Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that angiotensin-(1-7) [Ang-(1-7)] interacts with kinins and augments bradykinin (BK)-induced vasodilator responses by an unknown mechanism. In this study, we evaluated whether the potentiation of the BK-induced vasodilation by Ang-(1-7) may be attributable to inhibition of BK metabolism, release of nitric oxide, or both. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers. 125I-[Tyr0]-BK metabolism was determined in vascular rings by assessing the degradation of the peptide by high-performance liquid chromatography. Ang-(1-7) augmented the vasodilation induced by BK in a concentration-dependent manner in rings preconstricted with the thromboxane analog U46619. The EC50 of BK (2.45 +/- 0.51 nmol/L versus 0.37 +/- 0.08 nmol/L) was shifted leftward by 6.6-fold in the presence of 2 mumol/L concentration of Ang-(1-7). The response was specific for BK. since Ang-(1-7) did not augment the vasodilation induced by either acetylcholine (0.05 mumol/L) or sodium nitroprusside (0.1 mumol/L). Moreover, neither angiotensin I nor angiotensin II (Ang II) duplicated the augmented BK response of Ang-(1-7). Pretreatment of vascular rings with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NA; 100 mumol/L) completely abolished the effects of Ang-(1-7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 mumol/L) was without effect. The potent specific BK B2 receptor antagonist, Hoe 140. nearly abolished the BK and the Ang-(1-7) potentiated responses at 2 mumol/L, whereas at a lower concentration (20 nmol/L) Hoe 140 shifted the response curve to the right for both Ang-(1-7) and vehicle; however, the augmented response to Ang-(1-7) persisted. Preincubation of vascular rings with 20 mumol/L of the AT1 (CV11974), AT2 (PD123319), or nonselective (Sar1 Thr8-Ang II) receptor antagonists had no significant effect on the Ang-(1-7)-enhanced vasodilator response to BK. Lisinopril (2 mumol/L) significantly enhanced the BK-induced vasodilator response while at the same time it abolished the synergistic action of Ang-(1-7) on BK. In addition, pretreatment with 2 mumol/L Ang-(1-7) significantly inhibited the degradation of 125I-[Tyr0]-BK and the appearance of the BK-(1-7) and BK-(1-5) metabolites in coronary vascular rings. Ang-(1-7) inhibited purified canine angiotensin converting enzyme activity with an IC50 of 0.65 mumol/L. In conclusion. Ang-(1-7) acts as a local synergistic modulator of kinin-induced vasodilation by inhibiting angiotensin converting enzyme and releasing nitric oxide.
 ...
PMID:Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. 903 33

As an antihypertensive regimen, angiotensin I-converting enzyme (ACE) inhibition appears to have an antiproliferative cardiovascular effect that is not caused by blood pressure reduction alone. On the other hand, ACE inhibition has been shown to induce neocapillarization in hypertrophied myocardium. The possible mechanisms behind these beneficial cardiovascular effects of ACE inhibition are the suppression of angiotensin II formation and the potentiation of bradykinin. Angiotensin II receptor antagonism appears to have a similar antiproliferative effect on myocardium and vascular smooth muscle as ACE inhibition. This suggests that the antiproliferative action of both regimens is due only to the reduction of the pressor and growth effects of angiotensin II, or that both regimens have an additional, similarly effective antiproliferative action. Recently, knowledge about angiotensin II receptors has almost exponentially expanded. The two main classes of angiotensin II receptors, type 1 and 2 (AT1 and AT2), have been shown to belong to the same receptor family. However, their signal transduction and function seem to differ totally. The function and signal transduction of AT1 are to a large extent known. All the well-known physiological and pathophysiological effects of angiotensin II have been attributed to AT1. On the other hand, AT2 has quite recently been shown to mediate antiproliferation and differentiation at least in some tissues and cells, e.g. in vascular endothelial cells and some cells of neuronal origin. This review highlights the recent findings on angiotensin II receptors, and discusses the mechanisms behind the beneficial cardiovascular effects of interfering with the renin-angiotensin system.
 ...
PMID:The role of angiotensin receptors in cardiovascular diseases. 907 21

1. The vasoconstrictor peptide antiotensin II (AII) can stimulate angiogenesis, an important process in wound healing, tumour growth and chronic inflammation. To elucidate mechanisms underlying AII-enhanced angiogenesis, we have studied a subcutaneous sponge granuloma model in the rat by use of 133Xe clearance, morphometry and quantitative in vitro autoradiography. 2. When injected directly into the sponge, AII (1 nmol day-1) increased 133Xe clearance from, and fibrovascular growth in sponge granulomas, indicating enhanced angiogenesis 6 to 12 days after implantation. This AII-enhanced angiogenesis was inhibited by daily doses (100 nmol/sponge) of the specific but subtype non-selective AII receptor antagonist (Sar1, Ile8)AII, and by the selective non-peptide AT1 receptor antagonists losartan and DuP 532. In contrast, AII-enhanced neovascularization was not inhibited by the AT2 receptor antagonist PD123319, nor was it mimicked by the AT2 receptor agonist CGP42112A (each at 100 nmol/sponge day-1). 3. AI (1 nmol/sponge day-1), the angiotensin converting enzyme (ACE) inhibitors captopril (up to 100 micrograms/sponge day-1) and lisinopril (40 micrograms/sponge day-1), or AII receptor antagonists did not affect angiogenesis in the absence of exogenous AII. 4. [125I]-(Sar1, Ile8)AII binding sites with characteristics of AT1 receptors were localized to microvessels and to non-vascular cells within the sponge stroma from 4 days after implantation, and were at higher density than in skin throughout the study. 5. [125I]-(Sar1, Ile8)AII binding sites with characteristics of AT2 receptors were localized to non-vascular stromal cells, were of lower density and appeared later than did AT1 sites. 6. The ACE inhibitor [125I]-351A bound to sites with characteristics of ACE, 14 days after sponge implantation. [125I]-351A bound less densely to sponge stroma than to skin. 7. We propose that AII can stimulate angiogenesis, acting via AT1 receptors within the sponge granuloma. AT1 and AT2 receptors and ACE develop sequentially during microvascular maturation, and the role of the endogenous angiotensin system in angiogenesis will depend on the balanced local expression of its various components. Pharmacological modulation of this balance may provide novel therapeutic approaches in angiogenesis-dependent diseases.
 ...
PMID:Sequential development of angiotensin receptors and angiotensin I converting enzyme during angiogenesis in the rat subcutaneous sponge granuloma. 910 6

Angiotensin-converting enzyme inhibitors (ACE-I) and specific nonpeptide angiotensin II (ANG II) receptor antagonists have been used extensively to treat a variety of cardiovascular disorders in experimental animals and humans. Despite their widespread use, only a limited amount of data has been published regarding the effect that renin-angiotensin system (RAS) blockade may have on ANG II receptors, and very often this information is contradictory. The present study was designed to investigate whether changes in plasma ANG II levels induced by RAS blockade could alter glomerular ANG II receptor characteristics. Captopril was employed as an ACE-I with losartan and TCV-116, two AT1 receptor antagonists of different chemical structure. Two experimental protocols were established. Protocol 1 contained 3 experimental groups: controls (Sprague-Dawley rats, 250-300 g BW), and animals treated with either captopril (0.5 g/l via drinking water) or losartan (10 mg/kg BW p.o.). In protocol 2, the animals were treated as in protocol 1 except that losartan was replaced by TCV-116 (1 mg/kg BW p.o.). At the end of treatment (3 days), all groups were killed by decapitation, blood was collected for plasma renin activity (PRA) measurement, and hearts and kidneys were excised. ANG II receptors were assessed by radioligand binding assays on membrane preparations of purified glomeruli, by displacement of 125I-[Sar1, Ile8]-ANG II with specific nonpeptide antagonists of AT1 (losartan) and AT2 (PD 123319) receptor subtypes. RAS blockade by either ACE-I or AT1 antagonists increased PRA. The binding assays showed that renal glomeruli from treated rats and controls expressed a single population (AT1) of ANG II receptors. The density of glomerular AT1 receptors was not modulated by captopril, but was significantly lower in animals treated with either losartan (Bmax: 854 +/- 169 vs. 379 +/- 79 fmol/mg protein and Kd: 59 +/- 6 vs. 45 +/- 6 nM for controls and losartan, respectively) or TCV-116 (480 +/- 72 vs. 188 +/- 16 fmol/mg protein and Kd: 45 +/- 9 vs. 37 +/- 18 nM for controls and TCV-116, respectively) than in their controls. No changes in receptor affinity (Kd) were detected. Previous membrane "acid-wash" did not modify the results. We conclude that short-term RAS blockade by AT1 antagonists, but not by ACE-I, induces true downregulation of renal glomerular ANG II receptors. No AT2 receptor subtype was detected.
 ...
PMID:Modulation of renal glomerular angiotensin II receptors by ace inhibition and AT1 receptor antagonism. 911 Mar 82

As a net effect of ACE-inhibitors and AT1-receptor antagonists on the renin-angiotensin system (RAS) cardioprotection due to vasodilative (reduction of blood pressure, afterload reduction), antiproliferative (reduced cell growth, reduction of "vascular" and/or "ventricular remodeling", reduced formation of extracellular matrix), as well as antiadrenergic actions and due to the stimulating effect on natriuresis, reduction of blood pressure, preload reduction can be expected. These aims of therapy have mostly been confirmed for the action of ACE-inhibitors by experimental and clinical studies but except for the treatment of arterial hypertension and few preliminary reports concerning the treatment of cardiac dysfunction, no comparable data are available for AT1-receptor antagonists. To date, an antithrombotic and profibrinolytic action could only be demonstrated for ACE-inhibitors. This effect has been discussed to be responsible for the improvement of long-term prognosis in patients with coronary artery disease. Despite the similar spectrum of action there exist important differences between ACE-inhibitors and AT1-receptor antagonists that might underline the need of an individual use of these drugs: the dual action of ACE-inhibitors on the RAS and the kinin system bears many benefits but has been also shown to be accompanied by side-effects, mainly chronic dry cough, in a relatively high percentage of patients thus leading to discontinuation of therapy in 8-14%. This respective side-effect can be prevented by the use of AT1-receptor antagonists. It has been discussed whether the incomplete action of ACE-inhibitors on AT1-receptor-mediated effects is at least in part responsible for the efficacy of this drug which is relatively high (75-80%) as compared to other substances. Due to their direct action, AT1-receptor-blockers might also be of high effectiveness for the treatment of severe heart failure. A combination of the ACE-inhibitor-mediated activation of the kinin-system with the more specific blockade of AT1-receptors by AT1-receptor antagonists might be of benefit and is currently under investigation. Finally, it has been discussed that the increased AT II concentration in case of AT1-receptor-blockade activates AT2-receptor-mediated mechanisms thus leading to an additive vasoprotective effect.
 ...
PMID:[Pathophysiological mechanisms of the renin-angiotensin system and its pharmacologic modification by ACE inhibitors or angiotensin II (type 1) receptor blockers in cardiovascular diseases]. 923 95

The octapeptide hormone, angiotensin II, binds to two major subtypes of cell surface receptors: the AT1 and the AT2 angiotensin receptors. The important physiological and pathophysiological effects of angiotensin II on cardiovascular regulation and salt-water balance are mediated by the AT1 receptor subtype. As a consequence of the outstanding clinical success of angiotensin-converting enzyme inhibitors, the appearance of AT1 receptor inhibitors in the therapy of hypertension and other cardiovascular diseases was preceded with great expectations. The available experimental and clinical data indicate that the first AT1 receptor inhibitor, losartan, has the same therapeutic potential as angiotensin-converting enzyme inhibitors, but it does not evoke the angiotensin-independent side-effects of ACE inhibitors, such as dry cough or angioedema. The physiological importance and the biochemical, molecular biological and pharmacological properties of AT1 and AT2 receptors are reviewed in this paper, and a summary of the available clinical data is presented.
 ...
PMID:[AT1 angiotensin receptor inhibition as a new therapeutic possibility]. 941 27

Cardiac expression of angiotensin II (Ang II) AT1 and AT2 receptor subtypes is species dependent, and changes in their relative proportion may influence myocardial hypertrophy and fibrosis. Regional differences in the distribution of Ang II receptors in the normal and failing human heart were assessed using 125I-(Sar1,Ile8)Ang II binding and quantitative autoradiography. Receptor subtypes were distinguished by their affinity for selective nonpeptide antagonists (losartan and PD123319) and sensitivity to dithiothreitol. Ventricular and atrial tissues displayed a heterogeneous distribution of ligand binding sites. AT2 receptors predominated, representing 70% to 77% of the sites in normal and noninfarcted myocardium. Endocardial, interstitial, perivascular and infarcted regions in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy exhibited a significantly greater density (P < .001) of high affinity AT2 binding sites (Kd = 0.57 nmol/liter) compared with adjacent noninfarcted myocardium. Regions displaying the relative increase in AT2 binding sites corresponded to areas of fibroblast proliferation and collagen deposition, shown by picrosirius red staining. AT1 binding sites were localized to nerves, occurred at relatively low density in coronary vessels and represented only 23% to 29% of myocardial 125I-(Sar1,Ile8)Ang II binding sites. The border zone between infarcted and noninfarcted myocardium characteristically contained numerous microvessels, exhibiting perivascular AT2 receptors and endothelial angiotensin converting enzyme activity, as demonstrated by binding of 125I-351A. Specific myocardial AT2 receptor mRNA transcripts (approximately 3 kb) were identified and exhibited alternative splicing of untranslated 5' exons. The differential distribution of cardiac Ang II receptor subtypes and selective increase in binding to AT2 sites in the diseased heart suggest that cells bearing the AT2 receptor represent a significant target for Ang II, possibly contributing to its growth-related actions.
 ...
PMID:Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. 943 95

The actions of des-Asp angiotensin I, a nine aminoacid peptide, on the contractility of the aortic rings of the normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied. In the presence of captopril which prevented its degradation to angiotensin III by angiotensin converting enzyme, des-Asp-angiotensin I exerted direct concentration-dependent contractile action on the aortic rings. The contractile action was concentration-dependently attenuated by the AT1 receptor antagonist, losartan, but was not affected by the AT2 receptor antagonist, PD123319; indicating that angiotensin AT1 receptors mediate the direct contractile action. The response to des-Asp-angiotensin I was qualitatively different from that to angiotensin III i.e. lower potency and a likely higher efficacy suggesting that the two angiotensins act on different subtypes of angiotensin receptor. The response of the aortic rings to angiotensin III and des-Asp-angiotensin I in the SHR was significantly lower than the corresponding responses in WKY. Des-Asp-angiotensin I attenuated in a concentration-dependent and U-shape manner the response of the aortic ring to angiotensin III in the SHR but not in the WKY. Significant attenuation occurred in the pico to nano molar range of des-Asp-angiotensin I which is within the physiological concentration of the nonapeptide. Although these findings are the first demonstration of a direct and modulatory action of des-Asp-angiotensin I on the blood vessels of the SHR and raise the possibility of its involvement in blood pressure control, its exact role remains to be further studied.
 ...
PMID:Actions of des-Asp angiotensin I on the aortic rings of the normo- and hypertensive rats. 950 92

RENIN-ANGIOTENSIN ANTAGONISTS: The renal effects of angiotensin II receptor antagonists (AT1 blockers) can be compared with another class of drugs inhibiting the renin-angiotensin-aldosterone system, i.e. the angiotensin I converting enzyme inhibitors (ACE1). SIMILAR BUT SPECIFIC EFFECTS: The renal effects of these two classes of drugs are similar but each class has specific effects explained by several mechanisms. i) The system includes a large number of active peptides (angiotensin II, angiotensin III, angiotensin 1-7) which exert various effects according to their specific receptor(s): ii) several types of angiotensin II receptors have been identified (AT1, AT2, AT4 ...). Only AT1 blockers are available in clinical practice. iii) Receptor or enzyme blockade can produce varying effects; ACE inhibition is not specific since increased bradykinin activity is associated with the suppression of angiotensin peptide generation. EXPERIMENTAL AND CLINICAL TRIALS: Experimental and recent clinical studies have shown that AT1 blockers can induce, like ACE1, hypotension, renal vasodilation and natriuresis. The definite effects on discrete renal structures (vessels, glomeruli, tubules) differ however in magnitude which may suggest specific indications according to the pathophysiological background (renal disease, congestive heart failure, etc.).
 ...
PMID:[Renal effects of AT1 angiotensin receptor antagonists (AT1ra)]. 953 2

Angiotensin AT1 receptor antagonists represent a new class of drugs for the treatment of hypertension. They are specific for the renin-angiotensin system, selective for the angiotensin AT1 receptor, and act independently of the angiotensin II synthetic pathway. Blockade of the renin-angiotensin system at the receptor level should therefore be more complete. The high circulating levels of angiotensin II following angiotensin AT1 receptor blockade could be beneficial in stimulating other unblocked angiotensin receptors, especially the AT2 receptor. It has been proposed that the angiotensin AT2 receptor, which is re-expressed or up-regulated during pathological circumstances, counterbalances the effect of the stimulation of the angiotensin AT1 receptor. Through this mechanism, angiotensin AT1 antagonists may be superior to ACE inhibitors in cardiac and vascular remodelling as well as in kidney insufficiency. Long-term trials are required to demonstrate the possible clinical superiority of this new class of antihypertensive agents.
 ...
PMID:Does blockade of angiotensin II receptors offer clinical benefits over inhibition of angiotensin-converting enzyme? 967 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>