© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes
aDepartment of Preclinical and Clinical Pharmacology, University of Firenze, Viale G. Pieraccini 6, 50139 Firenze, Italy
bInstitute of Internal Medicine and Cardiology, University of Firenze, Firenze, Italy
cInstitute of Pharmacology and Toxicology, Universitad Complutense de Madrid, Madrid, Spain
* Corresponding author. Tel.: +39-55-427-1264; fax: +39-55-427-1285 mugelli{at}pharm.unifi.it
Objective: Cardiac hypertrophy due to pressure overload is associated with several cellular electrophysiological alterations such as prolongation of action potential duration (APD), decrease in transient outward current (Ito) and occurrence of the pacemaker current If. These alterations may play a role in sudden arrhythmic death, which is a major risk factor in myocardial hypertrophy and failure. Since angiotensin II is a key signal for myocyte hypertrophy, we tested if an 8-week treatment of old spontaneously hypertensive rats (SHR) with the antagonist of type-1 angiotensin II receptor (AT1), losartan (10 mg/kg/day), was able to influence the cellular electrophysiologic remodeling associated with cardiac hypertrophy. Methods: Left ventricular myocytes were isolated from control (CTR) or losartan-treated (LOS) 18-month old SHR. Patch-clamped LVM were superfused with a normal Tyrode's solution (to measure action potential) or appropriately modified Tyrode's solution (to measure Ito and If). Results: Heart weight to body weight ratio (HW/BW) was significantly smaller in LOS (5.69±0.25 mg/g) than in CTR rats (6.67±0.37 mg/g; P<0.05). Membrane capacitance, an index of cell size, was significantly reduced in LOS (342±12, n=92) vs. CTR (422±14 pF, n=96, P<0.001). APD was significantly shorter in LOS than in CTR (at –60 mV: 197±23 vs. 277±19 ms, n=28, P<0.001); this effect was paralleled by a larger maximum Ito density in the LOS group (LOS: 15.1±1.4 pA/pF, CTR: 10.0±0.8 pA/pF) (n=27, P<0.02). If, elicited by hyperpolarizing steps (range: –60 to –130 mV), was consistently recorded in SHR cells; however, its maximal specific conductance was significantly lower in LOS than in CTR rats (28.6±3.6 vs. 54.2±8.0 pS/pF, n=55, P<0.001). Voltage of half-maximal activation (V1/2) of both Ito and If was unchanged by the treatment. Conclusions: AT1 receptor blockade with losartan prevents the development of myocyte hypertrophy and associated electrophysiological alterations in old SHR.
KEYWORDS APD, action potential duration; AT1, type-1 angiotensin II receptor; Cm, membrane capacitance; HW/BW, heart weight to body weight ratio; If, pacemaker current; Ito; transient outward current; RAS, renin–angiotensin system; SHR, spontaneously hypertensive rats; V1/2, voltage of half maximal activation
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