Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women

Abstract

The aim of this study was to compare the effects of trandolapril and losartan on plasminogen activator inhibitor type 1 (PAI-1) levels and insulin sensitivity in hypertensive postmenopausal women. We studied 89 hypertensive (diastolic blood pressure >90 and <110 mm Hg) postmenopausal women, aged 51 to 60 years not taking any hormone replacement therapy. Diabetic, obese, and smoking patients were excluded. After a 4-week placebo period, they were randomized to receive 2 mg of oral trandolapril (n=45) or 50 mg of oral losartan (n=44) for 12 weeks according to a double-blind, parallel group design. At the end of the placebo and active treatment periods, blood pressure (BP) was measured, plasma samples were drawn to evaluate PAI-1 antigen levels, and insulin sensitivity was assessed. Both trandolapril and losartan reduced systolic BP (by a mean of 16.9 mm Hg and 15.2 mm Hg, respectively, P < .01 v placebo) and diastolic BP (by a mean of 13.1 mm Hg and 11.9 mm Hg, respectively, P < .01 v placebo) with no difference between the two treatments. The PAI-1 antigen levels were significantly decreased by trandolapril (from 36.9+/-21 ng/dL to 27.2+/-17 ng/dL, P < .05), but not by losartan (from 35.3+/-22 ng/dL to 37.1+/-23 ng/dL, P=not significant). Glucose infusion rate was significantly increased by trandolapril (from 6.67+/-0.56 mg/min/kg to 7.9+/-0.65 mg/min/kg, P < .05), but was not significantly modified by losartan (from 6.7+/-0.47 mg/min/kg to 6.9+/-0.50 mg/min/kg, P= not significant). In the trandolapril group the PAI-1 decrease correlated with glucose infusion rate increase (r=0.36, P=.045) These results provide evidence of different effects of angiotensin converting enzyme inhibitors and AT1 antagonists on fibrinolysis and suggest that the PAI-1 decrease induced by angiotensin converting enzyme inhibitors is related to their action on insulin sensitivity and is not dependent on angiotensin II antagonism but rather on other mechanisms. It remains to be seen whether these findings apply to other patient populations than postmenopausal women.

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

“…45,46,54 In the present study, imidapril significantly increased insulin sensitivity, as assessed by euglycemic-hyperinsulinemic clamp, whereas candesartan did not. These findings, which are in agreement with previous observations by ourselves and other authors, 35,[55][56][57] besides providing another possible explanation for the different effects of the two drugs on the fibrinolytic balance, also suggest that mechanisms other than Ang II inhibition, such as the increase in endogenous kinins because of ACE inhibition, might be responsible for the observed different influences of imidapril and candesartan on insulin sensitivity.…”

“…19,[29][30][31][32] Reasons for such different findings might be because of differences in experimental models, study population characteristics, duration of treatment and possible methodological bias. Some direct comparisons on the effects of ACE-Is and ARBs on plasma PAI-1 and t-PA have been performed, and again the results were controversial: [33][34][35][36][37][38] Some studies have shown that both ACE inhibition and AT1 antagonism were associated with a significant improvement in plasma fibrinolysis, 34 whereas others have observed a decrease in PAI-1 and/ or an increase in t-PA with ACE-Is but not with ARBs. 33,[35][36][37] Only a few studies have reported an improvement of fibrinolytic balance with ARBs.…”

“…Some direct comparisons on the effects of ACE-Is and ARBs on plasma PAI-1 and t-PA have been performed, and again the results were controversial: [33][34][35][36][37][38] Some studies have shown that both ACE inhibition and AT1 antagonism were associated with a significant improvement in plasma fibrinolysis, 34 whereas others have observed a decrease in PAI-1 and/ or an increase in t-PA with ACE-Is but not with ARBs. 33,[35][36][37] Only a few studies have reported an improvement of fibrinolytic balance with ARBs. 38 With this background, the present study was undertaken to compare the effects of 12-week treatment with the ACE-I imidapril and the ARB candesartan on plasma PAI-1 antigen level and activity and on plasma t-PA activity level in a homogeneous population of normoweight (body mass index (BMI)p25 kg m À2 ) hypertensive patients.…”

Effect of delapril–manidipine combination vs irbesartan–hydrochlorothiazide combination on fibrinolytic function in hypertensive patients with type II diabetes mellitus

“…In this study irbesartan monotherapy did not significantly affect the fibrinolytic balance, thus confirming previous findings. [22][23][24][25][26][27] Possible explanations for the dissimilar effect of ACE inhibition and Ang II antagonism on PAI-1 levels might be that: (a) the endothelial receptors that mediate PAI-1 expression in response to Ang II are not type I receptor subtypes, but rather the AT4 receptors, which specifically bind to the hexapeptide 3-8 fragment of Ang II, indicated as Ang IV; 41 (b) unlike ACE Inhibitors, Ang II antagonists have no effect on the endogenous kinins. 42 The addition of hydrochlorothiazide to irbesartan monotherapy produced a significant increase in PAI-1 activity, which confirms previous observations.…”

“…13 Variable effects have been reported for diuretics 14,15 and b-blockers, 16,17 whereas Ca-antagonists seem to be associated with an increase in plasma t-PA activity. 18,19 ACE inhibitors have been demonstrated to reduce plasma levels of PAI-1, [20][21][22][23][24] whereas contrasting results have been reported on the effects of the angiotensin II (Ang II) antagonists. [22][23][24][25][26][27] The aim of the present study was to evaluate the effects on plasma PAI-1 and t-PA activities of the combination of delapril, a nonsulphydryl, nonprolinic, lipophilic ACE inhibitor, with high affinity for the C-terminal site of ACE 28 with manidipine, a second-generation, lipophilic dihydropyridine Caantagonist, with good efficacy/tolerability profile 29 as compared to the combination of the Ang II AT1 receptor antagonists irbesartan with hydrochlorothiazide in the treatment of hypertensive patients with type II diabetes mellitus, a population with a great impairment of the fibrinolytic function.…”