TY - JOUR
T1 - Design and synthesis of new dihydrotestosterone derivative with positive inotropic activity
AU - Lauro, Figueroa Valverde
AU - Francisco, Díaz Cedillo
AU - Elodia, García Cervera
AU - Eduardo, Pool Gómez
AU - Marcela, Rosas Nexticapa
AU - Lenin, Hau Heredia
AU - Betty, Sarabia Alcocer
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/3
Y1 - 2015/3
N2 - There are several reports which indicate that some steroid derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action of steroid derivatives at cardiovascular level is very confusing. In order, to clarify these phenomena in this study, two dihydrotestosterone derivatives (compounds 5 and 10) were synthesized with the objective of to evaluate its biological activity on left ventricular pressure and characterize their molecular mechanism. In the first stage, the Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the steroid derivatives. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the compound 5 was evaluated by measuring left ventricular pressure in absence or presence of following compounds; nifedipine, flutamide, indomethacin, prazosin, isoproterenol, propranolol and metoprolol. The results showed that the compound 5 significantly increased the perfusion pressure and coronary resistance in comparison with dihydrotestosterone, compound 10 and the control conditions. Other data indicate that 5 increase left ventricular pressure in a dose-dependent manner (0.001-100 nM); nevertheless, this phenomenon was significantly inhibited only by propranolol or metoprolol at a dose of 1 nM. These data suggest that positive inotropic activity induced by the compound 5 is through β1-adrenergic receptor however, this effect was independent of cAMP levels. This phenomenon is a particularly interesting because the positive inotropic activity induced by this steroid derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.
AB - There are several reports which indicate that some steroid derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action of steroid derivatives at cardiovascular level is very confusing. In order, to clarify these phenomena in this study, two dihydrotestosterone derivatives (compounds 5 and 10) were synthesized with the objective of to evaluate its biological activity on left ventricular pressure and characterize their molecular mechanism. In the first stage, the Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the steroid derivatives. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the compound 5 was evaluated by measuring left ventricular pressure in absence or presence of following compounds; nifedipine, flutamide, indomethacin, prazosin, isoproterenol, propranolol and metoprolol. The results showed that the compound 5 significantly increased the perfusion pressure and coronary resistance in comparison with dihydrotestosterone, compound 10 and the control conditions. Other data indicate that 5 increase left ventricular pressure in a dose-dependent manner (0.001-100 nM); nevertheless, this phenomenon was significantly inhibited only by propranolol or metoprolol at a dose of 1 nM. These data suggest that positive inotropic activity induced by the compound 5 is through β1-adrenergic receptor however, this effect was independent of cAMP levels. This phenomenon is a particularly interesting because the positive inotropic activity induced by this steroid derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.
KW - Dihydrotestosterone derivative
KW - Inotropic activity
KW - Metoprolol
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=84921368944&partnerID=8YFLogxK
U2 - 10.1016/j.steroids.2014.12.026
DO - 10.1016/j.steroids.2014.12.026
M3 - Artículo
SN - 0039-128X
VL - 95
SP - 39
EP - 50
JO - Steroids
JF - Steroids
ER -