Treatment with irbesartan counteracts the functional remodeling of ventricular myocytes from hypertensive rats.
Changes in electrophysiological (action potential prolongation, decrease in transient outward current I(to), occurrence of the hyperpolarization-activated current I(f)) and contractile properties develop in hypertrophied ventricular myocytes, likely implicated in the increased propensity to arrhythmias. Angiotensin II is a key signal for myocyte hypertrophy; the effect of 8-week treatment with irbesartan, a type 1 angiotensin II receptor (AT(1)) antagonist, on cardiac remodeling was tested. Sixteen-month-old hypertensive rats (SHRs) were treated with irbesartan (20 mg/kg/d) or saline for 8 weeks. At the end of treatment, systolic blood pressure and heart weight to body weight ratio were reduced in irbesartan-treated compared with nontreated SHRs. Electrical and contractile properties were measured in isolated ventricular myocytes, by patch-clamp or video-dimension analysis, respectively. Action potential duration was significantly shorter in irbesartan-treated than in nontreated SHRs (at -60 mV: 119 +/- 24 ms vs 187 +/- 20 ms); correspondingly, maximal I(to) density was larger in irbesartan-treated than in nontreated SHRs (25.4 +/- 2.8 pA/pF vs 18.5 +/- 1.5 pA/pF). Maximal specific conductance of I(f) was lower in irbesartan-treated vs nontreated SHRs (24.8 +/- 3.0 pS/pF vs 35.2 +/- 4.0 pS/pF). Finally, the relaxation rate of shortening in field-stimulated intact myocytes was significantly faster in irbesartan-treated than in nontreated SHRs (7.3 +/- 0.5/s vs 5.7 +/- 0.3/s). Thus, AT(1) blockade with irbesartan, at an oral daily dosage that gave a slight but significant reduction of systolic blood pressure, largely counteracts the development of myocyte hypertrophy and associated functional alterations.
Cerbai
Elisabetta
E
Inter-University Center for Molecular Medicine, Department of Preclinical Pharmacology, University of Firenze, Italy.
De Paoli
Petra
P
Sartiani
Laura
L
Lonardo
Giuseppe
G
Mugelli
Alessandro
A
D000200:Action Potentials / Q000187:drug effects; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D002478:Cells, Cultured; D004594:Electrophysiology; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D015221:Potassium Channels; D013777:Tetrazoles; D000077405:Irbesartan