Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes.
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 I(f). 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 I(f)).


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). I(f), 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 I(f) was unchanged by the treatment.


CONCLUSIONS
AT1 receptor blockade with losartan prevents the development of myocyte hypertrophy and associated electrophysiological alterations in old SHR.
Cerbai
E
E
Department of Preclinical and Clinical Pharmacology, University of Firenze, Italy.
Crucitti
A
A
Sartiani
L
L
De Paoli
P
P
Pino
R
R
Rodriguez
M L
ML
Gensini
G
G
Mugelli
A
A
D000200:Action Potentials / Q000187:drug effects; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D004553:Electric Conductivity; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D019808:Losartan