1,720,994 research outputs found
Impact of beta-adrenoceptor antagonists on myofilament calcium sensitivity of rabbit and human myocardium
No full textbeta-Adrenoceptor antagonists (beta-blockers) are commonly used in clinical pharmacotherapy of cardiovascular diseases. Carvedilol and nebivolol possess beneficial effects on myocardial function in situations of oxidative stress associated with intracellular calcium overload. This preservation of contractile function might be due to direct scavenging capacities or ttl compensation of the intracellular calcium overload through direct impact on myofilament calcium sensitivity. Accordingly, we measured the relation between calcium and force in the absence and in the presence of 10(-6) M carvedilol, nebivolol, or propranolol in skinned right ventricular trabeculae of rabbit hearts. In rabbit myocardium. nebivolol (10(-6) M) altered the pCa(50%) by rightward shift (less sensitive) from 5.72 +/- 0.05 to 5.57 +/- 0.05 (p < 0.05). Maximal force development was reduced by nebivolol. In contrast, the same concentration of propranolol or carvedilol did not influence calcium sensitivity and force development. In additional experiments, we repeated this protocol in trabeculae from human failing hearts. As in rabbit trabeculae, nebivolol shifted the pCa(50%) by 0.16 +/- 0.04 pCa units to the right (p < 0.05). Experiments with intact rabbit trabeculae confirmed depressed contractility: when all beta-adrenoceptors were blocked by 10(-6) M propranolol, subsequent addition of 10(-6) M nebivolol reduced developed force of these muscles significantly from 3.1 +/- 0.9 to 1.7 +/- 0.4 mN/mm(2). We conclude that nebivolol desensitizes cardiac myofilaments slightly, whereas neither propranolol nor carvedilol had an effect
Levosimendan improves diastolic and systolic function in failing human myocardium
No full textCa2+-sensitizers increase myocardial contractility, but may worsen diastolic dysfunction. Levosimendan, through its unique troponin-C interaction, may preserve diastolic function. We investigated the effects of levosimendan (10(-7)-10(-5) M) on diastolic and systolic function in multicellular cardiac muscle preparations from end-stage failing human hearts (1 and 2.5 Hz, 37 degrees C, 1.25 mM [Ca2+], pH 7.4). Levosimendan improved systolic function: at 1 Hz, developed force (F-dev) increased from 13.84 +/- 3.27 to 16.40 +/- 3.57 (10(-7) M, P < 0.05), while diastolic force (F-dia) decreased from 5.32 +/- 0.67 to 4.94 +/- 0.61 mN/mm(2) (P < 0.05). Under control conditions, the increase in stimulation frequency from 1 to 2.5 Hz resulted in a decrease in F-dev of - 0.51 +/- 1.80 mN/mm(2) (negative force-frequency relationship). Levosimendan improved this relationship: at 10-7 M, this change became positive (+1.81 +/- 2.06 mN/mm(2), P < 0.05). Diastolic function was markedly improved in the presence of levosimendan; the increase in F-dia of 1.56 +/- 0.41 mN/mm(2) (control) was attenuated to 0.70 +/- 0.19 nN/mm(2) (P < 0.05). To allow for a more derailed analysis, preparations were sometimes divided into two groups, based on their force-frequency behavior. Twitch timing parameters were accelerated by levosimendan in preparations with a negative force-frequency relationship. Levosimendan improves both systolic and diastolic function in failing human myocardium. Effects are even more pronounced at higher heart rates and under prevailing diastolic dysfunction. (C) 2000 Elsevier Science B.V. All rights reserved
Transient and sustained impacts of hydroxyl radicals on sarcoplasmic reticulum function: protective effects of nebivolol
No full textThe hydroxyl radical ((OH)-O-.) is a very reactive oxygen-free radical species that has profound effects on myocardial contractility. We investigated the impact of (OH)-O-. on free radical induced injury in right ventricular rabbit cardiac trabeculae. Additionally, we investigated the protective properties of the beta-adrenoceptor antagonist nebivolol. The contractile response to a brief, 2 min exposure to (OH)-O-. consisted of a severe but transient rigor-like contracture, followed by a new steady state in which diastolic force (F-dia) remained increased and developed force (F-dev) remained decreased. In the new steady state sarcoplasmic reticulum function only partly recovered, reflected by a > 50% blunted force-frequency relationship. In the presence of nebivolol (10(-6) M), during the early phase the increase in F-dia was significantly smaller, and recovered better while F-dev was higher during peak. Moreover, nebivolol completely abolished blunting of the force-frequency relationship, which was observed in the sustained (OH)-O-. injury phase. The results indicate that hydroxyl radical injury induces systolic and diastolic dysfunction, and that nebivolol can effectively prevent a large part of this (OH)-O-. injury. (C) 1999 Elsevier Science B.V. All rights reserved
Protective Role of Nebivolol in Hydroxyl Radical Induced Injury
No full textIncreased oxidative stress has been postulated as one of the main mechanisms underlying stunned myocardium, and may play an important role in and during development of heart failure. Pharmacological interventions may attenuate or prevent detrimental effects of oxygen free radicals on the myocardium. Nebivolol has been shown to attenuate contractile dysfunction in hydroxyl radical mediated injury, but the mechanism(s) remain unknown. It was investigated whether nebivolol could partly attenuate the contractile dysfunction through a direct effect on the myofilaments. In demembranized muscles from explanted human hearts, nebivolol induced a slight desensitization of the myofilaments to calcium. Therefore, during the calcium overload that occurs during reperfusion after an ischemic event, the contractile dysfunction is less severe in the presence of nebivolol. We conclude that the protection of nebivolol in hydroxyl radical induced contractile dysfunction is mediated in part through a direct effect on the myofilaments, in addition to the previously shown preservation of sarcoplasmic reticulum function
Effects of the systemic beta-adrenoceptor antagonist nebivolol on ocular hemodynamics in glaucoma patients
No full textBackground: Systemic antihypertensive treatment in glaucoma patients with hypertension carries the potential risk of all additional deterioration in ocular hemodynamics due to the reduction in ocular perfusion pressure. Nebivolol is a beta(1)-selective adrenoceptor antagonist with known peripheral vasodilatory effects due to NO-releasing properties. The effect of a switch in systemic beta-blocker treatment to nebivolol on retrobulbar hemodynamics in glaucoma patients with arterial hypertension was therefore investigated. Material/Methods: Peak systolic (PSV) and end-diastolic (EDV) velocity in the short and long posterior ciliary arteries (SPCA, LPCA), central retinal artery (CRA), and ophthalmic artery (OA) were recorded by color Doppler imaging (CDI) in 23 glaucoma patients with arterial hypertension using their primary systemic beta-blocker medication and four weeks after a switch to nebivolol. Results: Compared with the first recording under the primary antihypertensive medication, the CDI measurements after four weeks of nebivolol treatment revealed a significant acceleration of the PSV in the SPCA and LPCA and the EDV in the SPCA and CRA. No significant differences in flow velocities were found for the OA. Intraocular pressure and systemic blood pressure remained unchanged. Conclusions: Switching blood pressure treatment to nebivolol in glaucoma patients with hypertension leads to accelerated blood flow in the small retrobulbar vessels. A stabilization of ocular perfusion might be of particular importance in this group of co-morbid patients
Pyruvate potentiates inotropic effects of isoproterenol and Ca2+ in rabbit cardiac muscle preparations
No full textCatecholamines and elevated extracellular Ca2+ concentration ([Ca2+](o)) augment contractile force by increased Ca2+ influx and subsequent increased sarcoplasmic reticulum (SR) Ca2+ release. We tested the hypothesis that pyruvate potentiates Ca2+ release and inotropic response to isoproterenol and elevated [Ca2+](o), since this might be of potential importance in a clinical setting to circumvent deleterious effects on energy demand during application of catecholamines. Therefore, we investigated isometrically contracting myocardial preparations from rabbit hearts at 37 degrees C, pH 7.4, and a stimulation frequency of 1 Hz. At a [Ca2+](o) of 1.25 mM, pyruvate (10 mM) alone increased developed force (F-dev) from 1.89 +/- 0.42 to 3.62 +/- 0.62 (SE) mN/mm(2) (n = 8, P < 0.05) and isoproterenol (10(-6) M) alone increased F-dev from 2.06 +/- 0.55 to 25.11 +/- 2.1 mN/mm(2) (P < 0.05), whereas the combination of isoproterenol and pyruvate increased F-dev overproportionally from 1.89 +/- 0.42 to 33.31 +/- 3.18 mN/mm(2) (P < 0.05). In a separate series of experiments, we assessed SR Ca2+ content by means of rapid cooling contractures and observed that, despite no further increase in F-dev by increasing [Ca2+](o) from 8 to 16 mM, 10 mM pyruvate could still increase F-dev from 26.4 +/- 6.8 to 29.7 +/- 7.1 mN/mm(2) (P < 0.05, n = 9) as well as the Ca2+ load of the SR. The results show that the positive inotropic effects of pyruvate potentiate the inotropic effects of isoproterenol or Ca2+, because in the presence of pyruvate, Ca2+ and isoproterenol induced larger increases in inotropy than can be calculated by mere addition of the individual effects
Load-Induced Cardiomyocyte Apoptosis in Cultured Multicellular Myocardial Preparations Is Unaltered in Presence of the beta-Adrenoceptor Antagonist Nebivolol
No full textOverload-induced heart failure is associated with enhanced apoptosis of cardiomyocytes, and increased mechanical load is an inductor of this apoptosis. It is unknown whether nebivolol, a third generation beta(1)-adrenoceptor antagonist, possesses properties that can attenuate this apoptosis. Multicellular preparations from rabbit hearts were mounted in a culture system that allows for measurement of contractile parameters over several days. Culturing these muscles on a constant high preload induces apoptosis of the cardiomyocytes. Of each heart, 1 preloaded muscle preparation was treated with nebivolol (10(-6) mol/l), 1 preloaded without continuous exposure to nebivolol (positive control) and 1 unloaded (negative control). After 48 h of continuous loaded contractions, apoptosis was assessed by TUNEL-assay to confirm that nuclei of myocytes were affected, or by DNA-ladder intensity analysis for semiquantification. Maximal twitch force development was slightly, but significantly, lower in preparations contracting in presence of nebivolol (compared to solvent) while twitch-timing parameters were similar. After 48 h of continuous contractions, no additional differences were observed between the groups regarding contractile parameters. DNA-ladder analysis showed a similar rate of apoptosis in presence of nebivolol. Nebivolol does not increase, nor decrease, the rate of load-induced cardiomyocyte apoptosis. Copyright (C) 2008 S. Karger AG, Base
Influence of pyruvate on economy of contraction in isolated rabbit myocardium
No full textBackground: Treatment of acute heart failure frequently requires positive-inotropic stimulation. However, there is still no inotropic agent available, which combines a favourable haemodynamic profile with low expenditure for energy metabolism. Pyruvate exhibits positive inotropic effects in vitro and in patients with heart failure. The effect on myocardial energy metabolism however remains unclear, but is meaningful in light of a clinical application. Aims and methods: We investigated the influence of pyruvate on contractility and oxygen consumption in isolated isometric contracting rabbit myocardium compared to P-adrenergic stimulation with isoproterenol. Results: Pyruvate (30 mM) increased developed force from 18.7 +/- 4.1 to50.8 +/- 12.1 mN/mm(2) (n= 10,p < 0.01). Force-time integral (FTI) increased by 329%, oxygen consumption assessed by diffusion-microclectrode technique increased from 2.86 +/- 0.30 mlO(2)/min 100 g to 6.28 +/- 1.28 mlO(2)/ min 100g(n=7,p < 0.05). Economy of myocardial contraction calculated as the ratio of total FTI to oxygen consumption remained unchanged. In contrast, while isoproterenol (10 mu M) produced a comparable increase in developed force from 21.4 +/- 8.3 to 67.3 +/- 15 mN/mm(2) (n=7,p < 0.01),FTI increased only by 260% and MVO2 increased from 2.96 +/- 0.43 to 6.12 +/- 1.01 mlO(2)/min 100 g (n=7,p < 0.01); thus, economy decreased by 23% (n=7,p < 0.05). Conclusion: Pyruvate does not impair economy of myocardial contraction while isoproterenol decreases economy. Regarding energy expenditure, pyruvate appears superior to isoproterenol for the purpose of positive inotropic stimulation. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved
- …
