Renin

Renin o carries out the first, rate-determining step in the renin-angiotensin cascade, and angiotensinogen is its only known substrate. It has been reasoned that this specificity may provide an opportunity for therapeutic intervention with few undesirable side effects. 

Having designed a (3-strand peptidomimetic using 3,5,5-linked pyrrolin-4-one units, 7 Smith et al. at the University of Pennsylvania and Merck 

The activities of renin in plasma and serum are measured in the diagnosis of hypertension. The natural substrate for renin is angiotensin. Several synthetic peptides have been used in renin assays. Recently, Nakamura-lmajo et al. (1992) used N-(2-pyridyl)glycine (pg) as a fluorescent tag on a nonapeptide. 

The assay was conducted by adding 10 / L of serum or plasma to 100 tiL containing 500 fiM substrate in 100 mM Mops-NaOH (pH 7.0), 1 mM phenylmethylsulfonyl fluoride, and 3 mM o-phenanthroline. The reaction mixture was incubated at 37°C for an hour, and then 60 fih was directly injected into the column. 

The assay is suitable for assaying enzyme in serum and plasma, and also recombinant human prorenin expressed in Chinese hamster ovary cells. Prorenin was activated by trypsin digestion. 

3 Structure-Based Design From Renin to HIV-1 Protease 

The crystal structures of aspartic proteases helped elucidate the meehanism of action for this family of enzymes. For example, in the crystal structure of native endothiapepsin, a water 

The residue side chains occupy subsites on alternate sides of the backbone, designated according to the nomenclature introduced by Schechter and Berger (PI, PI. .., SI, SI ) [19]. These experimental observations guided the design of inhibitor structures tailored to mimic 

There is no generally accepted Renin Unit. Schales and Haynes (155) defined one rabbit unit of renin (R.U.) as the amount of renin (expressed as micrograms of nitrogen) that was required per kilogram of body weight to cause a ri.se in blood pressure of 30 mm. Hg when injected intravenously into a lult rabbits. For the assay, at least four unanestketizcd animals were used and the blood pressure was measured in the artery of the ear by a membrane manometer (56). The extracts were injected intravenously in the right ear, which had been previously denervated, to prevent any effect on the blood pressure from introduction of the needle. 

It is important to inject such amounts of renin as will cause a rise in blood pressure between 20 and 40 mm. Hg as the response in this range is approximately proportional to the amount of renin given. It can be seen from the dose-response curve by Pickering and Prinzmetal (134) that this linearity is not present in the range above 40 mm. 

With increasing purity of an extract the amount of nitrogen associated with one ]R.U. will decrease as less inert proteins are present the rabbit ear method offers there- 

Effect of Human Renin on Humans, Dogs, and Rabbits (157) 

Effect on Mg. N/unit Units/kg. kidney Gram kidney for 1 unit 

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ANPs play an important role in the maintenance of cardiovascular homeostasis by counterbalancing the renin—angiotensin (RAS) system. ANP, the main circulating form of the natriuretic peptides, effectively relaxes vascular smooth muscle, promotes the excretion of sodium and water, and in the CNS inhibits vasopressin release and antagonizes AT-II induced thirst. 

Kidney Function. Prostanoids influence a variety of kidney functions including renal blood flow, secretion of renin, glomerular filtration rate, and salt and water excretion. They do not have a critical role in modulating normal kidney function but play an important role when the kidney is under stress. Eor example, PGE2 and -I2 are renal vasodilators (70,71) and both are released as a result of various vasoconstrictor stimuli. They thus counterbalance the vasoconstrictor effects of the stimulus and prevent renal ischemia. The renal side effects of NSAIDS are primarily observed when normal kidney function is compromised. 

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

In animal models, renin inhibitors after iv adrninistration have been shown to be equally efficacious as compared to ACE inhibitors in lowering blood pressure, and to have similar effects on the cardiovascular and renal parameters. Some of the renin inhibitors tested are enalkiren (A-64662), CGP 38 560A, CP 71362, KRI-1230, U-71039, ES6864, and PD-134672. The stmctures of enalkiren and the formula for PD-134672 are shown in Figure 4. 

Glonidine. Clonidine decreases blood pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance. It activates central a2 adrenoceptors ia the brainstem vasomotor center and produces a prolonged hypotensive response. Clonidine, most efficaciously used concomitantly with a diuretic in long-term treatment, decreases renin and aldosterone secretion. 

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 addition to being involved in the formation of urine, the kidney acts as an endocrine organ secreting renin, erythropoietin, prostaglandins (qv), and kinins it is also capable of synthesizing substances such as la,25-dihydroxycholecalciferol [32222-06-3] One of the principal functions of the... 

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). 

In an attempt to conserve sodium, the kidney secretes renin increased plasma renin activity increases the release of aldosterone, which regulates the absorption of potassium and leads to kafluresis and hypokalemia. Hypokalemia is responsible in part for decreased glucose intolerance (82). Hyponatremia, postural hypotension, and pre-renal azotemia are considered of tittle consequence. Hypemricemia and hypercalcemia are not unusual, but are not considered harmful. However, hypokalemia, progressive decreased glucose tolerance, and increased semm cholesterol [57-88-5] levels are considered... 

Mammals, fungi, and higher plants produce a family of proteolytic enzymes known as aspartic proteases. These enzymes are active at acidic (or sometimes neutral) pH, and each possesses two aspartic acid residues at the active site. Aspartic proteases carry out a variety of functions (Table 16.3), including digestion pepsin and ehymosin), lysosomal protein degradation eathepsin D and E), and regulation of blood pressure renin is an aspartic protease involved in the production of an otensin, a hormone that stimulates smooth muscle contraction and reduces excretion of salts and fluid). The aspartic proteases display a variety of substrate specificities, but normally they are most active in the cleavage of peptide bonds between two hydrophobic amino acid residues. The preferred substrates of pepsin, for example, contain aromatic residues on both sides of the peptide bond to be cleaved. 

Renin Kidney Conversion of angiotensinogen to angiotensin I regulation of blood pressure... 

In some patients with hypertension and in all patients with cardiac failure, the renin-angiotensin system is activated to an undesired degree, burdening the heart. The consequences of diminished ANG II generation by ACE inhibitors are multiple. In patients with hypertension, blood pressure is reduced as a result... 

Blood Pressure Control Renin-Angiotensin-Aldosteron System... 

Bader M, Paul M, Fernandesz-Alfonso M et al (1994) Molecular biology and biochemistry of the renin-angiotensin system, Chap. 11. In Swales ID (ed) Textbook of hypertension. Blackwell Scientific Publications, Oxford, London, Edinburgh, pp 214-232... 

Bader M, Peters J, Baltatu O et al (2001)Tissue renin-angiotensin systems new insights from experimental animal models in hypertension research. J Mol Med 79 76-102... 

Renin-Angiotensin-Aldosterone System ACE Inhibitors Nuclear Factor-icB... 

By themselves, potassium-sparing agents are relatively weak antihypertensives. In general, there are four ways to reduce the activity of the RAS. The first way is the use of p-blockers to reduce renin release from the juxtaglomerular (JG). The second way, the direct inhibition of the activity of renin, although being actively investigated has not been successful in the clinical arena thus far. The third way is to inhibit the activity of the... 

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