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)

At extremely low concentrations, in the picomole and the nanomole range, bradykinin produces contraction and relaxation of smooth muscle in the gastrointestinal and the urogenital tract. At the target organ, bradykinin interacts with discriminator proteins of the plasma membranes and triggers, via changes in certain membrane functions, its biological response:--The binding to the discriminator makes specific conformative and constitutional demands on the nonapeptide. The binding results from an angular conformation which exists in the solution. The complete sequence is responsible for this specific conformation. Consequently, the biological activity of partial sequences is low. The conformational analysis of analogues used in studies on the mechanism of action showed but slight differences from bradykinin. The interaction of these analogues with the discriminator protein is disturbed to a varying extent by modifications at positions 1, 5, 8 and 9 in the side chains. The affinity for the discriminator is affected, dependently on the respective configuration, by substitution on the beta-C atom in the two phenylalanine residues.--Bradykinin is not only bound to, but also degraded at, the plasma membranes of the rat uterus and duodenum. The bradykinin-degrading enzyme has been characterized as a kininase II with the aid of various inhibitors. The conformative and configurative prerequisites decisive for enzymatic degradation are others than those decisive for binding to the discriminator.--The changes in the activities of the membrane-bound adenylate and guanylate cyclases (produced by the bradykinin-discriminator complex) that take place at the rat duodenum and uterus in the presence of extracellular calcium ions contrast with each other: At the duodenum, the ratio between these two cyclic nucleotides is changed in favour of adenylate cyclase; and at the uterus, in favour of guanylate cyclase; Substances which increase or decrease the cAMP level may also potentiate or inhibit the relaxation of the duodenum. These bradykinin-induced changes in enzyme activity must be considered in connection with other effectors, e.g. prostaglandins and calcium ions.--The calcium-ion-dependence of the effect of bradykinin on the guinea-pig ileum and the rat uterus indicates the importance of these ions as additional second messengers. Bradykinin stimulates the influx of calcium ions into the ileum; it is ineffective if no extracellular calcium ions into the ileum; it is ineffective if no extracellular calcium ions are available. It seems that intracellular and membranal calcium is mobilized in the uterus, which is evidenced by results from experiments with EGTA on the isolated organ and by the release of calcium from plasma membranes after application of bradykinin. It is assumed that the observed changes in membrane functions are induced by the peptide-discriminator complex simultaneously and not in the form of a causal chain.
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PMID:[On the mode of action of bradykinin on smooth muscle (author's transl)]. 39 90

Nitroglycerin and the organic nitrates (RONO2) can be considered prodrugs that require conversion to an active intracellular moiety that initiates vascular smooth muscle relaxation. Vasodilation of veins and arteries occurs when the enzyme guanylate cyclase (GC) is activated, initiating the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP); this is the final pathway for vascular dilation caused by the nitrovasodilators (organic nitrates, sodium nitroprusside, and molsidomine) as well as endothelium-derived relaxing factor (EDRF). The common denominator appears to be the intracellular production of nitric oxide (NO), which is the activated product of organic nitrate denitration. Nitrate tolerance has been associated with a relative depletion or unavailability of thiol groups that are involved in the initial step of denitration of RONO2. Sulfhydryl groups (SH) are oxidized during this process; with continuous nitrate exposure, decreased nitrate metabolism within the vascular smooth muscle cell occurs as a direct result of the depletion of reduced SH groups. Thus, less NO is formed and cGMP production is diminished, with a subsequent decrease or absence of vasodilation. In addition, SH groups or thiols are required for the production of S-nitrosothiols (RSNO). These short-lived compounds have been identified as an end product of organic nitrate metabolism and as possibly obligatory for the induction of GC. It is unclear, however, as to whether S-nitrosothiols are a necessary by-product of NO production from organic nitrates. It appears that RSNO can be formed outside the cell membrane and may be able to induce vasorelaxation after penetrating the cell and initiating GC activation. Exogenous SH donors, particularly N-acetylcysteine (NAC), have been employed to provide intracellular thiols in efforts to prevent or reverse nitrate tolerance. Nitrate physiologic actions are accentuated following NAC administration in the absence of tolerance. Although controversial, the concept that NAC or other thiols might be able to prevent the development of nitrate tolerance is being actively studied in laboratories around the world. Methionine has also been utilized as an SH donor with some success. Not all data are consistent, however, and the ultimate role of thiol donors for the prevention or reversal of nitrate tolerance remains uncertain. Finally, there has been considerable interest in supplying thiols by use of the SH-containing angiotensin converting enzyme inhibitors, such as captopril. This approach does not seem promising, probably because insufficient thiol can be supplied by therapeutic dosages of these drugs.
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PMID:Interactions between organic nitrates and thiol groups. 192

We have synthesized an S-nitrosylated derivative of captopril, S-nitrosocaptopril, that manifests nitrosovasodilatory activity, inhibits angiotensin converting enzyme activity and inhibits platelet aggregation. The direct vasodilatory effects of S-nitrosocaptopril reflect the effects of the thionitrite bond, the presence of which does not in any way influence S-nitrosocaptopril's ability to inhibit angiotensin converting enzyme. Thionitrite stimulation of both vascular and platelet soluble guanylate cyclase activity leads to increases in intracellular cyclic GMP that are accompanied by vasodilatation and platelet inhibition, respectively. S-nitrosocaptopril is a novel hybrid molecule that has potential use in the treatment of hypertension regardless of renin status, angina pectoris and congestive heart failure.
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PMID:S-nitrosocaptopril. I. Molecular characterization and effects on the vasculature and on platelets. 265 76

Experiments were designed to elucidate the effects of S-nitrosocaptopril (SnoCap) on vascular reactivity. Rings of bovine femoral and coronary arteries were mounted for isometric tension recording in physiological saline solution. SnoCap induced dose-dependent relaxations in both the coronary and femoral arteries, but inhibited contractions in the coronary artery to a significantly greater degree. Relaxations to SnoCap were inhibited by methylene blue. Angiotensin I and angiotensin II induced dose-dependent contractions in the bovine femoral artery. The angiotensin II antagonist saralasin induced comparable inhibition of the response to angiotensin I and angiotensin II. Captopril (10(-6) M) and SnoCap (10(-6) M) equally inhibited contraction to angiotensin I, inducing a 50-fold shift in the dose-response curve. SnoCap inhibited contraction to angiotensin II, inducing a 5-fold shift in the dose-response curve and depressing the maximum response. In summary, the S-nitrosylated derivative of captopril is a unique compound that inhibits vascular reactivity through activation of soluble guanylate cyclase and inhibition of angiotensin converting enzyme. This combined nitrovasodilator and angiotensin converting enzyme inhibitor may have clinical utility in hypertension, coronary artery disease and congestive heart failure.
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PMID:S-nitrosocaptopril. II. Effects on vascular reactivity. 265 77

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of responses to bradykinin in the pulmonary vascular bed of the cat. 751 46

The generation of nitric oxide by the vascular endothelium maintains a continuous vasodilator tone that is essential for the regulation of blood flow and blood pressure. Nitric oxide also contributes to the control of platelet aggregation and has important antiatherogenic effects. These properties are mediated by the action of constitutive nitric oxide synthase and subsequent activation by nitric oxide of soluble guanylate cyclase. Impaired release of nitric oxide occurs in most animal and human models of hypertension, contributing to the increased peripheral resistance and most likely to the development of cardiovascular complications. Antihypertensive medications (angiotensin-converting enzyme [ACE] inhibitors and calcium channel blockers) appear to prevent the impairment of nitric oxide-mediated vasodilation in experimental hypertension, though in humans the data are not as clear. Reduced nitric oxide release appears therefore to be a consequence rather than a cause of high blood pressure, and the reduction in blood pressure per se is most important. In hyperlipidaemia, endothelium-dependent relaxations are reduced probably due to the inhibitory action of oxidized low-density lipoproteins on endothelium-dependent relaxations. Lipid-lowering strategies and, more recently, ACE inhibition have been demonstrated to improve nitric oxide dependent coronary vasodilation in hypercholesterolaemic patients with and without atheromatous coronary disease. Nitric oxide dependent vasodilation is also impaired in insulin- and non-insulin-dependent diabetes as well as in healthy aging. Endothelial dysfunction may be improved in non-insulin-dependent diabetes by administration of the antioxidants, supporting the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.
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PMID:Impairment and restoration of nitric oxide-dependent vasodilation in cardiovascular disease. 948 1

(1) On rat isolated pulmonary arteries, vasorelaxation by S-nitrosocaptopril (SNOcap) was compared with S-nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril. (2) SNOcap was equipotent as a vasorelaxant on main (i.d. 2-3 mm) and intralobar (i.d. 600 micro m) pulmonary arteries (pIC(50) values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2-3 min). (3) Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4) oxadiazolo(4,3-a)-quinoxalin-1-one; 3 micro M) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO. free radical scavenger; 100 micro M) whereas responses to nitroprusside were inhibited. (4) The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7 : 1; GSNO 25 : 1; nitroprusside >2000 : 1. (5) SNOcap, like captopril, concentration-dependently and time-dependently increased the EC(50) for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but differed for SNOcap and captopril. This difference reflected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (>/=5.6 h) SNOcap was more effective than captopril. (6) Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of S-nitrosothiols but different from nitroprusside and (ii) inhibits ACE at least as effectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.
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PMID:S-nitrosocaptopril: in vitro characterization of pulmonary vascular effects in rats. 1264 87

Chronic, low-level lead exposure causes hypertension in both animals and humans. The pathogenesis of lead-induced hypertension is multifactorial, including such diverse mechanisms as: inactivation of endogenous nitric oxide and downregulation of soluble guanylate cyclase by reactive oxygen species (ROS), leading to a functional deficiency in nitric oxide; heightened sympathetic activity and plasma norepinephrine together with depressed vascular and elevated renal beta-adrenergic receptor density; elevated plasma angiotensin-converting enzyme (ACE) activity, plasma renin activity (PRA), angiotensin II (Ang-II), and aldosterone levels; increased kininase I and kininase II activities; lead-induced inhibition of vascular smooth muscle Na(+)-K+ ATPase, leading to a rise in cellular Na+ and, hence, Ca2+; and a possible rise in endothelin and thromboxane generation. In this article, we present an overview of the epidemiology and proposed underlying mechanisms of lead-induced hypertension.
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PMID:Lead-induced hypertension: role of oxidative stress. 1525 67

Nitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system, where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties.
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PMID:NO-releasing hybrids of cardiovascular drugs. 1652 54

Nitric oxide (NO) is a physiologically important modulator of both vasomotor tone and platelet aggregability. These effects of NO are predominantly mediated by cyclic guanosine-3,'5'-monophosphate (cGMP) via activation of soluble guanylate cyclase. However, in patients with ischemic heart disease, platelets and coronary/peripheral arteries are hyporesponsive to the antiaggregatory and vasodilator effects of NO donors. NO resistance is also associated with a number of coronary risk factors and presents in different disease states. It correlates with conventional measures of "endothelial dysfunction," and represents a multifaceted disorder, in which smooth muscle and platelet NO resistance are equally important, as sites of abnormal NO-driven physiology. NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical (O(2)(-)) and of (reversible) inactivation of soluble guanylate cyclase. It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor, EDRF) and, as such, may contribute to the increased risk of ischemic events. Impairment in responsiveness to NO in ischemic patients implies a potential problem that those patients, in greatest need of nitrate therapy, may be least likely to respond. The prognostic impact of NO resistance at vascular and platelet levels has been demonstrated in patients with ischemic heart disease, and it has been shown that a number of agents (angiotensin-converting enzyme [ACE] inhibitors, perhexiline, insulin, and possibly statins) ameliorate this anomaly. The current review examines different aspects of the "NO resistance" phenomenon and discusses some related methodological issues.
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PMID:Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier? 1776 75


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