Obese female SHHF/Mcc-fa(cp) rats resist antihypertensive effects of renin-angiotensin system inhibition

Gender and obesity may influence response to pharmacological modulation of the renin-angiotensin system. We used SHHF/Mcc-fa(cp) rats to study effect of obesity and gender on the ability of an AT(1) receptor antagonist to dec rease blood pressure. After 2 weeks treatment with irbesartan (50 mg/kg), o nly lean and obese males showed significant decreases in blood pressure, wh ile obese females were completely resistant. Lean females showed a trend to ward lowering of pressure (p=0.06). However, irbesartan similarly shifted a ngiotensin II dose response curves to the right in all groups. Twelve weeks of irbesartan also failed to decrease blood pressure, but did significantl y reduce heart weight in obese females. In untreated rats, obese females ha d lower plasma renin activity and serum angiotensin converting enzyme activ ity compared to lean males, while lean and obese females had increased urin ary endothelin excretion. Despite an otherwise similar genetic background c ontributing to hyper tension and heart failure, obese females have differen t patterns of humoral activation compared to lean males, which may contribu te to their resistance to the depressor effects of irbesartan.