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)

1. The effect of high-dose adenosine administration on atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) release is not completely understood, and data concerning the effect of adenosine on renal and systemic hemodynamics in the pig are lacking. Measurements of central hemodynamics, renal blood flow and urine production were made in anesthetized pigs during infusion of adenosine. The relationship between these parameters and the plasma concentrations of ANP, ADH and renal renin production was examined. 2. Adenosine infusion at the rate of 140 mg/kg per minute resulted in a significant decrease in systolic, diastolic and mean arterial blood pressure as well as pulmonary arterial pressure. However, cardiac output and renal blood flow remained unchanged during adenosine infusion. Likewise, heart rate remained unchanged until the end of infusion when it increased significantly, Plasma ANP and ADH concentrations increased significantly within 30 min after adenosine infusion, reaching peak levels at 30 to 60 min. However, despite the significant decrease in arterial blood pressure, renal renin production did not change significantly. 3. The adenosine-induced rise in ANP, which is normally released by atrial stretch, may represent a direct effect of adenosine on the cardiac myocytes. The increase in ADH may be a result of decreased arterial blood pressure triggering stimulatory signals from the aortic arch and carotid body receptors to hypothalamic-pituitary sites of ADH production/release. Urine flow decreased dramatically within 30 min of adenosine infusion. Thus adenosine infusion at the given rate led to marked reduction in systemic and pulmonary arterial pressures without significant change in cardiac output, heart rate and renal blood flow. This was associated with a marked increase in plasma ANP and ADH levels with no significant change in renal renin production despite a marked reduction in arterial blood pressure. 4. Maintenance of renal blood flow despite marked reduction in perfusion pressure suggests that, at high doses, adenosine induces renal vasodilation in pigs as opposed to a combined afferent and efferent vasoconstriction known to occur under different experimental conditions.
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PMID:Effects of adenosine infusion on renal function, plasma ANP and ADH concentrations and central hemodynamics in anesthetized pigs. 906 86

During the past 16 years numerous studies have shown that adenosine is present in the normoxic kidney and accumulates when ATP hydrolysis prevails over ATP synthesis. Adenosine can induce renal vasoconstriction and a fall in glomerular filtration rate (GFR). The tubuloglomerular feed-back (TGF) mechanism refers to a series of events whereby changes in the NaCl concentration in the tubular fluid at the end of the thick ascending limb of Henle's loop are sensed by the macula densa which then elicits a twofold response in the juxtaglomerular apparatus: a change in the afferent arteriolar tone and GFR and an alteration in renin secretion from granular cells. While an increase in late proximal tubular flow rate, which increases the NaCl concentration and probably transport across the macula densa, lowers GFR and renin secretion, a low NaCl concentration at the macula densa elicits the opposite effects. One important role of the TGF response is to keep the fluid and electrolyte delivery to the distal tubule within certain limits, so that this part of the nephron can accomplish the fine adjustments in reabsorption to meet body needs. In this regard the TGF mechanism serves to establish an appropriate balance between nephron filtration rate and reabsorption in the proximal tubule and loop of Henle. Among several factors, adenosine is considered to be a potential candidate for mediating the TGF response from macula densa to extraglomerular mesangial cells, afferent arteriole, and granular cells. The TGF-mediated vasoconstriction and reduction in renin release following an elevation of the NaCl concentration at the macula densa can be blocked by theophylline and other adenosine-A1-receptor-specific antagonists. Furthermore, the TGF is potentiated by substances that can elevate extracellular adenosine concentrations such as dipyridamole. These and other findings support the concept that adenosine as a metabolic mediator may couple energy metabolism (ATP hydrolysis for tubular Na+ transport) with the control of renin secretion and GFR.
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PMID:Adenosine and tubuloglomerular feedback. 943 52

Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.
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PMID:Adenosine and cardioprotection in the diseased heart. 1047 69

Renin, as the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II, has been studied for more than 100 years. Transgenic and knockout mice for renin and other proteins involved in renin regulation and function have recently revealed new evidence that can improve our understanding of its biological relevance. Furthermore, transgenic mice have been the source of the novel cell line As4.1. This cell line has been effective in the analysis of renin secretion and regulation because of its similarity with renin-producing juxtaglomerular (JG) cells. Renin secretion and synthesis by the JG cells of the kidney is upregulated by cAMP and downregulated by intracellular calcium. The effect of cGMP, once elevated by nitric oxide, depends on the present level of cAMP in the cells, which can be stimulatory in the presence of and inhibitory in the absence of the other cyclic nucleotides. All known effectors of renin regulation affect one of these molecules. Adenosine and ATP, released by macula densa cells in response to high salt load in the distal tubule and stretch of the JG cell by renal perfusion pressure, increase calcium. Furthermore, noradrenaline, derived from sympathetic nerve endings, and prostaglandins, generated by macula densa cells under low-salt conditions, increase cAMP. In addition to its stimulatory effect on secretion, cAMP also effectively augments renin mRNA levels by acting at the transcriptional and posttranscriptional levels. Several DNA elements in the distal and proximal promoter regions as well as in intron I have been implicated in cAMP regulation and in tissue specificity of renin gene expression. A second intracellular renin isoform, coded by the same gene but applying a different promoter located in intron I, has recently been detected. Transgenic technology will help to clarify the function of this isoform as well as some of the other unresolved aspects of renin regulation and function and may become the motor of the second century in renin research.
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PMID:Regulation of renin: new evidence from cultured cells and genetically modified mice. 1086 75

Both the prevention and attenuation of chronic heart failure (CHF) are important issues for cardiologists. There are three different strategies to prevent patients from deleterious sequels. The first strategy is to remove the causes of CHF if possible; the second is to attenuate the events that may lead to CHF, such as myocardial ischaemia and reperfusion injury, cardiomyopathy and myocarditis, cardiac hypertrophy and ventricular remodelling; the third is to prevent or attenuate the progression of CHF. Adenosine has a number of actions which merit it as a possible cardioprotective and therapeutic agent for CHF. Firstly, adenosine induces collateral circulation via inducing growth factors and triggering ischaemic preconditioning, both of which induce ischaemic tolerance in advance. Adenosine is also known to reduce the release of noradrenaline, production of endothelin and attenuate the activation of renin-angiotensin system all of which are believed to cause cardiac hypertrophy and remodelling. Secondly, exogenous adenosine is known to reduce the severity of ischaemia and reperfusion injury. Thirdly, adenosine is reported to counteract neurohumoral factors, i.e., cytokine systems, known to be related to the pathophysiology of CHF. Recently, we revealed that adenosine metabolism is changed in patients with CHF and increases in adenosine levels may aid to reduce the severity of CHF. Thus, there are many potential mechanisms for cardioprotection attributable to adenosine and we postulate the use of adenosine therapy will be beneficial in patients with CHF.
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PMID:Adenosine therapy: a new approach to chronic heart failure. 1106 Aug 17

Adenosine was shown to inhibit norepinephrine (NE) release from sympathetic nerve endings. The purpose of this study was to examine whether endogenous adenosine restrains NE and epinephrine release from the adrenal medulla. The effects of an adenosine receptor antagonist, 1,3-dipropyl-8-(p-sulfophenyl) xanthine (DPSPX), on epinephrine and NE release induced by intravenous administration of insulin in conscious rats were examined. Plasma catecholamines were measured by HPLC with an electrochemical detector. DPSPX significantly increased plasma catecholamine in both control rats and rats treated with insulin. The effect of DPSPX on plasma catecholamine was significantly greater in rats treated with insulin. Additional experiments were performed in adrenalectomized rats to investigate the contribution of the adrenal medulla to the effect of DPSPX on plasma catecholamine. The effect of DPSPX and insulin on epinephrine in adrenalectomized rats was significantly reduced compared with that of the controls. Finally, we tested whether endogenous adenosine restrains catecholamine secretion partially through inhibiting the renin-angiotensin system. The effect of DPSPX on plasma catecholamine in rats pretreated with captopril (an angiotensin-converting enzyme inhibitor) was reduced. These results demonstrate that under basal physiological conditions, endogenous adenosine tonically inhibits catecholamine secretion from the adrenal medulla, and this effect is augmented when the sympathetic system is stimulated. The effect of endogenous adenosine on catecholamine secretion from the adrenal medulla is achieved partially through the inhibitory effect of adenosine on the renin-angiotensin system.
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PMID:Modulation of catecholamine release by endogenous adenosine in the rat adrenal medulla. 1154 80

Adenosine exerts physiologically significant receptor-mediated effects on renal function. For example, adenosine participates in the regulation of preglomerular and postglomerular vascular resistances, glomerular filtration rate, renin release, epithelial transport, intrarenal inflammation, and growth of mesangial and vascular smooth muscle cells. It is important, therefore, to understand the mechanisms that generate extracellular adenosine within the kidney. In addition to three "classic" pathways of adenosine biosynthesis, contemporary studies are revealing a novel mechanism for renal adenosine production termed the "extracellular cAMP-adenosine pathway." The extracellular cAMP-adenosine pathway is defined as the egress of cAMP from cells during activation of adenylyl cyclase, followed by the extracellular conversion of cAMP to adenosine by the serial actions of ecto-phosphodiesterase and ecto-5'-nucleotidase. This mechanism of extracellular adenosine production may provide hormonal control of adenosine levels in the cell-surface biophase in which adenosine receptors reside. Tight coupling of the site of adenosine production to the site of adenosine receptors would permit a low-capacity mechanism of adenosine biosynthesis to have a large impact on adenosine receptor activation. The purposes of this review are to summarize the physiological roles of adenosine in the kidney; to describe the classic pathways of renal adenosine biosynthesis; to review the evidence for the existence of the extracellular cAMP-adenosine pathway; and to describe possible physiological roles of the extracellular cAMP-adenosine pathway, with particular emphasis on the kidney.
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PMID:Role of the extracellular cAMP-adenosine pathway in renal physiology. 1155 6

The continuous infusion of 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), a non-selective antagonist of adenosine receptors, causes hypertension and marked cardiovascular structural changes in Wistar rats. Adenosine inhibits noradrenaline and renin release. We investigated the effects of sympathetic denervation, evaluated renin activity and the influence of angiotensin converting enzyme inhibition in DPSPX-treated rats. Captopril was given (30 or 100 mg kg(-l) day(-l); p.o.) from day -l to day 28. On day 0, constant infusions of DPSPX (90 microg kg(-l) h(-l); i.p.) or vehicle were started. On day 28, fragments of the left ventricle, mesenteric and tail arteries were processed for morphological studies. Plasma renin activity was increased in DPSPX-treated animals. Sympathetic denervation delayed and partially prevented blood pressure rise. Angiotensin converting enzyme inhibition prevented DPSPX-induced hypertension and morphological changes. Our results, although pointing to the involvement of the sympathetic system, suggest that other mechanisms are involved. We could not differentiate between the trophic and anti-hypertensive effects of angiotensin converting enzyme inhibition.
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PMID:Angiotensin converting enzyme inhibition prevents trophic and hypertensive effects of an antagonist of adenosine receptors. 1200 26

Angiotensin II (Ang II) is a potent vasoconstrictor in the peripheral circulation and has been implicated in many cardiovascular diseases associated with elevated oxidative stress. However, its direct vasomotor action and its linkage to oxidative stress-induced vascular dysfunction in the coronary microcirculation remain elusive. In this study, we directly assessed the vasomotor action of Ang II in isolated porcine coronary arterioles and also examined whether Ang II can modulate endothelium-dependent nitric oxide (NO)-mediated dilation via superoxide production. Ang II evoked vasoconstriction at a low concentration (1 nmol/L) and dilations at higher concentrations (>10 nmol/L). Ang II type 1 (AT(1)) receptor antagonist losartan abolished vasoconstriction, whereas Ang II type 2 (AT(2)) receptor antagonist PD 123319 eliminated vasodilation. Adenosine stimulated a significant arteriolar NO production and dilation. NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) abolished stimulated NO production and attenuated vasodilation. Pretreating vessels with a subvasomotor concentration of Ang II (0.1 nmol/L, 60 minutes) mimicked inhibitory effects of L-NMMA. Ang II-mediated inhibition was not observed in the presence of L-NMMA or after endothelial removal but was prevented by losartan, superoxide scavenger TEMPOL, or NADPH oxidase inhibitor apocynin. Dihydroethidium staining showed that Ang II elicited losartan- and TEMPOL-sensitive superoxide production in arterioles. These results demonstrate that Ang II evokes AT1 receptor-mediated vasoconstriction and AT2 receptor-mediated vasodilation of coronary arterioles. Ang II at a subvasomotor level impairs endothelium-dependent NO-mediated dilation attributable to elevated superoxide production via AT1 receptor activation of NADPH oxidase. These data may partly explain the impaired coronary flow regulation in heart diseases associated with an upregulated renin-angiotensin system.
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PMID:Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. 1259 45

Sympathomimetic stimulation, angiotensin II, or endothelin-1 is considered to be an essential stimulus mediating ventricular hypertrophy. Adenosine is known to protect the heart from excessive catecholamine exposure, reduce production of endothelin-1, and attenuate the activation of the renin-angiotensin system. These findings suggest that adenosine may also attenuate myocardial hypertrophy. To verify this hypothesis, we examined whether activation of adenosine receptors can attenuate cardiac hypertrophy and reduce the risk of heart failure. Our in vitro study of neonatal rat cardiomyocytes showed that 2-chloroadenosine (CADO), a stable adenosine analogue, inhibits protein synthesis of cardiomyocytes induced by phenylephrine, endothelin-1, angiotensin II, or isoproterenol, which were mimicked by the stimulation of adenosine A1 receptors. For our in vivo study, cardiac hypertrophy was induced by transverse aortic constriction (TAC) in C57BL/6 male mice. Four weeks after TAC, both heart to body weight ratio (6.80+/-0.18 versus 8.34+/-0.33 mg/g, P<0.0001) as well as lung to body weight ratio (6.23+/-0.27 versus 10.03+/-0.85 mg/g, P<0.0001) became significantly lower in CADO-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular dP/dtmax were improved significantly by CADO treatment. Similar results were obtained using the selective adenosine A1 agonist N6-cyclopentyladenosine (CPA). A nonselective adenosine antagonist, 8-(p-sulfophenyl)-theophylline, and a selective adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine, eliminated the antihypertrophic effect of CADO and CPA, respectively. The plasma norepinephrine level was decreased and myocardial expression of regulator of G protein signaling 4 was upregulated in CADO-treated mice. These results indicate that the stimulation of adenosine receptors attenuates both the cardiac hypertrophy and myocardial dysfunction via adenosine A1 receptor-mediated mechanisms.
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PMID:Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. 1456 7


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