²,

Oikawa³

et al. 2009

Annals of Surgery

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Objective-To determine whether the acute anti-inflammatory influence of epinephrine (EPI) extends to changes in heart rate variability (HRV) induced by the prototypical inflammatory stimulus, endotoxin (LPS).Summary Background Data-HRV reflects fluctuating cardiac autonomic inputs and is acutely reduced during the systemic inflammation induced by LPS as well as during severe critical illnesses such as sepsis and traumatic injury. While EPI may diminish proinflammatory cytokine release it is unknown whether this net anti-inflammatory activity extends to HRV.Methods-Healthy volunteers (n=17) were randomized to either saline+LPS (2ng/kg) or LPS + antecedent EPI infusion (30ng/kg/min) from −3 to 6 hours relative to LPS. HRV and blood samples were obtained prior to EPI and LPS as well as hourly afterwards. Plasma cytokines were measured by ELISA. Statistical analysis was by repeated measures ANOVA. This study was registered at Clinicaltrials.gov and is listed under the following ID number: NCT00753402

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“…Unfortunately the only β 1 ‐adrenoceptor selective agonist currently available for oral use in humans is xamoterol which is a partial β 1 ‐adrenoceptor agonist [ 5]. We have previously shown, in healthy volunteers, that following 2 weeks treatment with xamoterol cardiovascular β 1 ‐adrenoceptor‐mediated effects (exercise‐induced increase in heart rate and isoprenaline induced increase in systolic blood pressure) are attenuated [ 6]. This could be due to desensitization; it could also be due to an antagonist effect of the partial agonist xamoterol.…”

Section: Introductionmentioning

confidence: 99%

Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers

Schäfers¹,

Karl²,

Mennicke³

et al. 1999

Brit J Clinical Pharma

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Aims To study whether desensitization occurs after long-term administration of the b 1 -adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen. Methods In a double-blind, randomized design 10 young, healthy males received ketotifen (2×1 mg day −1 p.o.) or placebo for 3 weeks with xamoterol (2×200 mg day −1 p.o.) administered concomitantly during the last 2 weeks. b 1 -adrenoceptor mediated responses were assessed as exercise-induced tachycardia and isoprenaline-induced shortening of heart rate corrected electromechanical systole (QS 2 c); isoprenaline-induced tachycardia was measured as a mixed b 1 -/b 2 -adrenoceptor-mediated effect.Results The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS 2 c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise-and isoprenaline-induced tachycardia (mean dose ratios±s.e.mean: 1.20±0.05 and 2.46±0.23) and the isoprenaline-evoked shortening of QS 2 c (dose ratio 3.59±0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (−0.03; 0.04); isoprenaline tachycardia 0.03 (−0.15; 0.21); isoprenaline induced shortening of QS 2 c 0.13 (−0.22; 0.48)). Conclusions In humans xamoterol is a partial b 1 -adrenoceptor agonist with positive chrono-and inotropic effects at rest and antagonistic properties under conditions of b-adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of b 1 -adrenoceptor desensitization. Ketotifen does not change the b-adrenoceptor mediated responses of xamoterol after chronic dosing.

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Agonist-induced desensitization of beta-adrenoceptor function in humans. Subtype-selective reduction in beta 1- or beta 2-adrenoceptor-mediated physiological effects by xamoterol or procaterol.

Abstract: We investigated the effects of f%- (procaterol 2X50 jig/day for 9 days) and B1-(xamoterol 2 x200 mg/day for 14 days) adrenoceptor agonists on lymphocyte f%-adrenoceptor density and

Cited by 41 publications

References 32 publications

Effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy—echocardiographical follow-up

Effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy—echocardiographical follow-up

Influence of Acute Epinephrine Infusion on Endotoxin-Induced Parameters of Heart Rate Variability

Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers

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