ABSTRACT
BACKGROUND AND PURPOSE: At present there are no small molecule inhibitors that show strong selectivity for the Na(+) /Ca(2+) exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca(2+) currents and on the formation of early and delayed afterdepolarizations. EXPERIMENTAL APPROACH: Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. KEY RESULTS: ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 µM), ORM-10103 did not significantly change the L-type Ca(2+) current or the maximum rate of depolarization (dV/dtmax ), indicative of the fast inward Na(+) current. At 10 µM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca(2+) current. ORM-10103 did not influence the Na(+) /K(+) pump or the main K(+) currents of canine ventricular myocytes, except the rapid delayed rectifier K(+) current, which was slightly diminished by the drug at 3 µM. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 µM) in a concentration-dependent manner. CONCLUSIONS AND IMPLICATIONS: ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Benzopyrans/pharmacology , Heart Ventricles/drug effects , Myocytes, Cardiac/drug effects , Pyridines/pharmacology , Sodium-Calcium Exchanger/antagonists & inhibitors , Action Potentials , Animals , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/metabolism , Calcium Signaling/drug effects , Dogs , Dose-Response Relationship, Drug , Female , Guinea Pigs , Heart Ventricles/metabolism , Male , Myocytes, Cardiac/metabolism , Papillary Muscles/drug effects , Papillary Muscles/metabolism , Potassium/metabolism , Purkinje Fibers/drug effects , Purkinje Fibers/metabolism , Sodium/metabolism , Sodium-Calcium Exchanger/metabolism , Time FactorsABSTRACT
BACKGROUND: Chronic hydrocephalus is a common sequela of subarachnoid hemorrhage (SAH). The technical procedure used to treat intracranial aneurysms, whether neurosurgical clipping or endovascular coiling, may lead to differences in the incidence of chronic posthemorrhagic hydrocephalus. PURPOSE: To compare the effects of early neurosurgical and early endovascular treatment on the development of chronic hydrocephalus in patients with SAH. MATERIAL AND METHODS: A retrospective study included 102 clipped and 107 coiled patients with aneurysmal SAH. Clinical condition at admission and shunt dependence were verified from patient data records. The initial and follow-up computed tomography (CT) images were reviewed, and the amount and distribution of blood and the occurrence of hydrocephalus were registered. The values of the cella media index and the width of the third ventricle were calculated. Statistical analysis of the data was performed. RESULTS: No statistically significant differences in the incidence of chronic hydrocephalus or the need for shunting emerged between the treatment groups. After clipping 35% and after coiling 39% of the patients developed chronic hydrocephalus. Twenty-nine percent of the clipped and 31% of the coiled patients underwent a shunt operation. CONCLUSION: The treatment method used for acutely ruptured intracranial aneurysms, i.e., neurosurgical clipping or endovascular coiling, has no statistically significant effect on the development of chronic hydrocephalus.
