Evaluation of activity of an estrogen-derivative as cardioprotector drug using an ischemia-reperfusion injury model

Abstract

Myocardial ischemia/reperfusion injury is a serious problem involved in cardiovascular diseases. There data which indicate that some steroids induce cardioprotective effects on myocardial ischemia-reperfusion injury; however their activity and the molecular mechanism involved on myocardial ischemia-reperfusion injury are very confusing. Therefore, in this study some estrogen derivatives (compound 3 to 7) were synthesized with the objective of evaluating its activity on myocardial ischemia/reperfusion injury using an isolated heart model. Additionally, molecular mechanism involved in the activity exerted by the compounds 3 to 7 on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in absence or presence of following compounds; prazosin, metoprolol, indomethacin and nifedipine. The results showed that 7 reduce infarct size compared with the estrone and other estrogen derivatives (compounds 3, 4, 5, and 6). Other results showed that 7 significantly increase the perfusion pressure and coronary resistance in isolated heart in comparison with estrone, 3, 4, 5, and 6. Finally, other data indicate that 7 increased the left ventricular pressure in a dose-dependent manner; however, this phenomenon was significantly inhibited by nifedipine. In conclusion, all these data suggest that 7 exert a cardioprotective effect through calcium channels activation and consequently induce changes in the left ventricular pressure levels. This phenomenon results in decrease of myocardial necrosis after ischemia and reperfusion.

Keywords: Estrogen; ischemia/reperfusion injury left ventricular pressure; nifedipine.

Figure 1

Synthesis of an estrogen derivative (4). The first stage involve the reaction of estrone (1) with 3,5-dinitrobenzoic acid (2) to form 3. The second stage was achieved by the reaction of 3 with β-naphtol to form 4. i and ii = Dimethyl sulfoxide (DMSO)/K₂CO₃/rt.

Figure 2

Synthesis de an estrogen derivative (7). The first stage was achieved by reaction of 5 with 3,5-dinitrobenzoic acid (2) to form 6. The second stage involved the preparation of 7 by the reaction of 6 with β-naphtol. i and ii = DMSO/K₂CO₃/rt.

Figure 3

Comparison of cardioprotective effect of the compound 7 at a dose of 1 nM with the compounds 3, 4, 5, 6, estrone and the control conditions on the functional recovery of rat hearts subjected to ischemia and reperfusion.

Figure 4

Effect induced by estrone and its derivatives on perfusion pressure. The results show that the compound 7 significantly increase perfusion pressure (P = 0.05) through time in comparison with the compounds 3, 4, 5, 6, estrone and the control conditions. Each bar represents the mean ± S.E. of 9 experiments.

Figure 5

Activity exerted by estrone and its derivatives on coronary resistance. The results show that coronary resistance was higher (P = 0.05) in the presence of 7 in comparison with the compound 3, 4, 5, 6, estrone and the control conditions. Each bar represents the mean ± S.E. of 9 experiments.

Figure 6

Effect exerted by the compound 7 on left ventricular pressure (LVP) at dose of 0.001 to 100 nM using an isolated rat heart model.

Figure 7

Effect induced by the compound 7 on LVP through of estrogen receptors. The compound 7 [0.001 to 100 nM] was administered (intracoronary boluses, 50 μl) and the corresponding effect on the LVP was evaluated in the absence and presence of tamoxifen. The results showed that activity induced by 7 on LVP was not inhibited in the presence of tamoxifen. Each bar represents the mean ± S.E. of 9 experiments. LVP = left ventricular pressure.

Figure 8

Activity exerted by the compound 7 on LVP through of adrenergic receptors. The compound 7 [0.001 to 100 nM] was administered (intracoronary boluses, 50 μl) and the corresponding effect on the LVP was evaluated in the absence and presence of prazosin or metoprolol. The results showed that activity induced by 7 on LVP was not inhibited in the presence of prazosin or metoprolol. Each bar represents the mean ± S.E. of 9 experiments. LVP = left ventricular pressure.

Figure 9

Effects induced by the compound 7 on LVP through prostaglandins synthesis or calcium channel activation. Intracoronary boluses (50 μl) of the compound 7 [0.001 to 100 nM] were administered and the corresponding effect on the LVP was determined in the absence and presence of indomethacin or nifedipine. The results showed that 7 higher the LVP in a dependent dose manner and this effect was not inhibited in the presence of indomethacin. However, the activity induced by 7 on LVP was blocked by and nifedipine. Each bar represents the mean ± S.E. of 9 experiments. LVP = left ventricular pressure.