Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The brain is one of the organs where an intrinsic renin-angiotensin system (RAS) has been described. Stimulation of circumventricular or brainstem angiotensin II (Ang II) receptors engenders a distinct pattern of cardiovascular, endocrine, and behavioral responses featuring blood pressure increase, attenuation of the baroreceptor reflex, drinking, release of pituitary hormones such as vasopressin, oxytocin, and ACTH, and natriuresis. In contrast to most of the other central actions of Ang II, the natriuretic effect cannot be elicited by Ang II as a circulating hormone. Recently, we have shown that stimulation of Ang II AT-1 receptors in the circumventricular organs causes a selective release of norepinephrine (NE) in the paraventricular nucleus (PVN) and in the supraoptic nucleus (SON). As vasopressin is also released from the PVN and SON, it is possible that the Ang II-NE interaction is involved in the release of vasopressin, thereby contributing to central blood pressure regulation and volume control. Finally, a substantial body of results suggests that an overactivity of the brain renin-angiotensin system is one of the contributors to genetic hypertension. However, this idea needs further confirmation.
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PMID:Role of brain angiotensin in cardiovascular regulation. 138 68

Cardiac myocytes (AT-1 cells) derived from heart tumors of mice transgenic for an atrial natriuretic factor promoter, SV40 large T-antigen DNA transgene, demonstrate properties consistent with normal cardiac myocytes but retain the capacity to proliferate in culture. We studied the renin-angiotensin system (RAS) and related growth regulation of these cells because AT-1 cells (or transgenically similar cells) may be useful to repair injured myocardium. This study reveals two separate and distinct findings: 1) AT-1 cells proliferate or hypertrophy in response to angiotensin II (ANG II), depending on their competence to proceed through the cell cycle; and 2) AT-1 cells possess components of a RAS, and angiotensinogen antisense experiments suggest that the RAS is functional in these cells. Specifically, AT-1 cells proliferate in response to ANG II in low-serum medium but hypertrophy in response to ANG II when first treated with mitomycin C (at a concentration that inhibits DNA replication but is not cytotoxic). The ANG II-mediated proliferative and hypertrophic responses are inhibited by DuP 753. In addition, there is a significant increase in the protein-to-DNA ratio of cells, which are proliferation-inhibited in the absence of ANG II treatment (20%, P < 0.05). DuP 753 also inhibits this hypertrophy, suggesting that these cells possess a functional RAS. AT-1 cells contain mRNAs for angiotensin-converting enzyme, renin, angiotensinogen, and the AT1 receptor as determined by sequence analysis of polymerase chain reaction amplification products. Antisense oligonucleotides complementary to the angiotensinogen mRNA specifically inhibit angiotensinogen mRNA accumulation and proliferation of AT-1 cells. In summary, these cells contain a growth-regulating RAS, suggesting that such a system may play a significant role in left ventricular hypertrophy.
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PMID:Identification and antisense inhibition of a renin-angiotensin system in transgenic cardiomyocytes. 773 48

The AT-1 receptor antagonist, losartan potassium, produced a large rise in plasma renin activity (PRA) after peripheral, but not intracerebroventricular (ICV), administration. Peripheral, but not ICV administration of losartan also augmented the release of renin induced by peripheral administration of the beta-adrenergic agonist, isoproterenol. The increase in PRA induced by losartan plus isoproterenol was greater than the sum of the increases in PRA induced by the individual treatments. There was, however, no significant enhancement of the hypotensive action of isoproterenol by peripherally administered losartan. The AT-2 receptor antagonist, PD 123319, produced no increase in PRA after either peripheral or ICV injection. However, peripheral injection of PD 123319 slightly increased PRA after peripheral administration of isoproterenol. The data are discussed in terms of the relationship between renin-angiotensin systems and fluid intake, with special reference to the failure of peripherally administered losartan to block isoproterenol-induced water intake.
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PMID:Effect of nonpeptide angiotensin AT-1 and AT-2 antagonists on isoproterenol-induced renin release. 845 Dec 66

Recent studies have provided evidence of angiotensin converting enzyme (ACE)-independent angiotensin (Ang) II formation in tissue renin-angiotensin systems. We studied the effects of Ang II generated by ACE-independent pathways on renal hemodynamics. We used a synthetic peptide, [Pro11, D-Ala12]-Ang I (S), which yields Ang II by chymase, but not by ACE. Infusion of Ang I into a renal artery caused a decrease in renal blood flow, and reciprocally an increase in mean arterial pressure. Infusion of S (1 nmol/kg) caused a decrease in renal blood flow (-20%), but a larger dose was needed to increase mean arterial pressure. Studies with an intravital needle-probe CCD camera revealed that the Ang I infusion induced dose-dependent vasoconstriction of afferent and efferent arterioles (49% and 54%, respectively at 1 nmol/kg). In contrast, infusion of S elicited only 30% constriction of these vessels at a dose of 1 nmol/kg and induced no further constriction at higher doses, indicating that different segments of renal vessels responded in different fashions to Ang II formed via ACE-independent pathways. These vasoconstrictions were abolished by an angiotensin II receptor (AT-1) antagonist. Enzymatic assays using reverse-phase HPLC revealed that the ACE-dependent pathway was predominant in the rena1 cortex (approximately 80%). We also determined Ang II concentrations in renal cortex specimens obtained by needle biopsy. Intrarenal S infusion (10 nmol/kg) increased plasma and renal Ang II concentrations to 160% and 710% of the respective baseline levels. This study provides in vivo evidence of ACE-independent Ang II formation in renal tissue and suggests that this locally-formed Ang II influences the renal circulation in a paracrine fashion.
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PMID:Role of angiotensin II generated by angiotensin converting enzyme-independent pathways in canine kidney. 940 41

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.
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PMID:Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. 940 67

The central roles of nitric oxide (NO) in regulations of the blood pressure and heart rate were examined in anesthetized rats. Intracerebroventricular (i.c.v.) injection of Nomega-nitro-L-arginine methyl ester (L-NAME) caused dose-dependent increase in the blood pressure and heart rate. The pressor response of the blood pressure to L-NAME (2 micromol, i.c.v.) was reduced by L-arginine (5 micromol, i.c.v). Pretreatment with a ganglionic blocker, pentolinium (10 mg/kg, i.v.), significantly inhibited both pressor responses induced by L-NAME (2 micromol, i.c.v). The later pressor response of the blood pressure to L-NAME was also inhibited by the angiotensin II AT-1 blocker losartan (10 mg/kg, i.v). These results suggest that the response of the blood pressure to L-NAME is mediated by both the sympathetic nervous system and the renin-angiotensin system.
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PMID:Central administration of a nitric oxide synthase inhibitor causes pressor responses via the sympathetic nervous system and the renin-angiotensin system in Wistar rats. 960 97

We tested the hypothesis that the tissue-specific intrarenal renin-angiotensin system (RAS) can participate in the regulation of blood pressure independently of its endocrine counterpart, by generating two transgenic models that differ in their tissue-specific expression of human angiotensinogen (AGT). Human AGT expression was driven by its endogenous promoter in the systemic model and by the kidney androgen-regulated protein promoter in the kidney-specific model. Using molecular, biochemical, and physiological measurements, we demonstrate that human AGT mRNA and protein are restricted to the kidney in the kidney-specific model. Plasma ANG II was elevated in the systemic model but not in the kidney-specific model. Nevertheless, blood pressure was markedly elevated in both the systemic and kidney-specific transgenic mice. Acute administration of the selective ANG II AT-1 receptor antagonist losartan lowered blood pressure in the systemic model but not in the kidney-specific model. These results provide evidence for the potential importance of the intrarenal RAS in blood pressure regulation by showing that expression of AGT specifically in the kidney leads to chronic hypertension independently of the endocrine RAS.
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PMID:Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice. 1101 55

Chronic metabolic acidosis (CMA) in human beings is characterized by increased renin-angiotensin-aldosterone (RAA) activity and cortisol secretion as well as nitrogen wasting. The purpose of this study was to examine whether and to what extent increased RAA activity (i.e., angiotensin II or aldosterone) regulates acid-base equilibrium in CMA and thus might co-determine the severity of acidosis. CMA was induced in 8 normal subjects by oral NH4Cl administration (2.1 mmol/kg body weight per day) for 7 days, followed by a 7-day period of spironolactone (100 mg, 4 times a day by mouth), followed by a 4-day period of spironolactone and losartan (100 mg, every day by mouth). NH4Cl feeding was continued during all study periods. Spironolactone resulted in exacerbation of acidosis ((HCO3)p decreased from 19.8+/-0.4 mmol/L to 17.7+/-0.6 mmol/L, P<.005) because of a large increase in endogenous acid production, as evidenced by significant increases in net acid excretion (116 to 185 mmol/day, P<.005), urinary anion gap (+31 mEq/day, P<.05), and sulfate excretion (+32 mEq/day, P<.05). Plasma potassium increased from 4.2 to 4.6 mmol/L (P<.05) because of decreased urinary potassium excretion (from 108 to 92 mmol/day, P<.05). Plasma angiotensin II, cortisol, aldosterone, urinary aldosterone, urinary tetrahydrocortisol, free cortisol, and nitrogen excretion increased significantly. The subsequent addition of losartan to spironolactone administration resulted in further exacerbation of acidosis ((HCO3)p decreased to 15.7+/-0.4 mmol/L, P<.05) and hyperkalemia (5.0 mmol/L, P<.05) with no change in plasma anion gap. Renal potassium excretion decreased from 92 to 73 mmol/day (P<.05) on day 1. Exacerbation of acidosis was accounted for by a renal mechanism, as evidenced by the significant decrease in net acid excretion and unchanged urinary unmeasured anion and nitrogen excretion. We conclude the following: (1) AT-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect. Angiotensin II is an important modulator of the renal acid excretory response to CMA in human beings. (2) Inhibition of aldosterone action by spironolactone in CMA results in an increase in endogenous acid production and exacerbates acidosis by a non-renal mechanism that is mediated, at least in part, by exacerbated hyperglucocorticoidism.
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PMID:Acid-base and endocrine effects of aldosterone and angiotensin II inhibition in metabolic acidosis in human patients. 1107 65

Insulin resistance and hyperinsulinaemia are presumed to participate in the pathogenesis of essential hypertension (EH). Insulin resistance is characterised by an impaired insulin-mediated glucose uptake. Participation of the renin-angiotensin system in the development of hyperinsulinaemia in EH patients has not been unanimously proven. The present study aimed to asses the influence of antihypertensive therapy with angiotensin converting enzyme inhibitor (ACEI, enalapril = 10 mg/day) (9 male patients) or angiotensin II AT-1 receptor blocker (A II RB = losartan 50 mg/day) (9 male patients) respectively on insulin sensitivity in patients with EH. 3-hours euglycaemic clamp test with constant infusion of insulin (50 mU/m2/min) was performed twice: before and after 8 weeks of therapy with ACEI or A II RB respectively. The control group (CG) consisted of 12 healthy males (clamp test was performed once). Serum insulin concentration (I) was estimated by radioimmunoassay. Glucose disposal rate (M-value = mg/kg/min) and tissue insulin sensitivity (M/I value = mg/kg/min per mU/l) were calculated in subjects of the CG and in patients with EH before and after antihypertensive therapy with ACEI or A II RB, respectively. In CG the M-value (7.38 +/- 0.13) and tissue insulin sensitivity (M/I = = 6.76 +/- 0.19) were significantly higher than in EH before treatment with ACEI (M-value = 5.44 +/- 0.16; M/I = = 4.57 +/- 0.18) or A II RB (M-value = 5.75 +/- 0.21; M/I = 4.77 +/- 0.31), respectively. ACEI therapy was followed by a significant increase of both M (6.82 +/- 0.25) and M/I (5.68 +/- 0.25) values. In contrast to ACEI, treatment with A II RB did not influence neither M (5.75 +/- 0.21) nor M/I (4.79 +/- 0.21) values respectively. In contrast to A II RB, ACEI shows a beneficial effect on insulin sensitivity in EH patients. This effect does not seem to be mediated by an influence on the AT-1 receptor.
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PMID:[The effect of treatment with enalapril versus losartan on levels of insulin resistance in patients with essential hypertension]. 1123 38

In the effort to explain gender-related differences of the cardiovascular system, the renin-angiotensin system experienced intensive exploration. Indeed, the development of hypertension as well as the progression of coronary artery disease and heart failure have two factors in common: (1) display distinct gender specific characteristics and (2) are enhanced by the renin-angiotensin system. It is therefore interesting to note that data from experimental animals, epidemiological surveys, and clinical investigations suggest that the components of the circulating as well as tissue-based renin-angiotensin system are markedly affected by gender. However, the issue is complicated by counter-regulatory effects of estrogen on the system with the substrate, on one hand, and the processing enzymes as well as the chief receptor, on the other hand. In fact, angiotensinogen is up-regulated particularly by oral administration of estrogen, whereas renin, angiotensin-converting enzyme (ACE), and AT-1 receptor are down-regulated by the hormone. While under well-defined experimental conditions the net effect of estrogen appears to result in suppression of the renin-angiotensin system, the clinical situation may be more complex. The judgment is further complicated by the difficulty in precisely measuring the activity of the system at the tissue level. Moreover, clinically relevant read-outs for the activity of the renin-angiotensin system may be regulated multifactorially or only indirectly affected by the system. Nevertheless, the undisputable, profound biochemical changes in the renin-angiotensin system related to the estrogen status allow speculation that such interaction explains some of the differences in the cardiovascular system of men and women.
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PMID:Renin angiotensin system and gender differences in the cardiovascular system. 1186 Oct 38


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