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Nebivolol, carvedilol and metoprolol do not influence cardiac Ca(2+) sensitivity
A Bundkirchen1, K Brixius, B Bölck
1Labor für Herzmuskelphysiologie und Molekulare Kardiologie, Klinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmann-Strasse 9, D-50924 Cologne, (Lindenthal), Germany.
Abstract:
It has been argued that some beta-adrenoceptor antagonists may directly influence myofibrillar cross-bridge interaction in cardiac skinned fiber preparations of animal models. The present study investigates the effects of nebivolol, metoprolol and carvedilol on tension development of Triton X-100 skinned fibers obtained from human failing myocardium as well as on force of contraction and intracellular Ca(2+) transient in isolated trabeculae. In skinned fiber preparations, none of the beta-adrenoceptor antagonists (10 microM) influenced Ca(2+) sensitivity of tension development or maximal Ca(2+) activated tension (DT(max)): control: EC(50) for Ca(2+): 1.28+/-0.05 microM, DT(max): 14.09+/-0.59 mN/mm(2); nebivolol: 1.36+/-0.1 microM, 14.14+/-0.95 mN/mm(2); carvedilol: 1.32+/-0.11 microM, 13.83+/-0.90 mN/mm(2); metoprolol: 1.34+/-0.14 microM, 13.72+/-0.36 mN/mm(2). Simultaneous measurement of force and Ca(2+) transient in the presence of the beta-adrenoceptor antagonists (3 microM) showed that the decrease in force of contraction was paralleled by a similar decrease in the intracellular Ca(2+) transient. In conclusion, none of the investigated beta-adrenoceptor antagonists influenced Ca(2+) sensitivity of myofibrillar tension development in human failing myocardium.
Insights
Beta-blockers like nebivolol, metoprolol, and carvedilol do not directly affect myofibrillar calcium sensitivity in human heart failure. Their impact on contraction force is linked to changes in intracellular calcium transients, not direct cross-bridge interaction.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Beta-adrenoceptor antagonists are widely used for cardiovascular conditions.
- Previous research suggested potential direct effects of some beta-blockers on cardiac myofibrils.
- The specific impact of nebivolol, metoprolol, and carvedilol on human cardiac muscle function requires further investigation.
Purpose of the Study:
- To investigate the direct effects of nebivolol, metoprolol, and carvedilol on myofibrillar function in human failing myocardium.
- To determine if these beta-adrenoceptor antagonists alter calcium sensitivity or maximal tension development in cardiac skinned fibers.
- To examine the relationship between these drugs, force of contraction, and intracellular calcium transients in isolated trabeculae.
Main Methods:
- Human failing myocardium was used to prepare Triton X-100 skinned fibers.
- Experiments measured calcium sensitivity and maximal calcium-activated tension (DTmax) in skinned fibers.
- Force of contraction and intracellular calcium transients were simultaneously measured in isolated trabeculae.
Main Results:
- Nebivolol, metoprolol, and carvedilol (at 10 microM) did not affect the calcium sensitivity or maximal tension development in human cardiac skinned fibers.
- In isolated trabeculae, the observed decrease in contraction force with these drugs (at 3 microM) correlated with a reduction in intracellular calcium transients.
- No direct influence on myofibrillar calcium sensitivity was found for the tested beta-adrenoceptor antagonists.
Conclusions:
- The studied beta-adrenoceptor antagonists do not directly alter the calcium sensitivity of myofibrillar tension in human failing hearts.
- The effects of nebivolol, metoprolol, and carvedilol on cardiac contractility are primarily mediated through modulation of intracellular calcium handling.
- These findings clarify the mechanism of action of common beta-blockers in the context of human heart failure.