| Tri-acetyl-luteolin (TRALT) and tetra-acetyl-luteolin (TEALT) were oriented synthesized to improve the pharmacokinetics of luteolin and were examined their pharmacological effects by observing the relaxation effects of luteolin(LT), TEALT and TRALT on norepinephrine (NA)-induced contractions in the aorta rings isolated from rats with or without endothelium. The results showed that they all attenuated the contraction in a concentration-dependent manner and in an endothelium-independent manner.Effect of vasodilation of tetra-acetyl-luteolin is the strongest one among them.Moreover, the anti-anoxia activity of luteolin and its acetylated derivates were observed. the mean survival times of rats in three treated groups is longer than the positive drug control group(22.9±2.5), and the survival time of the rats treated by tetra-acetyl-luteolin(29.3±3.0) was significantly longer than luteolin(23.0±3.5) and its tri-acetyl-luteolin groups(24.9±3.4)(P< 0.05). Hence, we selected tetra-acetyl-luteolin to investigate the pharmacokinetics and pharmacodynamics of anti-myocardial ischemia of rats in vivo.To investigate the pharmacodynamic efficacy and mechanism of Tetra-acetyl-luteolin on the experimental animal model of acute myocardial infarction (AMI) through hemodynamics, myocardial contractility and dilatity. The rat model of acute myocardial infarction (AMI) was induced by Piturin (Pit) injection, the influence on blood-lipids in hyperlipidemia rats and hemorheological parameters in acute hypostasis rats were also studied. The results are①In rats with AMI by Piturin injection, Tetra-acetyl-luteolin desent significantly the raised ST segment and T wave in ECG leadⅡ, slowed down significantly HR and lowered significantly the raised BP, LVSP and LVEDP, increased-dp/dtma-, but no obvious influence on+dp/dtmaX.②In rats ligated the left desend branch of cornary artery, Tetra-acetyl-luteolin desent significantly the raised ST segment and T wave in ECG lead II, slowed down HR and lowered BP, LVEDP, LVSP and MVO2I, increased-dp/dtmax, but no obvious influence on+dp/dtmax.It reduced the myocardial infarction size and lowered serum LDH, CK, MDA and increased serum SOD, NO.③Tetra-acetyl-luteolin lowered significantly serum TC, TG, LDL and increased HDL in hyperlipidemia rats fed with hyperlipidemia food.④Tetra-acetyl-luteolin lowered whole blood viscosity, whole blood reduction viscosity and AI of acute hypostasis rats. The results indicated Tetra-acetyl-luteolin could improve hemodynamics and myocardial dilatity in AMI animal model, did not influence myocardial contractility maredly and decreased myocardial oxygen consumption. It could improve myocardial enzyme activity and energy metabolism in AMI. Those mentioned above are the main mechanism of Tetra-acetyl-luteolin against AMI,simultaneously it could regulate blood lipids in acute hyperlipidemia rats and lower whole blood viscosity, improve hemorheology in acute hypostasis rats, and tetra-acetyl-luteolin may protect myocardium from ischemia injury.Accurate and reproducible HPLC methods were developed and validated for the determination of concentrations of luteolin (LT) and tetra-acetyl-luteolin (TALT) in rat plasma. The linear calibration curves were obtained in the concentration range of 0.04-1.6μg.mL-1 (r=0.9997 and r=0.9990) with a lower limit of quantification (LLOD) of 0.04μg.mL-1. The average recoveries were 96.1%(RSD%=2.4%) and 93.3%(RSD%= 2.3%), respectively.The pharmacokinetics of luteolin and tetra-acetyl-luteolin was investigated by HPLC method. The plasma concentration-time curves of luteolin and tetra-acetyl-luteolin could both be evaluated by the two compartment model. Luteolin's Tmax, Cmax,AUC, t1/2 were 0.47 h,895ng.mL-1. and 3443 ng.h.mL-1,3.70 h, respectively; tetra-acetyl-luteolin's Tmax, Cmax,AUC, t1/2 were 0.51 h,1666ng.mL-1,4937 ng.h.mL"1,4.38h respectively.Above all, tetra-acetyl-luteolin showed potent effect of anti-myocardial ischemia of rats in vivo, and had good pharmacokinetic profiles, which provide the basis for developing it further.
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