We examined the effects of
MET-88 on haemodynamics and
cardiac hypertrophy in rats with an aortocaval shunt (A-V shunt). On the day of surgery, an A-V shunt was produced by using an 18-gauge needle in Wistar rats as described by Garcia and Diebold.
MET-88 and
captopril were orally administered to rats 1 week after surgery, and the administration was continued for 3 weeks. Four weeks after the surgery, A-V shunt-operated rats had biventricular
hypertrophy and higher right atrial pressure (RAP) and left ventricular end-diastolic pressure (LVEDP) than
sham-operated rats. Compared with untreated A-V shunt rats, those treated with
MET-88 showed significant attenuation of the development of left ventricular (LV)
hypertrophy and of the increased LVEDP.
Captopril-treated A-V shunt rats also failed to show increases in LV weight and LVEDP. In in vitro studies,
MET-88 had no effect on
renin and
angiotensin-converting enzyme (ACE) activities in the plasma of normal rats. These results suggest that
MET-88 improved LV
hypertrophy and
LV dysfunction in rats with an A-V shunt. Furthermore, the data indicate that the beneficial effects of
MET-88 may be attributed to some pathway, not involving the renin-angiotensin system, such as myocardial energy metabolism, venous return, etc. We conclude that
MET-88 may be a novel agent for the
therapy of chronic
heart failure.