Background Caveolin-3 (cav-3) mutations are linked to the long-QT syndrome (LQTS) causing distinct clinical symptoms. Hyperpolarization-activated cyclic nucleotide channel 4 (HCN4) underlies the pacemaker current I It associates with cav-3 and both form a macromolecular complex. Methods To examine the effects of human LQTS-associated cav-3 mutations on HCN4-channel function, HEK293-cells were cotransfected with HCN4 and wild-type (WT) cav-3 or a LQTS-associated cav-3 mutant (T78M, A85T, S141R, or F97C). HCN4 currents were recorded using the whole-cell patch-clamp technique. Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction. HCN4 current properties were differentially modulated by LQTS-associated cav-3 mutations. When compared with WT cav-3, A85T, F97C, and T78M did not alter the specific effect of cav-3, but S141R significantly increased HCN4 current density. Compared with WT cav-3, no significant modifications of voltage dependence of steady-state activation curves were observed. However, while WT cav-3 alone had no significant effect on HCN4 current activation, all LQTS-associated cav-3 mutations significantly accelerated HCN4 activation kinetics. Conclusions Our results indicate that HCN4 channel function is modulated by cav-3. LQTS-associated mutations of cav-3 differentially influence pacemaker current properties indicating a pathophysiological role in clinical manifestations.

In order to evaluate the influence of urinary flow rate at different pH values on the pharmacokinetics of the basic antiarrhythmic drug flecainide 7 healthy men received 50 mg flecainide under 4 different conditions: 1. acidic urine (pH 5) and a high fluid load (125 ml.h-1) 2. acidic urine (pH 5) and a low fluid load (25 ml.h-1) 3. alkaline urine (pH 8) and a high fluid load (125 ml.h-1) 4. alkaline urine (pH 8) and a low fluid load (25 ml.h-1) At acidic pH the half-life, the amount of unchanged drug in the urine (Ae), renal clearance (CLR) and area under the curve (AUC) were independent of the fluid load. At alkaline pH Ae (5.8 vs 2.6 mg) and CLR (73 vs 33 ml.min-1) were significantly affected by fluid load (high vs low), whereas half-life and AUC were not different (15.7 vs 16.0 h, 1480 vs 1540 ng.ml-1.h). When comparing acidic and alkaline urinary pH conditions, half-life, Ae, CLR, and AUC were different. For a high fluid load the values at acidic vs alkaline pH were half-life 10.0 vs 15.7 h; Ae 15.9 vs 5.8 mg; CLR 288 vs 73 ml.min-1; AUC 976 vs 1480 ng.ml-1.h. For a low fluid load the corresponding values at acidic vs alkaline pH were half-life 10.1 vs 16.0 h; Ae 15.9 vs 2.6 mg; CLR 267 vs 33 ml.min-1; AUC 1045 vs 1540 ng.ml-1.h. It is concluded that urinary pH affects flecainide pharmacokinetics independently of urinary flow rate, and that a high flow enhances the elimination of flecainide only with an alkaline urine. This effect of flow rate does not appear to be of clinical relevance.

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Non-prescription drugs can be a potential risk for patients who are also taking other pharmaceutical preparations or having concomitant disease. This is because such drugs may cause harmful interactions, most of them previously unknown. All doctors should avoid unsupervised use of non-prescription medication.

Ranolazine is a new drug for use in patients with stable angina pectoris. Unlike other antianginal drugs ranolazine does not alter heart rate or systemic blood pressure. Inhibition of the persistent or late sodium current (I(Na,late)) by ranolazine reduces [Na(+) ](i)-dependent Ca(2+) overload and the effects of ischaemia. Moreover, ranolazine holds potential promise to be effective in treatment of atrial fibrillation and diastolic heart failure.