| Objective: By measuring the strength and relatively selective of R/S-, R- and S-TJ0711 blocking the adrenergic receptor, defining the main antihypertensive mechanism of this compound. And comparing with the enantiomers and the racemate, find out if there were differences between them. Studying the effects of a long-term treatment with R/S-TJ0711 to the renal hypertensive rats (RHR), including the determination of blood glucose levels; the content of Renin, Angiotensin-Ⅱ, Endothelin in blood plasma. And to explore the differences of the response of aorta to vaso-active substance in RHR with different doses of R/S-TJ0711, to observe the morphological changes of vascular. Making a preliminary assessment to TJ0711, whether does it have the protective effect to the function of vascular?Methods: Experiments in isolated organs observe the blocking activity of TJ0711 on each adrenoceptor, measuring the pA2 of TJ0711 toβ1,β2,α1 andα2 adrenergic receptor apart with right atria and tracheas of Guinea pig, anococcygeus muscles and spermatic ducts of rats, comparing the differences of them. Making the hypertensive rat model with"two-kidney and one-clip", after 6 to 8 weeks, do the next step experiment: determine of blood glucose levels, according to kit instructions to assay the content of Renin, Angiotensin-Ⅱ, Endothelin in blood plasma with corresponding ELISA kit. By performing the experiment of the isolated thoracic aortic rings, explore the response of aortic to phenylephrin, KCl, sodium nitroprusside, acetylcholine. And making the pathology of aortic, measuring the middle membrane and tube wall thickness as well as inner and outer diameter of vessels.Results: The pA2 of R/S-TJ0711, S-TJ0711 and R-TJ0711 to blockβ1- adrenoceptor are: 7.35±0.0543, 7.22±0.1305, 7.17±0.1462; to blockβ2- adrenoceptor are 6.24±0.1257, 6.11±0.2680, 6.23±0.0837; to blockα1- adrenoceptor are: 7.63±0.1277, 7.37±0.1175, 7.33±0.2090; to blockα2- adrenoceptor are: 5.70±0.4840, 6.08±0.2396, 5.64±0.2340. By comparing with the block activity to each receptor, there is no significant difference between R-TJ0711 and S-TJ0711; on blockα1- adrenoceptor, there is significant difference between the enantiomers and the racemate, but there is no significant difference between R- and S-, and on the others receptor, there is no significance difference between the enantiomers and the racemate. There is a higher selectivity onβ1 andα1 receptor.The long-term treatments with TJ0711 have no influence on the blood glucose levels of RHR. Compared with the model group, the content of Renin, Angiotensin-Ⅱ, Endothelin in blood plasma in the treatment group's animal is significantly lower. Apart from TJ0711 high, medium and low doses group, the maximum contraction of isolated aortic rings to 60mmol/L KCl respectively from model group's 0.297±0.035 g force/mg tissue to 0.256±0.0684, 0.226±0.0378, 0.254±0.05 g force/mg tissue; the maximum contraction of isolated aortic rings to phenylephine respectively from model group's 0.38±0.07 g force/mg tissue to 0.31±0.05, 0.29±0.03, 0.30±0.04 g force/mg tissue, the sensitivity of response is also decreased; the diastolic response of aorta to Ach is remarkably increased, the maximum relaxation rate of isolated aortic rings to Ach respectively from model group's 67.3±7.26% to 82.5±16.02%, 84.3±15.51%, 81.6±19.0%; the maximum responses of isolated aortic rings to sodium nitroprusside are not significantly different in all groups. The ratio of the vascular medial and the vessel wall, the vascular medial and inner diameter is also significant decreased.Conclusion: TJ0711 is a new kind of selectiveα1/β1-adrenoceptor blocking agent with a chiral center, and there is no significant difference between the enantiomers; has no influence on the blood glucose levels, has beneficial effect on reduction in blood pressure. It can decrease the response of aortic to vasoconstrictor substances; increase the response of aortic to endothelium-dependent vasodilation substances, and protect the form and function of arteries. |
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