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Handbook of Experimental Pharmacology - Part 5

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Ks thuốc ức chế kéo dài APD và ngăn chặn các rối loạn nhịp tâm thất ở động vật với nhồi máu cơ tim cấp tính và tập thể dục đặt lên trên một chữa lành nhồi máu cơ tim (MI) (Busch et al 1996; Gogelein et al 2000). QT kéo dài xảy ra một cách phụ thuộc vào liều lượng, và có thể được nhấn mạnh bởi sự kích thích β-adrenergic (Shimizu và Antzelevitch 1998) | Structural Determinants of Potassium Channel Blockade 139 Tamargo et al. 2004 . Conversely in ventricular myocytes the plateau voltage is more positive 20 mV allowing IKs to be substantially more activated so that IKs block would be expected to prolong the APD markedly. The net result of both effects would be less drug-induced dispersion in repolarization and a reduced risk of arrhythmogenesis Varro et al. 2000 . IKs blockers prolong the APD and suppress ventricular arrhythmias in animals with acute myocardial infarction and exercise superimposed on a healed myocardial infarction MI Busch et al. 1996 Gogelein et al. 2000 . This QT prolongation occurs in a dose-dependent manner and can be accentuated by P-adrenergic stimulation Shimizu and Antzelevitch 1998 . In arterially perfused canine left ventricular wedge preparations chromanol 293B prolongs the APD but does not induce TdP arrhythmias. However in the presence of chromanol 293B isoproterenol abbreviated the APD of epicardial and endocardial myocytes but not in M cells accentuating transmural dispersion of repolarization and inducing TdP Shimizu and Antzelevitch 1998 . These studies in canine preparations however may not be representative for humans since canine repolarization appears to be less dependent upon IKs than other species Mazhari et al. 2001 Stengl et al. 2003 and chromanol 293B was shown to markedly prolong human and guinea pig APD Bosch et al. 1998 . Furthermore under normal conditions chromanol 293B and L-7 minimally prolong the APD regardless of pacing frequency in dog ventricular muscles and Purkinje fibers probably because other K currents may provide sufficient repolarizing reserve Roden 1998 . However when the repolarizing reserve is decreased by QT-prolonging drugs IKr or IK1 blockers remodeling hypertrophy heart failure or inherited disorders IKs blockade can produce a marked prolongation of the ventricular APD an enhanced dispersion of repolarization and TdP arrhythmias Shimizu and .