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

The availability of specific competitive antagonists stimulated investigation of the physiological and pathological role of angiotensin (A-II) and permitted the qualitative and quantitative characterization of numerous angiotensin receptor sites. The specific, competitive antogonists for A-II inhibit both the direct actions of A-II on isolated smooth muscle preparations and the stimulation of specific vascular receptor sites by which A-II evokes prostaglandin biosynthesis and release. Converting enzyme inhibitors a) block the action of exogenous A-I; b) lower blood pressure in conditions associated with high plasma renin levels (e.g., two-kidney renal hypertension, dehydrated diabetes insipidus rats, or in hemorrhagic shock); c) enhance responses to exogenous bradykinin (by inhibiting bradykininase); but d) do not block the effects of A-II at its receptor sites. A-II-receptor antagonists a) block the action of both A-I and A-II, b) lower blood pressure in high renin states, but c) have no effect on bradykinin degradation or action. Angiotensin receptor and synthesis antagonists have been shown to decrease the overall peripheral resistance and to reverse the renal cortical vasoconstriction during hemorrhagic shock and to prolong survival time in hemorrhaged dogs. It is our belief that angiotensin antogonists have therapeutic potential in hemorrhagic shock and would be expected (alone or in combination with alpha-andrenergic blockade) to overcome vascular shutdown and enhance organ perfusion (especially in the kidney).
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PMID:Angiotensin antogonists as pharmacological tools. 18 93

Components of the renin-angiotensin system were studied in established cell culture lines of 3T3 and SV3T3 mouse fibroblasts. The renin content in 3T3 cells was significantly higher than in virus-transformed SV3T3 cells. With time after infection, renin decreased in Simian virus 40 transformed cells, while it increased steadily in mock-infected 3T3 cells. In contrast to renin, angiotensinase activity was higher in SV3T3 cells. Angiotensin II stimulated cell proliferation in 3T3 mouse fibroblasts and decreased their renin content in a dose-related manner. In contrast, saralasin, an angiotensin receptor antagonist, inhibited cell growth in 3T3 and SV3T3 cells and caused an increase of cellular renin concentration. The angiotensin fragments angiotensin (2-8) heptapeptide and angiotensin (4-8) pentapeptide had no effect on cell growth. A significant negative correlation was found between cell proliferation and renin levels in 3T3 and SV3T3 cells irrespective of the treatment. Our results indicate (1) that angiotensin II may be involved in cell growth regulation, (2) that a negative feedback exist between angiotensin II added and intracellular renin content, and (3) that virus infection causes a decrease in intracellular renin synthesis, while non-specific angiotensinase activity is increased under this condition.
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PMID:Effects of angiotensin II and angiotensin II antagonist saralasin on cell growth and renin in 3T3 and SV3T3 cells. 22 Feb 72

Diuretic and vasodilator drugs alter the BP response to saralasin causing drug interactions. Saralasin-induced BP reduction is related directly to PRA and intravascular volume. Diuretic agents deplete intravascular volume and elevate PRA, enhancing saralasin hypotension. Vasodilating agents increase PRA and may induce angiotensin dependence of BP. Thus, with potent vasodilators, saralasin can induce hypotension. Rebound hypertension has been reported after saralasin infusion in several patients with accelerated or malignant hypertension. Theoretically, this BP elevation could be related to sustained release of renin resulting from disinhibition of an intrarenal angiotensin receptor inhibitory to renin release. Since propranolol can block saralasin-induced renin release, angiotensin and beta-blockers could constitute a beneficial drug interaction.
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PMID:Drug interactions with saralasin. 28 59

1. The renal artery of conscious dogs was acutely narrowed over 30 s to reduce renal artery pressure distal to the stenosis to 40 mmHg and the stenosis was maintained for 1 h. The distal renal artery pressure was rapidly restored to a plateau slightly below pre-stenosis values within 10--15 min. Rises in systemic blood pressure and plasma renin activity were small and transient. 2. This restoration was an active process, mediated by the intrarenal effects of angiotensin II (AII), since it was greatly diminished or abolished when the renal artery was narrowed in the presence of angiotensin I-converting enzyme inhibitor or angiotensin receptor antagonist (1-Sar-8-Ile AII). However, it was not diminished by 'total' autonomic effector blockade. 3. This angiotensin II-mediated restoration of renal artery pressure may be of homeostatic significance for the maintenance of glomerular filtration rate.
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PMID:Intrarenal action of angiotensin II in restoring renal artery pressure after acute renal artery stenosis. 72 9

The influence of the renin-angiotensin system on the control of cell communication was investigated in isolated ventricular cell pairs of adult rats. It was found that angiotensin II (1 microgram/ml) reduced the junctional conductance (gj) by about 55% within 20 s. This effect of angiotensin II was suppressed by DuP 753--an angiotensin receptor blocking agent. Enalapril (1 microgram/ml)--an angiotensin converting enzyme inhibitor--caused an increase in junctional conductance (106%) within 2 min. The effect of enalapril on gj was not related to activation of beta-adrenergic receptors or cAMP-dependent protein kinase. The effect of angiotensin II on gj was suppressed by staurosporine--a potent inhibitor of protein kinase C. This finding indicates that the peptide is changing gj through activation of protein kinase C. The increase in cell coupling caused by enalapril raises the possibility that the antiarrhythmic action of enalapril as well its effect in congestive heart failure are related to an increase in electrical synchronization of cardiac myocytes.
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PMID:The role of the renin-angiotensin system in the control of cell communication in the heart: effects of enalapril and angiotensin II. 128 Jul 22

Angiotensin II (ANG II) is the primary mediator of the renin-angiotensin system, which has an important functional role in cardiovascular homeostasis. The angiotensin receptor and its functional correlates have been redefined by the cloning of angiotensin receptors and the discovery and widespread study of specific nonpeptide ANG II-receptor antagonists losartan (AT1 selective) and PD123177 (AT2 selective). With these antagonists, it has been possible to extend the concept of ANG II-receptor heterogeneity to virtually every tissue and species. The losartan-sensitive sites have been shown to mediate all of the major ANG II-induced biologic effects, including vasoconstriction, aldosterone and catecholamine release, and central, ANG II-induced drinking behavior. The function of the AT2 site is not fully understood, but it may be involved in neuronal ion channel modulation and in fibroblast collagen metabolism. The presence of AT2 sites in fetal tissues and in discrete locations in the brain has encouraged continued research. Losartan, which represents the first of a new class of therapeutic agents, is currently undergoing clinical trials. A growing number of other AT1-selective ANG II-receptor antagonists are under development, including L-158,809, SKF 108566, and GR117285. Rat AT1-receptor subtypes have been cloned and sequenced (AT1A and AT1B). Human ANG II receptors have also been cloned and shown to have high affinity for losartan. A number of atypical angiotensin-binding sites have been identified from mycoplasma, amphibians, and mouse neuroblastoma, which are not sensitive to either losartan or PD123177.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II receptors and functional correlates. 129 Jun 17

Considerable evidence now indicates that a separate and distinct renin-angiotensin system (RAS) is present within the brain. The necessary precursors and enzymes required for the formation and degradation of the biologically active forms of angiotensins have been identified in brain tissues as have angiotensin binding sites. Although this brain RAS appears to be regulated independently from the peripheral RAS, circulating angiotensins do exert a portion of their actions via stimulation of brain angiotensin receptors located in circumventricular organs. These circumventricular organs are located in the proximity of brain ventricles, are richly vascularized and possess a reduced blood-brain barrier thus permitting accessibility by peptides. In this way the brain RAS interacts with other neurotransmitter and neuromodulator systems and contributes to the regulation of blood pressure, body fluid homeostasis, cyclicity of reproductive hormones and sexual behavior, and perhaps plays a role in other functions such as memory acquisition and recall, sensory acuity including pain perception and exploratory behavior. An overactive brain RAS has been identified as one of the factors contributing to the pathogenesis and maintenance of hypertension in the spontaneously hypertensive rat (SHR) model of human essential hypertension. Oral treatment with angiotensin-converting enzyme inhibitors, which interfere with the formation of angiotensin II, prevents the development of hypertension in young SHR by acting, at least in part, upon the brain RAS. Delivery of converting enzyme inhibitors or specific angiotensin receptor antagonists into the brain significantly reduces blood pressure in adult SHR. Thus, if the SHR is an appropriate model of human essential hypertension (there is controversy concerning its usefulness), the potential contribution of the brain RAS to this dysfunction must be considered during the development of future antihypertensive compounds.
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PMID:Regulatory role of brain angiotensins in the control of physiological and behavioral responses. 136 94

The role of angiotensin receptor subtypes 1 and 2 was assessed on neointima formation after injury in rat carotid artery. The effects of angiotensin converting enzyme inhibition by perindopril (3 mg.kg-1 x day-1 p.o.) and selective blockade of angiotensin subtype 1 receptors by DuP 753 (5 and 30 mg.kg-1 x day-1 p.o.) were compared on proliferative response to balloon injury. In rats treated 6 days before and for 14 days after injury, perindopril significantly reduced (-76%, p < 0.01) myointimal hyperplasia. In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization. Only at 30 mg.kg-1 x day-1 was DuP 753 able to reduce neointima formation (-47%, p < 0.05). This dose was equipotent to perindopril on the renin-angiotensin system as assessed by the pressor response to angiotensin II and angiotensin I. Therefore, blockade of subtype 1 receptors was a less effective means of suppression of myointimal growth than angiotensin converting enzyme inhibition, suggesting that another angiotensin receptor subtype or converting enzyme substrates are involved in this process. For the determination of whether angiotensin subtype 2 receptors were implicated, the specific subtype 2 receptor antagonist CGP 42112A (1 mg.kg-1 x day-1) was continuously infused perivascularly for 14 days in the vicinity of the injured carotid artery. CGP 42112A was as effective in preventing neointima formation as perindopril (-73%, p < 0.01, versus -76%, p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. 145 89

Angiotensin II (Ang II) is a potent effector peptide of the renin-angiotensin system that exerts a wide variety of physiological actions on the cardiovascular, renal, endocrine, and central and peripheral nervous systems. Angiotensin exerts its actions by binding to specific receptors in the plasma membrane of various tissues. Structure-activity relationship studies and competition-binding experiments have identified a potency series of angiotensin analogues. Such studies have demonstrated that target organs display different preferences for Ang II and homologues such as Ang III and des-[Phe8] angiotensin II. Similarly, agents that normally are considered to be pure receptor antagonists for a given response (tissue) are full agonists in other tissues. Indirect evidence obtained from the above studies have led to the speculation that there are multiple angiotensin receptor subtypes among various tissues as well as within single cell types. Multiple mechanisms of signal transduction have been demonstrated for angiotensin. For example, depending on the effector organ, angiotensin stimulates phosphoinositide turnover and release of internal calcium, modulates voltage-dependent calcium channels, directly activates calcium channels, and inhibits adenylate cyclase activity. Recently, the identification of selective, high-affinity peptide and nonpeptide antagonists has resulted in further characterization of angiotensin receptors into distinct subtypes. In addition, dithiothreitol, an agent that reduces disulfide bridges, has been a useful tool in the characterization of angiotensin receptors as the subtypes apparently are not affected equally by this agent. However, further work needs to be performed to characterize angiotensin receptors with respect to heterogeneity, structure, transducing mechanisms, and physiological function.
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PMID:The angiotensin II receptor and the actions of angiotensin II. 170 24

The sites that initiate angiotensin effects on vascular and extravascular tissues have historically been identified as "the angiotensin II (Ang II) receptor." However, this unitary perspective of a single receptor responding to a single hormone has been revised with the molecular cloning of angiotensin-responsive receptors. The mammalian proto-oncogene MAS has been identified as a novel neuronal angiotensin receptor, which responds preferentially to Ang III, and has other unusual pharmacological properties. Although its tissue distribution suggests it may function normally in the brain in sites not normally associated with angiotensins, it shares many structural and functional features with the cloned vascular Ang II receptor. The understanding of the MAS/angiotensin receptor may compel a basic rethinking of many aspects of the cardiovascular biology of the renin-angiotensin system.
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PMID:Molecular and cell biology of angiotensin receptors. 172 48


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