Potent inhibition of thrombin by the newly synthesized arginine derivative No. 805. The importance of stereo-structure of its hydrophobic carboxamide portion

Four stereoisomers of 4-methyl-1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid were synthesized and examined for the inhibitory effect on thrombin. The inhibitory potency varied largely with the stereo-configuration of the 4-methyl-2-piperidinecarboxylic acid portion. The (2R, 4R)-isomer was the most potent inhibitor with a Ki of 0.019 μM, while the (2R, 4S) and (2S, 4R)-isomers showed the values of Ki 0.24 and 1.9 μM, respectively. The least potent inhibitor, (2S, 4S)-isomer, showed a Ki of 280 μM which is approximately 15,000 times that of (2R, 4R)-isomer.     

Plasma endothelin levels during myocardial ischemia and reperfusion

Endothelin, an endothelium-derived vasoconstrictive peptide, has a strong potency of coronary artery constriction. However, the role of endogeneous endothelin under pathophysiological conditions has not yet been known. In this study, we examined plasma endothelin concentration in dogs with myocardial ischemia and reperfusion. Anesthetized open-chest dogs underwent either 45 minutes occlusion of the left anterior descending coronary artery followed by 3 hours reperfusion, or 4-10 hours of continuous occlusion. Plasma concentration of endothelin from the central vein was measured by the highly sensitive enzyme-immunoassay. Plasma endothelin concentration increased 2.2-fold with the peak level at 60 minutes after release of the ligated artery, but occlusion per se caused no remarkable change. These data suggest that reperfusion of the occluded artery might be needed to increase the plasma concentration of endothelin in case of myocardial infarction.