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Silvia Salem, Heike Bruck,
Ferdinand H Bahlmann,
Mirjam Peter,
Jutta Passlick-Deetjen,
Axel Kretschmer,
Sonja Steppan,
Michaela Volsek,
Andreas Kribben,
Marc Nierhaus,
Vera Jankowski,
Walter Zidek,
Joachim Jankowski
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ABSTRACT: Arteriosclerosis and cardiovascular disease are strongly associated with vascular calcification. Hyperphosphatemia is an essential risk factor for increased vascular calcification. End-stage renal disease (ESRD) patients could serve as an in vivo model for accelerated calcification. This study focuses on the most likely protective effects of magnesium ion (Mg(2+)) on phosphate-induced vascular calcification ex vivo/in vitro. Furthermore, plasma Mg(2+) concentrations of ESRD and healthy controls were investigated for association with surrogate parameters of vascular calcification in vivo.
Aortic segments of male Wistar-Kyoto rats were incubated and the phosphate concentration of the medium was elevated. The aortic segments were incubated in the absence and presence of MgCl(2); tissue calcification was quantified by different methods. Serum Mg(2+) concentrations of patients with chronic kidney disease (CKD stage 5; ESRD) and patients without CKD (controls) were associated with carotid intima media thickness (IMT) and aortic pulse wave velocity (PWV) as surrogate parameter for arteriosclerosis and arterial stiffening.
Incubation of aortic segments in the presence of β-glycerophosphate and NaH(2)PO(4) caused an increased tissue Ca(2+) deposition compared to control conditions. This increased amount of Ca(2+) in the aortic rings was significantly decreased in the presence of Mg(2+). In CKD patients, but not in controls, magnesium serum concentration was associated with the IMT of the carotid arteries. In addition, CKD patients with higher magnesium serum concentration had a significantly lower PWV.
Elevated phosphate concentrations in the culture media induce ex vivo/in vitro medial calcification in intact rat aortic rings in the presence of alkaline phosphatase. Mg(2+) ions reduced ex vivo/in vitro vascular calcification despite increased phosphate concentration. This hypothesis is additionally based on the fact that CKD patients with high Mg(2) serum levels had significantly lower IMT and PWV values, which may result in a lower risk for cardiovascular events and mortality in these patients. Therefore, Mg(2+) supplementation may be an option for treatment and prevention of vascular calcification resulting in a reduction of cardiovascular events in CKD patients.
American Journal of Nephrology 12/2011; 35(1):31-9. · 2.54 Impact Factor
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ABSTRACT: This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor.
Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (<30mlmin(-1) ).
Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively.
Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.
British Journal of Clinical Pharmacology 11/2010; 70(5):703-12. · 2.96 Impact Factor
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ABSTRACT: Many invasive and noninvasive methods have been proposed for guiding optimal programming of cardiac resynchronization therapy (CRT) devices. However, results are not satisfying. Preliminary results suggest that cardiac output (CO) measurements using inert gas rebreathing (IGR) might be an eligible method to tailor atrioventricular (AV) and ventriculo-ventricular (VV) programming. The aims of the present study were: (1) to evaluate whether an optimization of CRT can be obtained by noninvasive CO measurements and (2) to evaluate whether acute hemodynamic improvements obtained by this approach relate into increase in cardiac exercise capacity.
In 24 patients on CRT, iterative VV- and AV-delay optimization was done using the IGR method. This blinded, randomized, crossover study compared the responses to optimization during two periods: a 4-week optimized and a 4-week standard programming. Exercise capacity after optimization was assessed after each period by New York Heart Association (NYHA) classification, a 6-minute walking test, and quality of life (QoL) questionnaire.
CO could be determined by IGR in all patients. The NYHA class decreased by 17.8% (2.8 ± 0.3 vs 2.3 ± 0.4, P < 0.001), the mean (± standard deviation) distance walked in 6 minutes was 9.3% greater after optimization (456 ± 140 m vs 417 ± 134 m, P < 0.001), and the QoL improved by 14.5% (41.8 ± 10.4 vs 36.5 ± 9.5, P < 0.001). The portion of responders to CRT increased from 66.5% to 87.5%.
CRT optimization by iterative CO measurements leads to an increase in CO and an improvement of exercise capacity. Our results suggest that this method might become an important additive tool to adjust CRT programming.
Pacing and Clinical Electrophysiology 10/2010; 33(10):1188-94. · 1.35 Impact Factor
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ABSTRACT: Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP <180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (-16.3 to -29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (-28.7 to -44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (>/=25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.
Journal of the American Society of Nephrology 01/2009; 20(3):655-64. · 9.66 Impact Factor
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ABSTRACT: In vitro, Arg389Gly beta1-adrenoceptor (AR) polymorphism exhibits decreased beta-AR signalling. In vivo, beta1-AR-mediated cardiac effects of exercise showed no genotype-dependent differences in Arg389 vs. Gly389 beta1-AR subjects. We studied in 16 male subjects homozygous Arg389 or Gly389 beta1-AR, whether blockade of parasympathetic activity might unmask genotype-dependence of exercise effects. Subjects were infused with atropine (10 microg/kg i.v. loading dose followed by continuous i.v. infusion of 0.15 microg/kg/min throughout exercise-time); 20 min after start of atropine bicycle-exercise in supine position (25, 50, 75 and 100 W for 5 min each) was performed and heart rate, contractility, blood pressure, plasma noradrenaline and plasma-renin activity were assessed. Exercise-evoked increases in all but one parameters were not different between Arg389 and Gly389 beta1-AR subjects; only plasma noradrenaline increased slightly more in Gly389 vs. Arg389 beta1-AR subjects. In conclusion: It appears to be unlikely that lack of Arg389Gly beta1-AR genotype-dependence of exercise-effects can be explained by influences of parasympathetic activity.
Pharmacogenetics and Genomics 02/2006; 16(1):9-13. · 3.48 Impact Factor
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ABSTRACT: At present, nine adrenoceptor (AR) subtypes have been identified: alpha(1A)-, alpha(1B)-, alpha(1D)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)-, and beta(3)AR. In the human heart, beta(1)- and beta(2)AR are the most powerful physiologic mechanism to acutely increase cardiac performance. Changes in betaAR play an important role in chronic heart failure (CHF). Thus, due to increased sympathetic activity in CHF, betaAR are chronically (over)stimulated, and that results in beta(1)AR desensitization and alterations of down-stream mechanisms. However, several questions remain open: What is the role of beta(2)AR in CHF? What is the role of increases in cardiac G(i)-protein in CHF? Do increases in G-protein-coupled receptor kinase (GRK)s play a role in CHF? Does betaAR-blocker treatment cause its beneficial effects in CHF, at least partly, by reducing GRK-activity? In this review these aspects of cardiac AR pharmacology in CHF are discussed. In addition, new insights into the functional importance of beta(1)- and beta(2)AR gene polymorphisms are discussed. At present it seems that for cardiovascular diseases, betaAR polymorphisms do not play a role as disease-causing genes; however, they might be risk factors, might modify disease, and/or might influence progression of disease. Furthermore, betaAR polymorphisms might influence drug responses. Thus, evidence has accumulated that a beta(1)AR polymorphism (the Arg389Gly beta(1)AR) may affect the response to betaAR-blocker treatment.
Journal of Pharmacological Sciences 02/2006; 100(5):323-37. · 2.08 Impact Factor
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ABSTRACT: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent.
In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling.
We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed.
With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects.
Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment.
Journal of the American College of Cardiology 01/2006; 46(11):2111-5. · 14.16 Impact Factor
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ABSTRACT: Background and Objective: 2-Adrenergic receptors (2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu 2-AR variants; Thr164Ile 2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether 2-AR polymorphisms affect 2-AR–mediated venodilation in healthy subjects in vivo.Methods: We studied dilation of phenylephrine-preconstricted dorsal hand veins induced by terbutaline (50-1000 ng/min) using the Aellig hand vein technique in subjects homozygous for the 3 most common 2-AR haplotypes (group A, Arg16Gln27Thr164 [wild type (WT)] [n = 10]; group B, Gly16Gln27Thr164 [n = 8]; and group C, Gly16Glu27Thr164 [n = 9]) and in 8 subjects heterozygous for Thr164Ile 2-AR (group D) at baseline and after 2 weeks of treatment with oral terbutaline, 5 mg 3 times daily.Results: Terbutaline dose-dependently dilated hand veins; sensitivity to terbutaline was 2-fold higher in haplotype group A versus group B or C; maximal dilation, however, was not haplotype-dependent. In Thr164Ile subjects terbutaline sensitivity but not maximal dilation was 4-fold lower than in WT subjects. Long-term terbutaline treatment desensitized venous 2-AR in a haplotype-dependent manner: The extent of desensitization (reduction in maximal venodilation) was largest for haplotype A, modest for haplotype B, and almost absent for haplotype C. Long-term terbutaline treatment also desensitized venous Thr164Ile 2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile 2-AR subjects.Conclusion: 2-AR–mediated dilation of human hand veins is influenced by the 3 most common 2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile 2-AR. Long-term terbutaline treatment desensitizes venous 2-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) showing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than haplotype C (Gly16Glu27Thr164).
Clinical Pharmacology & Therapeutics 08/2005; 78(3):232-238. · 6.04 Impact Factor
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ABSTRACT: In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity.
We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay).
With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect.
According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.
Cardiovascular Research 07/2005; 66(3):512-9. · 6.06 Impact Factor
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ABSTRACT: The intrinsic sympathomimetic activity (ISA) of a beta-adrenoceptor blocker can be mediated by beta(1)- or beta(2)-adrenoceptors. The aim of this study was to characterize the ISA of the beta-adrenoceptor blocker carteolol in healthy volunteers. Two approaches were employed. First, we assessed the effects of carteolol (20, 40 or 80 mg p.o.) on blood pressure, heart rate and heart-rate corrected duration of electromechanical systole (QS(2)c, a measure of cardiac contractility) in the volunteers. Carteolol dose-dependently increased systolic blood pressure, heart rate and contractility and decreased diastolic blood pressure. The beta(1)-adrenoceptor blocker bisoprolol did not attenuate these carteolol effects, but rather enhanced the effects on heart rate and systolic blood pressure. Second, we treated volunteers for 7 days with 1 x 20 mg/day carteolol and assessed lymphocyte beta(2)-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and functional responsiveness (by 10 muM isoprenaline-induced increase in lymphocyte cyclic AMP content). Carteolol significantly reduced lymphocyte beta(2)-adrenoceptor density and function. After withdrawal of carteolol lymphocyte beta(2)-adrenoceptor density and function recovered only very slowly and had not returned to control levels 11 days after carteolol withdrawal. In conclusion, the fact that, on the one hand, the cardiovascular effects of carteolol were not attenuated by the beta(1)-adrenoceptor blocker bisoprolol and, on the other, carteolol significantly decreased lymphocyte beta(2)-adrenoceptor density and function is in favour of the idea that the ISA of carteolol is mediated by beta(2)-adrenoceptors. Involvement of an additional receptor site (e.g. the propranolol-resistant state of the beta(1)-adrenoceptor), however, cannot be excluded.
Archiv für Experimentelle Pathologie und Pharmakologie 12/2004; 370(5):361-8. · 2.65 Impact Factor
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ABSTRACT: In subjects heterozygous for Thr164Ile beta2-adrenoceptor (beta2AR) polymorphism, cardiac responses to beta2AR agonist stimulation are blunted. In this study, we investigated agonist-induced desensitization of Thr164Ile beta2ARs. For this purpose, we assessed in six subjects with heterozygous Thr164Ile beta2ARs and in 10 subjects with homozygous wild-type (WT) beta2ARs the effects of 2-wk oral treatment with 3 x 5 mg/day terbutaline on terbutaline infusion-induced increases in heart rate (HR) and contractility [measured as shortening of HR-corrected duration of electromechanical systole (QS2c)]. Compared with WT beta2AR subjects, Thr164Ile subjects exhibited a blunted terbutaline-induced maximum increase in HR (WT 32 +/- 4 beats/min, Thr164Ile 19 +/- 3 beats/min, P < 0.05) and contractility (WT -54 +/- 2 ms, Thr164Ile -37 +/- 6 ms, P < 0.05). Two-week oral terbutaline treatment desensitized cardiac beta2AR responses to terbutaline infusion (increase in HR: WT 10 +/- 2 beats/min, Thr164Ile 8 +/- 4 beats/min; increase in contractility: WT -22 +/- 5 ms Thr164Ile: -17 +/- 6 ms); however, the extent of desensitization was larger in WT than Thr164Ile beta2AR subjects. Thus, after 2-wk oral terbutaline treatment cardiac, beta2AR responses did not differ anymore between WT and Thr164Ile beta2AR subjects. We conclude that agonist-induced desensitization of cardiac beta2ARs is more pronounced in WT than Thr164Ile subjects. Thus cardiac Thr164Ile subjects appear to be somewhat protected against agonist-induced desensitization.
AJP Heart and Circulatory Physiology 11/2003; 285(5):H2034-8. · 3.71 Impact Factor
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ABSTRACT: Volunteers homozygous for Glu27 beta(2)-adrenergic receptor (beta(2)AR) polymorphism have delayed onset of agonist-induced desensitization of cardiac beta(2)AR responses.
To determine whether this can also be demonstrated for Glu27Glu beta(2)AR natively expressed in circulating lymphocytes, we assessed the effects of 2 weeks of oral treatment with 3 x 5 mg/d terbutaline on lymphocyte beta(2)AR density (determined by [-]-[iodine 125]iodocyanopindolol binding) and responsiveness (assessed as [-]-isoproterenol hydrochloride [INN, isoprenaline] [1 nmol/L to 1 micromol/L]-induced lymphocyte cyclic adenosine monophosphate increases) in 23 healthy volunteers (13 with wild-type beta(2)AR [group A], 5 homozygous for Glu27 with Gly16Gly or Arg16Gly [group B], and 5 homozygous for Gly16 with Gln27Gln or Gln27Glu [group C]). Before terbutaline treatment, lymphocyte beta(2)AR density and isoproterenol-induced lymphocyte cyclic adenosine monophosphate accumulation were not significantly different in the genotype groups; 2 weeks of terbutaline treatment significantly decreased lymphocyte beta(2)AR density and responsiveness in the 3 genotype groups to a nearly identical extent, and no differences were observed. In time-course studies, however, in groups A and C lymphocyte beta(2)AR showed significant (P <.05, repeated-measures ANOVA) down-regulation as early as 24 hours after the first terbutaline intake, whereas in group B significant (P <.05, repeated-measures ANOVA) beta(2)AR decreases were observed only 72 hours after the first terbutaline intake. Thus the time course of lymphocyte beta(2)AR down-regulation in group B was significantly (P <.01, 2-way ANOVA) different from that in groups A and C.
The extent of lymphocyte beta(2)AR down-regulation after long-term terbutaline treatment in volunteers homozygous for the Gly16 or Glu27 beta(2)AR polymorphism was genotype-independent and was nearly identical to that in wild-type beta(2)AR volunteers. However, the onset of beta(2)AR down-regulation was delayed in volunteers homozygous for the Glu27 beta(2)AR polymorphism.
Clinical Pharmacology & Therapeutics 09/2003; 74(3):255-63. · 6.04 Impact Factor
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ABSTRACT: The aim of this study was to find out whether, in humans, the increase in vagal tone accompanying cardiac beta-adrenoceptor (beta-AR) stimulation might be different dependent on beta1- or beta2-AR stimulation. For this purpose we studied, in six male healthy volunteers (aged 28+/-1 years), the effects of atropine infusion (0.15 microg/kg/min continuously) on increase in heart rate (HR) and contractility (determined as shortening of HR-corrected duration of electromechanical systole-QS2c) evoked by infusion of isoprenaline (3.5-35 ng/kg/min, increasing HR and QS2c via beta1-and beta2-AR), terbutaline (25-150 ng/kg/min, increasing HR and QS2c via beta2-AR), adrenaline (20-160 ng/kg/min, increasing HR via beta2-and QS2c via beta1-AR) and bicycle exercise in supine position (increasing HR and QS2c via beta1-AR). The three beta-AR agonists and exercise increased HR and shortened QS2c in a dose- or work-load-dependent manner, respectively. Atropine enhanced HR-increasing effects of all three beta-AR agonists and exercise; increases were larger for beta2-AR (terbutaline, adrenaline) mediated effects than for beta1-AR (exercise) mediated effects. Moreover, atropine enhanced beta-AR agonists-induced QS2c shortening; however, atropine effects on QS2c were markedly less pronounced than on HR. From the results we conclude that, in humans, beta1-and beta2-AR mediated stimulation evoked HR-increases are composed of two components: increases via direct beta-AR stimulation and simultaneously decreases via increase in vagal tone. In addition, beta-AR mediated increases in contractility are also dampened by simultaneous activation of vagal tone but to a lesser extent possibly because human ventricular myocardium is only sparsely parasympathetically innervated.
Archiv für Experimentelle Pathologie und Pharmakologie 07/2003; 367(6):572-7. · 2.65 Impact Factor
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ABSTRACT: Studies performed have shown that the Arg16Gly allele in beta-adrenoceptors (beta2AR) enhances susceptibility to agonist-induced down-regulation, while the Gln27Glu polymorphism diminishes it. In this study, we tested whether similar phenotypes occur in vivo. We assessed 32 volunteers (mean age 25 +/- 2 years) with different genotypes (group A: wild-type beta2AR, n = 16; group B: homozygous Glu27, n = 10; group C: homozygous Gly16, n = 6) for the effect of 2 weeks treatment with 3 x 5 mg/day oral terbutaline on terbutaline infusion-induced increases in heart rate and contractility (i.e. shortening of heart rate-corrected duration of electromechanical systole, QS2c). At baseline, terbutaline infusion increased heart rate and contractility similarly among subjects in the three groups. Treatment with oral terbutaline for 14 days reduced the ability of intravenous (i.v.) terbutaline to increase heart rate and contractility. The extent of this reduction was similar but the time course of desensitization differed among the three groups. While in groups A and C terbutaline infusion-induced increases in heart rate and contractility were reduced within 24 h after oral ingestion of terbutaline, a significant effect on response to terbutaline infusion was not evident for the first 3 days of terbutaline treatment in group B. The Arg16Gly and the Gln27Glu variants of the beta2AR do not alter the extent of agonist-induced beta2AR desensitization in vivo but Glu27 homozygotes develop desensitization more slowly. This result may have implications for cardiac side-effects in patients who are Glu27 homozygotes and who receive beta2AR agonist therapy.
Pharmacogenetics 03/2003; 13(2):59-66.
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ABSTRACT: The purpose of this study was to elucidate whether the neuronal noradrenaline reuptake transporter (uptake1) undergoes age-dependent regulation in the human heart.
Aging is associated with various alterations in cardiovascular function.
We determined uptake1 density (by [3H]-nisoxetine binding to membranes) and activity (by accumulation of [3H]-noradrenaline into tissue slices) in the right atria (RA) of 42 patients (age range 3 months to 76 years) undergoing open-heart surgery without apparent heart failure. Moreover, the effects of 1 micromol/l desipramine on the noradrenaline-induced positive inotropic effect were assessed in the isolated, electrically driven RA trabeculae of these patients.
There was a significant negative correlation between RA uptake1 density and age; moreover, RA uptake1 activity was significantly reduced in elderly patients. Desipramine (1 micromol/l) significantly shifted noradrenaline concentration-response curves to the left; this shift was significantly more pronounced in younger patients than in older patients.
With increasing age, human myocardial uptake1 activity decreases, possibly because of age-dependent downregulation of uptake1 density.
Journal of the American College of Cardiology 11/2002; 40(8):1459. · 14.16 Impact Factor
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ABSTRACT: The sympathetic and parasympathetic nervous system play a powerful role in controlling cardiac function by activating adrenergic
and muscarinic receptors. In the human heart there exist α1-, β1- and β2-adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) α2-adrenoceptors. β1- and β2-adrenoceptors are quite evenly distributed in the human heart while M2-receptors are heterogeneously distributed (more receptors in atria than in ventricles). Stimulation of β1- and β2-adrenoceptors causes increases in heart rate and force of contraction while stimulation of M2-receptors decreases heart rate (directly in atria) and force of contraction (indirectly in ventricles). Pathological situations
(such as heart failure) or pharmacological interventions (for example, β-blocker treatment) can alter the distribution of
β1- and β2-adrenoceptors in the human heart, while M2-receptors are only marginally affected. On the other hand, relatively little is known on distribution and functional role
of α1- and α2-adrenoceptor subtypes in the human heart.
Archiv für Kreislaufforschung 11/2001; 96(6):528-538. · 7.35 Impact Factor
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ABSTRACT: The concept to use the human skin microcirculation as a pharmacological in-vivo test system is old; however, methods developed
in the 50s have been abandoned because of side effects and/or use of radioactive substances.
We describe a newly developed minimally invasive method that allows in-vivo pharmacology in the human skin microcirculation
injecting very low doses of a substance or drug without any systemic effects. The double injection technique (DIT) bears the
potential to predict the effects of a drug and/or the vascular reactivity or dysfunction of other less accessible areas of
the circulation (e. g. the myocardium).
The DIT has been applied for studies in healthy volunteers and patients with atherosclerosis; the focus of interest was endothelial
(dys-) function and the effect of exogenous vasoactive drugs. Using endothelin antagonists, we investigated the role of endogenous
endothelin under physiological conditions and in atherosclerosis. The NO-synthase inhibitor L-NMMA has been applied to study
the L-arginine-NO-pathway and the role of endothelial adrenoceptors.
Ongoing studies with the DIT comparing coronary and skin microcirculation may help to develop minimally invasive methods to
predict the effects of drugs and vascular function in the heart.
Die Mikrozirkulation der Haut wurde schon in den frühen 50er Jahren für pharmakologische Untersuchungen beim Menschen eingesetzt;
allerdings wurden die damals entwickelten Methoden wegen der damit verbundenen Nebenwirkungen und/oder des Risikos der eingesetzten
radioaktiven Substanzen verlassen.
Die vorliegende Arbeit faßt die bisherigen Erfahrungen mit einer von uns neu entwickelten, minimalinvasiven Methode zusammen,
der Doppelinjektionstechnik (DIT). Die DIT erlaubt es, unter In-vivo-Bedingungen die pharmakologische Wirkung kleinster Mengen
einer Substanz ohne systemische Wirkungen zu untersuchen. Diese Methode ist daher geeignet, die Wirkung von einer Substanz
sowie die Gefäßreagibilität oder- dysfunktion zu untersuchen und möglicherweise auf andere, weniger gut zugängliche Gefäßareale
(wie zum Beispiel das Myokard) zu schließen.
Die DIT wurde in verschiedenen Studien bei gesunden Probanden und Patienten mit koronarer Herzkrankheit eingesetzt; Schwerpunkt
der Untersuchungen waren die Endothel (dys-) funktion und die Wirkung von vasoaktiven Substanzen. Erstmals wurden in vivo
beim Menschen mit dieser Methode Endothelinantagonisten eingesetzt, um die Wirkung von endogenem Endothelin unter physiologischen
Bedingungen und bei Patienten mit Atherosklerose zu untersuchen. Der Stickstoffmonoxid-Synthase-Hemmer LNMMA wurde mittels
DIT eingesetzt, um den L-Arginin-NO-Stoffwechsel zu untersuchen.
Derzeit laufen Studien mittels DIT, in denen koronare und kutane Mikrozirkulation verglichen werden; bei positivem Ergebnis
würden diese Studien zur Entwicklung minimalinvasiver Methoden beitragen, um die Wirkung von Medikamenten und die Gefäßfunktion
am Herzen vorherzusagen.
Herz 04/1999; 24(7):576-580. · 0.92 Impact Factor
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ABSTRACT: β1- and β2-adrenoceptors (AR) are polymorphic. β1-AR: There is a Gly389Arg polymorphism of the β1-AR with the Gly389 exhibiting reduced in vitro responsiveness upon agonist-induced stimulation. To study this in vivo we assessed exercise-induced increase in heart rate and shortening of heart rate-corrected duration of electromechanical systole (QS2c—a measure of inotropism) in 12 volunteers homozygous for Gly389 and 12 volunteers homozygous for Arg389. In both groups, exercise caused nearly identical increases in heart rate and shortening of QS2c, indicating that the differential responsiveness observed in vitro is not of major functional importance in vivo. β2-AR: There are at least three polymorphisms of the β2-AR: the Arg16Gly and the Gln27Glu polymorphisms differ from the wild-type (WT, Arg16, Gln27) β2-AR in vitro in their susceptibility to agonist-induced downregulation. We studied in 16 WT-volunteers, 6 volunteers homozygous for Glu27 and 6 volunteers homozygous for Gly16, the effects of 2-week treatment with 3×5 mg/day p.o. terbutaline on terbutaline infusion-induced increases in heart rate and shortening of QS2c. In all three groups, oral terbutaline treatment reduced terbutaline infusion-induced increases in heart rate and shortening of QS2c to a similar extent, indicating that the differential susceptibility to agonist-induced downregulation of the Gly16 and Glu27 polymorphism of the β2-AR observed in vitro is not of major functional importance in vivo. Finally, there is a Thr164Ile polymorphism of the β2-AR with Ile164 exhibiting reduced in vitro responsiveness upon agonist-induced stimulation. We studied in 12 WT-volunteers and in 6 volunteers heterozygous for the Ile164 polymorphism the effects of terbutaline infusion on heart rate and QS2c. In the Ile164 volunteers increases in heart rate and shortening of QS2c induced by the terbutaline infusion were significantly (p<0.05) lower than in the WT-volunteers, indicating that in healthy volunteers heterozygous for the Ile164 polymorphism of the β2-AR cardiac β2-AR responsiveness is reduced. In conclusion, these three examples show that for any given polymorphism, in vivo studies have to be performed in order to test whether data obtained in vitro reflect the in vivo situation.
International Congress Series 1244:69-76.
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