Losartan and its metabolite E3174 modify cardiac delayed rectifier K(+) currents

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• The study investigates the impact of losartan, a type 1 angiotensin II receptor antagonist, and its metabolite E3174 on cardiac electrophysiology.
• Focus is on their effects on transmembrane action potentials and specific ion currents (hKv1.5, HERG, I(Ks)).

Purpose of the Study:

• To analyze the effects of losartan and E3174 on transmembrane action potentials.
• To determine their influence on hKv1.5, HERG, and I(Ks) currents in cardiac myocytes.

Main Methods:

• Utilized microelectrode techniques for guinea pig ventricular action potential recordings.
• Employed whole-cell patch-clamp and perforated-nystatin-patch configurations for ion current measurements (hKv1.5, HERG, I(Ks)).

Main Results:

• Losartan and E3174 modulated hKv1.5 current, causing transient increases followed by voltage-dependent block (E3174 more potent).
• Differential effects on HERG currents were observed: losartan decreased, E3174 increased, and both shifted activation curves.
• Both agents inhibited I(Ks) currents, with distinct voltage-dependence characteristics.

Conclusions:

• Losartan and E3174 significantly modify cardiac ion channel function (hKv1.5, HERG, I(Ks)) at therapeutic concentrations.
• These modifications can alter cardiac action potential repolarization, suggesting potential clinical implications.