We found recently that in Ren-2 transgenic hypertensive rats
(TGR) addition of soluble epoxide hydrolase inhibitor (sEHi) to
treatment with angiotensin-converting enzyme inhibitor (ACEi),
surprisingly, increased the mortality due to heart failure (HF)
induced by creation of the aorto-caval fistula (ACF). Since TGR
exhibit sex-related differences in mortality, we examined here if
such differentiation exists also in the response to the treatment
with ACEi (trandolapril), alone or combined with sEHi [cis-4-[4-
(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid, (c-AUCB)].
ACEi improved survival in males to 74 % (vs. 0 %) and in
females to 65 % (vs. 32 %). ACEi and sEHi combined also
improved the survival in male ACF TGR, however, it was
significantly less (38 %) than after ACEi alone. In contrast, in
females the combined treatment significantly improved the final
survival rate (84 %). There were no significant sex-linked
differences in survival rate in untreated or treated normotensive
Hannover Sprague-Dawley rats. In conclusion, in HF patients
with co-existing hypertension and RAS hyperactivity, the sex may
co-determine the rate of HF progression, and can influence the
effectiveness of the therapeutic measures applied. Therefore, in
the relevant pre-clinical studies the sex-linked differences should
be seriously considered. Our data indicate that TGR might be
an optimal model for such studies.