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Calcium sensitization as new principle of inotropic therapy in end-stage heart failure?
N Zimmermann1, P Boknik, E Gams
1Klinik für Thorax- und Kardiovaskuläre Chirurgie, Heinrich Heine-Universität, Düsseldorf, Germany.
Objective:
Due to shortage of donor hearts and increasing waiting-lists of patients with end-stage heart disease, new pharmacological principles for bridging therapies are necessary. The positive inotropic effects of cAMP-increasing drugs (e.g. catecholamines, phosphodiesterase-inhibitors) are diminished in the failing myocardium. Hence, we investigated the usefulness and mechanism of the two calcium sensitizers, levosimendan and CGP 48506 in preparations from end-stage failing human hearts since the exact mechanism of the positive inotropic effects is not yet clearly understood.
Methods:
Failing human hearts which required orthotopic heart transplantation due to idiopathic dilated cardiomyopathy were investigated. Contraction experiments were performed using muscle strips of ventricles. Calcium sensitization was investigated in skinned fibers and phosphodiesterase activity was measured in ventricular homogenate. In addition, cAMP levels were quantified in myocytes from guinea-pig hearts.
Results:
In muscle stripes from failing human hearts levosimendan (10 micromol/l) increased the force of contraction only to 112.8 +/- 6.7% of predrug values. In contrast, CGP 48506 increased the force of contraction to 311 +/- 59% of predrug values at 100 micromol/l. The time to peak tension and time of relaxation were increased to 175 +/- 4% and 205 +/- 15% of control levels at 100 micromol/l. Skinned fibers from failing human hearts were sensitized to calcium with an EC50 of 10 micromol/l. Other mechanisms of action were excluded since CGP 48506 affected neither the activity of phosphodiesterase isoenzymes I-IV in failing human hearts, nor cAMP levels in guinea-pig cardiomyocytes. On the other hand, levosimendan (1 micromol/l) increased cAMP content from 6.3 +/- 0.3 to 8.1 +/- 0.3 pmol/mg protein.
Conclusion:
CGP 48506 is an inotropic agent with calcium-sensitizing properties in the human heart, that is devoid of inhibitory activity on human cardiac phosphodiesterase isoenzymes. It offers, therefore, a new form of positive inotropic therapy that can be useful for the bridging treatment of heart failure before transplantation. On the other hand, levosimendan is a calcium sensitizer showing less-effective inotropic effects accompanied by increased cAMP levels.
Insights
CGP 48506 demonstrates potent calcium-sensitizing effects in failing human hearts, offering a novel therapeutic approach for heart failure. Levosimendan shows weaker inotropic effects and increases cAMP levels.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Shortage of donor hearts necessitates new therapies for end-stage heart failure.
- Conventional cAMP-increasing drugs have diminished effects in failing myocardium.
Purpose of the Study:
- Investigate the efficacy and mechanism of calcium sensitizers levosimendan and CGP 48506.
- Clarify the mechanism of positive inotropic effects in end-stage failing human hearts.
Main Methods:
- Muscle strips from failing human hearts were used for contraction experiments.
- Calcium sensitization was assessed in skinned fibers.
- Phosphodiesterase activity and cAMP levels were measured.
Main Results:
- CGP 48506 significantly increased contraction force (311%) and prolonged relaxation in failing human hearts.
- Levosimendan showed a modest increase in contraction force (112.8%) and elevated cAMP levels.
- CGP 48506 demonstrated calcium-sensitizing properties (EC50 of 10 micromol/l) without affecting phosphodiesterase activity.
Conclusions:
- CGP 48506 is a novel calcium sensitizer with significant positive inotropic effects in the human heart.
- CGP 48506 offers a promising new therapy for bridging heart failure patients awaiting transplantation.
- Levosimendan exhibits less potent inotropic effects and increases cAMP levels, suggesting a different mechanism of action.