Renin, human

Piaacidil has a short half-life and most human studies were carried out ia slow-release formulatioas. The reductioa ia blood pressure produced by piaacidil is accompanied by tachycardia and fluid retention. Plasma catecholamines and renin activity are iacreased. Other side effects are headache, di22iaess, and asthenia. 

In normal human subjects, ANP infusion for one hour causes increased absolute and fractional sodium excretion, urine flow, GFR, and water clearance (53—55). As shown in many in vitro and in vivo animal studies, ANP achieves this by direct effect on the sodium reabsorption in the inner medullary collecting duct, ie, by reducing vasopressin-dependent free-water and sodium reabsorption leading to diuresis and by indirect effect through increased hemodynamic force upon the kidney. ANP inhibits the release of renin and aldosterone resulting in the decreased plasma renin activity and aldosterone concentration (56,57). 

Urata H, Kinoshita A, Misono KS, Bumpus FM. Husain A Identification of a highly specific chy-mase as the major angiotensin Il-forming enzyme in the human heart. J Biol Chem 1990 265 22348. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R Mast cells a unique source of renin. Proc Natl Acad Sci USA 2004 101 13607. Mackins CJ, Kano S, Sevedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 2006 116 1063. 

Table 5.4 Hypothetical experiment measuring the IC50 values of a competitive inhibitor for HIV aspartyl protease and for human renin, at a fixed substrate concentration of 50 iM...

For a series of renin inhibitors a good correlation between the measured membrane permeability and log D was found (r2 = 0.8). The model has been validated against a human perfusion model [10], as well as being extended by including molecular weight as a third parameter [27]. A further development of the model is to chronically cannulate the animals so that they can be allowed to recover [28]. This model should avoid any effects from the anesthetic on the absorption process. 

Carilli, J. A. Lewicki, J. D. Baxter, and M. N. James, Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution, Science 243 1346 (1989). 

Walter E, Kissel T (1995) Transport of peptidomimetic renin inhibitors across monolayers of a human intestinal cell line (Caco-2) Evidence for self-enhancement of paracellular transport route. J Pharm Sci 3 215-230. 

Matsui T, Hayashi A, Tamaya K, Matsumoto K, Kawasaki T, Murakami K, Kimoto K. (2003) Depressor effect induced by dipeptide, Val-Tyr, in hypertensive transgenic mice is due, in part, to the suppression of human circnlating renin-angiotensin system. Clin Exp Pharmacol Physiol 30 262-265. 

In connection with the synthesis of cytohalasin B, a pyrrole derivative 13 was prepared from methyl (5)-3-aminophenylbutyrate (78JA7775). In connection with the synthesis of l,2,4-triazolo[4,3-a]pyrazine derivatives with human Renin inhibitor activity, a /3,y-diamino acid derivative was transformed into a pyrrolidin-2-one (91JMC151). 

Lapteva, N., Nieda, M., Ando, Y., Ide, K., Hatta-Ohashi, Y., Dymshits, G., Ishikawa, Y., Juji, T., and Tokunaga, K., Expression of renin-angiotensin system genes in immature and mature dendritic cells identified using human cDNA microarray, Biochem. Biophys. Res. Commun., 285, 1059-1065, 2001. 

Compound No. Structure IC50 (M), Human Plasma Renin... 

Angiotensin II, the primary end product of the renin-angiotensin system, acts on the juxtaglomerular cells to inhibit the release of renin this process is therefore a negative feedback mechanism. The half-life of renin in the circulation is 10 to 30 minutes, with inactivation occurring primarily in the liver. Small amounts of renin are eliminated by the kidneys. Pure human renin... 

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