Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats.
Hypertension is a common cause of heart failure, and ventricular arrhythmias are a major cause of death in heart failure. The spontaneous hypertension heart failure (SHHF) rat model was used to study altered ventricular electrophysiology in hypertension and heart failure. We hypothesized that a reduction in the inward rectifier K(+) current (I(K1)) and expression of pacemaker current (I(f)) would favor abnormal automaticity in the SHHF ventricle. SHHF ventricular myocytes were isolated at 2 and 8 mo of age and during end-stage heart failure (>/=17 mo); myocytes from age-matched rats served as controls. Inward I(K1) was significantly reduced at both 8 and >/=17 mo in SHHF rats compared with controls. There was a reduction in inward I(K1) due to aging in the controls only at >/=17 mo. We found a significant increase in I(f) at all ages in the SHHF rats, compared with young controls. In controls, there was an age-dependent increase in I(f). Action potential recordings in the SHHF rats demonstrated abnormal automaticity, which was abolished by the addition of an I(f) blocker (10 muM zatebradine). Increased I(f) during hypertension alone or combined increases in I(f) with reduced I(K1) during the progression to hypertensive heart failure contribute to a substrate for arrhythmogenesis.
Sridhar
Arun
A
Ohio State Univ., College of Pharmacy, 500 W. 12th Ave., Columbus, OH 43210, USA.
Dech
Spencer J
SJ
Lacombe
Veronique A
VA
Elton
Terry S
TS
McCune
Sylvia A
SA
Altschuld
Ruth A
RA
Carnes
Cynthia A
CA
D000200:Action Potentials; D000375:Aging / Q000502:physiology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001835:Body Weight / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology; D003971:Diastole / Q000502:physiology*; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D006352:Heart Ventricles / Q000473:pathology*; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology*; D009929:Organ Size / Q000235:genetics; D018408:Patch-Clamp Techniques; D051381:Rats; D011918:Rats, Inbred SHR; D011920:Rats, Inbred WF; D017208:Rats, Wistar
D001552:Benzazepines; D002316:Cardiotonic Agents; C043636:zatebradine