Kazunobu Kawakami

Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome

Many drugs associated with acquired long QT syndrome (LQTS) directly block human ether‐a‐go‐go‐related gene (hERG) K+ channels. Recently, disrupted trafficking of the hERG channel protein was proposed as a new mechanism underlying LQTS, but whether this defect coexists with the hERG current block remains unclear. This study investigated how ketoconazole, a direct hERG current inhibitor, affects the trafficking of hERG channel protein.

Blockade of HERG cardiac K+ current by antifungal drug miconazole.

1 Miconazole, an imidazole antifungal agent, is associated with acquired long QT syndrome and ventricular arrhythmias. Miconazole increases the plasma concentration of QT‐prolonging drugs by inhibiting the hepatic cytochrome P450 metabolic pathway, but whether it has direct effects on cardiac ion channels has not been elucidated. 2 To determine the mechanism underlying these clinical findings, we investigated the effect of miconazole on human ether‐a‐go‐go‐related gene (HERG) K+ channels. 3 HERG channels were heterologously expressed in human embryonic kidney 293 (HEK293) cells and whole‐cell currents were recorded using a patch‐clamp technique (23°C). 4 Miconazole inhibited HERG peak tail current in a concentration‐dependent manner (0.4–40 μM) with an IC50 of 2.1 μM (n=3–5 cells at each concentration, Hill coefficient 1.2). HERG block was not frequency‐dependent. It required channel activation, occurred rapidly, and had very slow dissociation properties. 5 The activation curve was shifted in a negative direction (V1/2: −9.5±2.3 mV in controls and −15.3±2.4 mV after 4 μM miconazole, P<0.05, n=6). Miconazole did not change other channel kinetics (activation, deactivation, onset of inactivation, recovery from inactivation, steady‐state inactivation). 6 The S6 domain mutation, F656C, abolished the inhibitory action of miconazole on HERG current indicating that miconazole preferentially binds to an aromatic amino‐acid residue within the pore‐S6 region. 7 Our findings indicate that miconazole causes HERG channel block by binding to a common drug receptor, and this involves preferential binding to activated channels. Thus, miconazole prolongs the QT interval by direct inhibition of HERG channels.

Comparison of HERG channel blocking effects of various β‐blockers – implication for clinical strategy

β‐Blockers are widely used in the treatment of cardiovascular diseases. However, their effects on HERG channels at comparable conditions remain to be defined. We investigated the direct acute effects of β‐blockers on HERG current and the molecular basis of drug binding to HERG channels with mutations of putative common binding site (Y652A and F656C). β‐Blockers were selected based on the receptor subtype. Wild‐type, Y652A and F656C mutants of HERG channel were stably expressed in HEK293 cells, and the current was recorded by using whole‐cell patch‐clamp technique (23°C). Carvedilol (nonselective), propranolol (nonselective) and ICI 118551 (β2‐selective) inhibited HERG current in a concentration‐dependent manner (IC50 0.51, 3.9 and 9.2 μM, respectively). The IC50 value for carvedilol was a clinically relevant concentration. High metoprolol (β1‐selective) concentrations were required for blockade (IC50 145 μM), and atenolol (β1‐selective) did not inhibit the HERG current. Inhibition of HERG current by carvedilol, propranolol and ICI 118551 was partially but significantly attenuated in Y652A and F656C mutant channels. Affinities of metoprolol to Y652A and F656C mutant channels were not different compared with the wild‐type. HERG current block by all β‐blockers was not frequency‐dependent. Drug affinities to HERG channels were different in β‐blockers. Our results provide additional strategies for clinical usage of β‐blockers. Atenolol and metoprolol may be preferable for patients with type 1 and 2 long QT syndrome. Carvedilol has a class III antiarrhythmic effect, which may provide the rationale for a favourable clinical outcome compared with other β‐blockers as suggested in the recent COMET (Carvedilol Or Metoprolol European Trial) substudy.

Successful treatment of severe orthostatic hypotension with erythropoietin

KAWAKAMI, K., et al.: Successful Treatment of Severe Orthostatic Hypotension with Erythropoietin. A 71‐year‐old man, who was diagnosed with familial amyloidosis type I, was admitted for treatment of severe orthostatic hypotension associated with recurrent syncopal attacks. Head‐up tilt testing demonstrated severe orthostatic hypotension (114/72 mmHg in the supine position and 62/34 mmHg in the upright position) with syncope or presyncope. Oral midodorine and fludrocortisone therapies failed to prevent his symptoms. After administration of subcutaneous erythropoietin, his blood pressure drop in the upright position was decreased and symptoms disappeared unassociated with improvement of anemia. Although previous reports have shown that the mechanism by which erythropoietin improves orthostatic hypotension is related to improvement in anemia, other mechanisms may also play a role. (PACE 2003; 26[Pt. I]:105–107)