Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane-bound aminopeptidase P (AP-P) participates in the degradation of bradykinin in several vascular beds. We have developed an inhibitor of AP-P called apstatin (1) (N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]-L-prolyl-L-prolyl-L-al aninam ide); IC50,human = 2.9 microM. In the rat, apstatin can potentiate the vasodilatory effect of bradykinin, reduce blood pressure in an aortic-coarctation model of hypertension, and reduce cardiac damage and arrhythmias induced by ischemia/reperfusion. In this study, we have determined structure-activity relationships for apstatin analogues as well as for other chemical classes of inhibitors using AP-P isozymes from different sources. The most potent inhibitor was one in which the N-terminal residue of apstatin was replaced with a (2S,3R)-3-amino-2-hydroxy-5-methyl-hexanoyl residue (6, IC50,human = 0.23 microM). The (2R,3S)-analogue of 6 was equipotent with 6 while the (2S,3S)- and (2R,3R)-analogues were considerably less potent. Apstatin analogues lacking the L-alanine or having hydroxyproline in place of the proline in the second position had reduced affinity. Certain thiol-, carboxylalkyl-, and hydroxamate-containing compounds were inhibitory in the low micromolar range. Human cytosolic AP-P isozymes and Escherichia coli AP-P exhibited different inhibitor profiles than mammalian membrane-bound AP-P isozymes. The effects of the compounds on X-Pro dipeptidase (prolidase) and leucyl aminopeptidase are also presented.
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PMID:Apstatin analogue inhibitors of aminopeptidase P, a bradykinin-degrading enzyme. 1039 80

The pathogenesis of ascending aortic aneurysm (AAA) involves many factors; elastin degradation could lead to initial dilation, and changes in the collagen structure predispose the aneurysm to rupture. Prolidase is an enzyme that catalyzes the final step of collagen breakdown by liberating free proline for collagen recycling. The enzyme activity may be a step-limiting factor in the regulation of collagen biosynthesis. Consequently, in this study we sought to determine serum prolidase activity in AAAs. Eighty consecutive patients with the diagnosis of hypertension or chest pain, referred for echocardiographic examination in the outpatient cardiology clinic, were included in the study. The subjects were grouped into three categories according to the aortic diameter; control group without aortic dilatation (<or= 3.7 cm, n = 20), medium (3.8-4.3 cm, n = 36), and large (>or= 4.4 cm, n = 24) group. We assessed the association of serum prolidase activity with the presence and severity of AAAs, clinical characteristics and laboratory parameters. Serum prolidase activity was significantly higher in the patients without aortic dilatation (1386.3 +/- 320.5 U/L) compared to medium group (1212.0 +/- 282.5 U/L) and large group (1072.2 +/- 192.3 U/L): control group vs. medium group (P = 0.023) and control group vs. large group (P < 0.001). Ascending aortic diameter was inversely correlated with serum prolidase activity and in multivariate analysis, serum prolidase activity was the only independent predictor of aortic dilatation (beta = -0.44, P = 0.006). In conclusion, the presence of AAAs is associated with low serum prolidase activity.
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PMID:Dilatation of the ascending aorta is associated with low serum prolidase activity. 2038 38