| H219 | Possible intracellular mechanisms to increase the contractile function of the myocardium. |
| A.Varró | |
| Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, HU. | |
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A number of new positive inotropic compounds with diverse mechanisms of action have been discovered over the past 25 years. Phosphodiesterase inhibitors (milrinone, vesnarinone, olprinone) and β-adrenoceptor stimulators (dopamine, dobutamine, denopamine) indirectly increase intracellular cAMP level and thereby enhance cytosolic Ca2+ and force development. Forskolin and its water soluble derivate NKH 477 directly activate cAMP. These drugs have the benefit also to accelerate relaxation, but as a possible disadvantage they may induce Ca2+ overload and triggered arrhythmias. Ca2+ channel activators (BAYK 8644, YC-170, CGP 28392) directly affect Ca2+-channel gating and consequently increase Ca2+ influx into the myocytes, but they remained only useful pharmacologic tools due to its vasoconstrictor property. Positive inotropic actions can be also achieved by elevations of the intracellular Na+ activity either by inhibiting Na-K pump (digitalis) or by increasing Na+ influx (DPI 201 106, BDF 9148, BDF 9198), but these mechanism also associated with significant arrhythmic risk. Sensitisation of Ca2+ to the myofilaments is a new promising mechanisms which can be avoid of proarrhythmic complications. The Ca2+ sensitisation can occur with different mode of actions inducing stabilization of the conformation of the Ca2+-troponin complex (levosimendan), acting directly on the actin-myosin interaction (EMD 57033) or to lower the Ca2+ threshold for actin sliding (pimodendan). Most of the Ca sensitizers also inhibit phosphodiesterase III which effect can be advantageous to decrease the possibility of impairment of relaxation. Promising new drug with other mechanisms are also under investigations such as gingerol which selectively activate SERCA and possible drugs which inhibit phospholamban, thereby enhance Ca2+ uptake. |