Inhibition of angiotensin-converting enzyme reduces susceptibility of hypertrophied rat myocardium to ventricular fibrillation.
Left ventricular (LV) hypertrophy increases susceptibility to reperfusion arrhythmias and the angiotensin-converting enzyme inhibitor, ramipril, may reduce that susceptibility via regression of LV hypertrophy. Rats (n=12 per group) were subjected to abdominal aortic constriction (AC) or sham-operation (SH) and from 3 to 6 weeks after surgery, 3 AC groups received ramipril (0.01, 0.1, or 1 mg/kg per day p.o.) while the SH and 1 AC group received vehicle. Six weeks after surgery (ie after 3 weeks of treatment), the hearts were excised and subjected to independent Langendorf perfusion of left and right coronary beds. The left coronary bed was then subjected to ischemia (7 min) and reperfusion (5 min). Hypertrophied hearts from the vehicle AC group showed a significant increase in the incidence of reperfusion-induced ventricular fibrillation (VF) compared with control hearts from the SH group (92%* vs 33%: *p<0.05); this difference was abolished by ramipril (42%, 50%, and 42%, at 0.01, 0.1, or 1 mg/kg per day, respectively). The LV weight/body weight ratio was significantly increased in all AC groups (regardless of ramipril treatment) relative to the SH group. At the cellular level, myocyte length was significantly increased in the vehicle AC group, but was normalized by ramipril treatment (1 mg/kg per day). At the molecular level, atrial natriuretic factor (ANF) mRNA expression was also significantly increased in the vehicle AC group, but was again normalized by ramipril treatment (1 mg/kg per day). In conclusion, short-term treatment with ramipril reduced susceptibility to severe ventricular arrhythmias in hypertrophied rat hearts. This protection was achieved in the absence of a significant reduction in LV weight, but was accompanied by regression of myocyte hypertrophy, as reflected by reductions in cell size and ANF expression.
Shimada
Yasuyuki
Y
Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, United Kingdom. yasuyuki.shimada@ma8.seikyou.ne.jp
Gunasegaram
Suba
S
Yokoyama
Hiroyuki
H
Avkiran
Metin
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000737:chemistry / Q000473:pathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D017257:Ramipril