Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the brain contains cathepsins at high concentrations which exhibit a non-specific renin-like activity at acidic pH, the presence of specific renin in the brain has been demonstrated by characterizing its specific properties. Renin was separated from cathepsin by affinity chromatography on casein-Sepharose. Brain renin showed neutral pH optima for the reaction to generate angiotensin I. The presence of inactive prorenin was also found. The isoelectric points of brain renin were significantly lower differences from that of renal or plasma renin. Immunohistochemical studies demonstrated a wide-spread localization of renin in many different regions. Angiotensin II, the final product of the prohormone-to-hormone conversion reaction mediated by renin and angiotensin converting enzyme, was found to exist in the same cell as renin by immunohistochemical studies of brain sections and with cloned and cultured neuroblastoma cells. This is the first demonstration of the mechanism of peptide hormone formation in neuronal cells. Similar intracellular formation was demonstrated in gonadotrophs of adenohypophysis. Coexistence of renin and angiotensin II was demonstrated in some cells. Electrophysiological studies have shown that angiotensin II functions to disinhibit the inhibition of neuronal response to electrical stimuli in the hippocampus.
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PMID:Brain renin. 704 40

Studies were performed to quantitate the effects of progressive increases in renal venous pressure (RVP) on renin secretion (RS) and renal hemodynamics. RVP was raised in 10 mmHg increments to 50 mmHg. Renin secretion rate increased modestly as RVP was increased to 30 mmHg and then increased sharply after RVP exceeded 30 mmHg. Glomerular filtration rate (GFR), renal blood flow (RBF), and filtration fraction (FF) did not change significantly when RVP was elevated to 50 mmHg. GFR and RBF were also measured after the renin-angiotension system (RAS) was blocked with the angiotensin converting enzyme inhibitor (CEI) SQ 14225. After a 60-min CEI infusion, RBF was elevated (32%), GFR was unchanged, FF was decreased, and total renal resistance (TRR) was decreased. As RVP was increased to 50 mmHg, GFR and FF decreased to 36.3 and 40.0% of control, respectively, RBF returned to a value not significantly different from control, and TRR decreased to 44.8% of control. The data indicate that the RAS plays an important role in preventing reductions in GFR during increased RVP because blockade of angiotensin II (ANG II) formation by the CEI results in marked decreases in GFR at high RVPs. The decreases in GFR after ANG II blockade and RVP elevation were not due to lack of renal vasodilation, since TRR was maintained below while RBF was maintained either above or at the pre-CEI levels.
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PMID:Renal hemodynamic responses to increased renal venous pressure: role of angiotensin II. 705 57

The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacokinetics and efficacy of renin inhibitors. 758 99

The components of the Renin-Angiotensin System (RAS) have been found to be expressed in the brain. Angiotensinogen, the high molecular weight precursor of the system, is widely distributed and expressed in areas not related to control of blood pressure and body fluid homeostasis as well. It has been shown that it is regulated by steroid hormones independently from the liver and that it is also regulated in a different manner in several brain areas. Angiotensin II, the effector peptide of the system, may be generated in the brain via the classical pathway, using renin and angiotensin converting enzyme or directly from angiotensinogen by cathepsin G or tonin. N-terminal peptides of angiotensin II have been found in several brain areas with ANG (1-7) involved in vasopressin release however without influence on blood pressure and with ANG III acting as potent as ANG II. Transgenic animals may be used to study the pathophysiology of an activated brain RAS.
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PMID:The brain renin-angiotensin system: molecular mechanisms of cell to cell interactions. 773 73

The analysis of currently used therapeutic targets provides considerable input in the choice of current and future therapies for dilated cardiomyopathy and congestive heart failure. Of the ion flux agents, a definitive answer concerning digoxin will soon be available. Currently, digoxin is likely of benefit to patients with persistent heart failure and significantly enlarged hearts despite therapy with preload and afterload reducing agents. Most currently available calcium channel blocking agents do not appear to be effective, although newer agents such as amlodipine and felodipine have yet to be adequately tested. Vesnarinone, which operates through the sodium and potassium rectifying channels and has limited phosphodiesterase inhibition, appears to provide a significant improvement in mortality and in symptoms. Part of the latter effect may be due to its anticytokine properties, which are currently being investigated. Analysis of vascular endothelial agents indicate that not all of the vasoactive agents improve survival, as demonstrated with prazosin and flosequinan. The dose of agents may be important, again demonstrating that less is better. Finally, those with additional effects, such as inositol triphosphate stimulation, may offer additional unique properties that may, in the future, provide benefit. Phosphodiesterase inhibitors are potentially beneficial in the short term but clearly should be avoided for long-term use. Lower doses of these agents are now being investigated, but the weight of evidence is against agents that operate primarily through phosphodiesterase inhibition. Renin angiotensin agents are the most efficacious of therapies available at this time. New angiotensin converting enzyme inhibitors are likely to add little to what is already known.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New medical therapies for advanced left ventricular dysfunction. 779 29

Renin-like activity (RLA) and angiotensin I-converting enzyme-like activity (ACELA), two key enzymes of the renin-angiotensin cascade (RAS), were sought in the dogfish rectal gland. RLA was 1.1 +/- 0.2 ng Ang I/mg protein/hr after incubation with porcine angiotensinogen and 0.8 +/- 0.1 ng Ang I/mg protein/hr after incubation with homologous plasma. ACELA was 7.22 +/- 1.08 and 8.87 +/- 1.9 nmol hippurate generated/min/mg protein respectively, at 0 and 37 degrees. The presence of these enzymes may indicate the presence of an endogenous RAS-like system in the rectal gland. Angiotensin II (Ang II) and atrial natriuretic peptide (ANP) binding sites were demonstrated autoradiographically in the subcapsular region of the gland, suggesting a possible interaction of the two hormones in the blind outer ends of the rectal gland tubules. Immunoreactivities toward Ang II, ANP, bombesin, vasoactive intestinal polypeptide (VIP), glucagon, and somatostatin were differentially localized in the rectal gland within three concentric zones with potentially different functional activities. In the capsule, there was a strong positive ir-glucagon reaction and a slightly weaker reaction for ir-somatostatin and VIP. In the blind outer ends of the tubules (in the subcapsular zone), strong immunoreactivity was present toward all the tested peptides except glucagon and somatostatin. In the inner zone and in the central canal, only a weak immunoreactivity toward Ang II and glucagon was observed.
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PMID:Renin-like activity, angiotensin I-converting enzyme-like activity, and osmoregulatory peptides in the dogfish rectal gland. 790 83

Although angiotensin converting enzyme inhibitor therapy is an established approach in the treatment of chronic heart failure, the required dosage remains unclear. This open 6 month study investigated the influence of different captopril dosages on the clinical course and neurohumoral activity of patients with severe heart failure (left ventricular ejection fraction < or = 20%). Eighty-five patients in New York Heart Association class II-IV despite treatment with digitalis, diuretics, and captopril (mean dose +/- SEM 28 +/- 2 mg.day-1 at baseline) for > or = 3 months received either 'low dose' captopril (< 75 mg.day-1, mean 32 +/- 2 mg.day-1; n = 46) or 'high dose' captopril (> or = 75 mg.day-1, mean 99 +/- 4 mg.day-1; n = 39) during the follow-up period. Both groups were comparable in clinical, haemodynamic and neurohumoral parameters at baseline. Functional state improved significantly only in the high dose group (P < 0.0001). Of 31 low dose and 20 high dose patients considered as heart transplantation candidates at baseline, 21 low dose and only six high dose patients remained on the waiting list (P < 0.0001). In patients in the low dose group, eight deaths were observed (P < 0.001). Seven patients remained on low dose captopril due to adverse effects. The initially elevated plasma levels of aldosterone and atrial natriuretic peptide decreased significantly only in high dose patients (P < 0.01). Renin increased significantly in both groups. These observations underline the necessity of suppressing neurohumoral overactivation with adequate doses of captopril reflected by sequential humoral plasma determination.
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PMID:Clinical and neurohumoral response of patients with severe congestive heart failure treated with two different captopril dosages. 844 5

The purpose of this study was to delineate the effects of prolonged (1 and 5 wk) unilateral ureteral obstruction (UUO) on the intrarenal renin-angiotensin and kallikrein-kinin systems in the rat. Systolic blood pressure (SBP) and plasma angiotensin (ANG) II levels were significantly higher at 1 and 5 wk of obstruction than in sham-operated groups. Also, plasma renin activity and ANG I levels were elevated at 1 wk (P < 0.05), and plasma angiotensin-converting enzyme (ACE)-kininase II activity was elevated at 5 wk (P < 0.05). Blockade of ANG II receptors with losartan (Dup 753) prevented the rise in SBP after UUO and normalized SBP in chronically hypertensive UUO rats. Renin mRNA levels and ANG II content were elevated in the obstructed kidneys at 1 and 5 wk compared with sham-operated kidneys (P < 0.05). ACE-kininase II activity was elevated in both the obstructed and contralateral kidneys at 5 wk compared with sham-operated kidneys (P < 0.05). In marked contrast to renin, total immunoreactive kallikrein contents and tissue kallikrein mRNA levels in the obstructed kidneys were reduced to 25% of sham-operated kidneys both at 1 and 5 wk (P < 0.001). The results indicate that urinary obstruction activates renin and suppresses kallikrein gene expression. Activation of ACE-kininase II by UUO also serves to enhance intrarenal ANG II generation and kinin degradation. The results implicate ANG II overproduction and kinin deficiency in the pathogenesis of UUO-induced hypertension and intrarenal vasoconstriction.
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PMID:Upregulation of renin-angiotensin system and downregulation of kallikrein in obstructive nephropathy. 849 41

1. Renin mRNA is expressed in several extrarenal tissues, including brain. The aim of the present study was to quantify renin mRNA in the hypothalamus in response to a low NaCl diet and angiotensin converting enzyme inhibitor treatment, both of which are well-known stimuli of renin mRNA in kidney. 2. Groups of six Sprague-Dawley rats were given either a normal diet, low NaCl chow (0.04% NaCl), enalapril (0.25 mg/mL in drinking water), or low NaCl + enalapril, for 7 days. Renin mRNA in the hypothalamus was quantified by a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) technique. 3. Renin mRNA concentration in the hypothalamus of rats receiving a normal diet was 52 +/- 3 S.E. fg/microgram total RNA. Low NaCl had no effect (57 +/- 7), whereas values were significantly lower in rats treated with enalapril, either given alone (38 +/- 2; P = 0.002) or combined with a low NaCl diet (33 +/- 4; P = 0.003). 4. In conclusion, we have quantified renin mRNA in the rat hypothalamus and shown that it can be suppressed significantly by enalapril. This response is opposite to that seen in the kidney after enalapril.
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PMID:Renin mRNA concentration in rat hypothalamus is decreased by enalapril. 858 14

Growing evidence points to the existence of the components of the kallikrein-kinin-system (KKS) in cardiac and vascular tissue forming systemic and local KKS pathways involving different cell types like endothelial cells, cardiomyocytes and vascular smooth muscle cells. Kinins may contribute to the regulation of the cardiovascular system in health and disease and to the pharmacological effects of cardiovascular agents via autocrine-paracrine mechanisms. Based on observations from experimental models of hypertension, hypertrophy, ischemia, remodelling and preconditioning one can assume that modulation of local KKS pathways is instrumental for endogenous cardio- and vasculoprotective mechanisms. The role of kinins as possible mediators of such protective mechanisms is not only based on the existence of their generating pathways and their release, but also on observations that kinins, when given locally or being increased by inhibition of their breakdown, exert beneficial cardiovascular effects, whereas antagonism of their receptors worsens these effects. Indispensable pharmacological tools like ACE inhibitors and kinin receptor antagonists have helped to clarify these assumptions, which are now further elucidated by molecular biology and by clinical research. Especially the wealth of experimental and clinical findings with ACE inhibitors present a continuous challenge to investigate the role of kinins in the cardiovascular system and to have a closer look at the interdependence of KKS and the Renin-Angiotensin-System (RAS). Within our decade one might not only reach a clearer molecular perception of kinins in the cardiovascular system, and their role in human health and disease, but might also come to improved innovative treatment by modulation of the KKS pathways.
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PMID:Kinins in the cardiovascular system. 885 52


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