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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.
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PMID:Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. 910 37

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.
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PMID:Modulation of renal glomerular angiotensin II receptors by ace inhibition and AT1 receptor antagonism. 911 Mar 82

For heart, kidneys, lungs and liver alike, fibrosis represents a common pathway to their failure. Understanding pathophysiologic mechanisms involved in organ fibrosis are therefore of considerable interest, particularly given the potential for protective pharmacological strategies. Tissue repair involves inflammatory cells, including members of the monocyte/macrophage lineage, integral to initiating the repair process; and myofibroblasts, phenotypically transformed interstitial fibroblasts, responsible for collagen turnover and fibrous tissue formation. Each of these cellular events in the microenvironment of repair are associated with molecular events that lead to the de novo generation of angiotensin II (ANG II). In an autocrine/paracrine manner, this peptide regulates expression of TGF-beta 1 via angiotensin (AT1) receptor-ligand binding. It is this cytokine that contributes to phenotypic conversion of fibroblasts to myofibroblasts (myoFb) and regulates myofibroblast turnover of collagen. Angiotensin-converting enzyme (ACE) inhibition or AT1 receptor antagonism each prevent many of these molecular and cellular responses that eventuate in fibrosis and therefore have been found to be protective interventions.
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PMID:Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. 931 15

We determined whether local bradykinin production modulates cardiac adrenergic activity. Depolarization of guinea pig heart sympathetic nerve endings (synaptosomes) with 1 to 100 mmol/L K+ caused the release of endogenous norepinephrine (10% to 50% above basal level). This release was exocytotic, because it depended on extracellular Ca2+, was inhibited by the N-type Ca(2+)-channel blocker omega-conotoxin and the protein kinase C inhibitor Ro31-8220, and was potentiated by the neuronal uptake-1 inhibitor desipramine. Typical of adrenergic terminals, norepinephrine exocytosis was enhanced by activation of prejunctional angiotensin AT1-receptors and attenuated by adrenergic alpha 2-receptors, adenosine A1-receptors, and histamine H3-receptors. Exogenous bradykinin enhanced norepinephrine exocytosis by 7% to 35% (EC50, 17 nmol/L), without inhibiting uptake 1. B2-receptor, but not B1-receptor, blockade antagonized this effect. The kininase II/angiotensin-converting enzyme inhibitor enalaprilat and the addition of kininogen or kallikrein enhanced norepinephrine exocytosis by approximately equal to 6% to 40% (EC50, 20 nmol/L) and approximately equal to 25% to 60%, respectively. This potentiation was prevented by serine protease inhibitors and was antagonized by B2-receptor blockade. Therefore, norepinephrine exocytosis is augmented when bradykinin synthesis is increased or when its breakdown is inhibited. This is the first report of a local kallikrein-kinin system in adrenergic nerve endings capable of generating enough bradykinin to activate B2-receptors in an autocrine/paracrine fashion and thus enhance norepinephrine exocytosis. This amplification process may operate in disease states, such as myocardial ischemia, associated with severalfold increases in local kinin concentrations.
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PMID:Bradykinin B2-receptor activation augments norepinephrine exocytosis from cardiac sympathetic nerve endings. Mediation by autocrine/paracrine mechanisms. 935 50

Angiotensin-converting enzyme (ACE) inhibition alone or in combination with the angiotensin type-I receptor (AT1) antagonist losartan augments circulating levels of the bioactive peptide angiotensin-(1-7) [Ang-(1-7)]. Hence, we determined whether Ang-(1-7) contributes to the hypotensive effects produced by the combined administration of lisinopril and losartan in spontaneously hypertensive rats by blocking the peptide's synthesis with either of two structurally different neprilysin inhibitors. Intravenous administration of CGS 24592 (30 mg/kg) to rats in which blood pressure was normalized by 9 days of therapy with lisinopril and losartan elicited an elevation of mean arterial pressure that was sustained throughout the infusion period and for 20 minutes thereafter. The hypertensive response was associated with a 62% reduction in circulating levels of Ang-(1-7) and no change in plasma angiotensin II (Ang II). Intravenous infusion of one other neprilysin inhibitor (SCH 39370, 30 mg/kg) produced an increase in mean blood pressure of a magnitude similar to that found with CGS 24592. Pretreatment with the nonselective antagonist [Sar1,Thr8]-Ang II abolished any additional pressor effects of either neprilysin inhibitor in spontaneously hypertensive rats treated with lisinopril or losartan. However, neither the endothelin A antagonist BQ123 nor the kinin B2 antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors. These data suggest that inhibition of Ang-(1-7) formation in rats exposed to the combined blockade of Ang II production and activity is associated with a reversal of the antihypertensive actions produced by these therapies. Thus, endogenous Ang-(1-7) functions as a vasodilator hormone in this form of genetic hypertension.
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PMID:Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. 945 28

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.
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PMID:Vascular hypertrophy in hypertension: role of the renin-angiotensin system. 952 May 14

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.
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PMID:Link between angiotensin II and TGF-beta in the kidney. 952 2

Angiotensin II (Ang II) treatment was recently shown to activate Jak2, Stat1, and Stat3 proteins in cardiac myocytes. Angiotensin-converting enzyme (ACE) inhibitors have been shown to be an effective clinical treatment following myocardial infarction, implying that inhibition of Ang II production is beneficial in this pathological condition. Some of the effects of Ang II in cardiac myocytes may be mediated by the JAK-STAT signaling pathway. The AT1 receptor was the first G-protein-coupled-receptor reported to activate the JAK-STAT pathway. Recently, however, another G-protein-coupled-receptor (i.e. serotonin) was also shown to signal through the JaK2 and STAT proteins in myoblasts. We hypothesized that Ang II treatment might also activate Stat5 transcription factors in cardiac myocytes. In this study, we provide evidence that the G-protein-coupled, Ang II type I (AT1) receptor couples to activation of Stat5 through Jak2 kinase in neonatal rat ventricular myocytes. Angiotensin II induces a 1.5- to 10-fold increase in a Stat5 transcription complex, which binds to the prolactin-inducing element (PIE). By Western analysis, Stat5 protein levels were shown to be tyrosine phosphorylated two- to three-fold over control, following. Ang II treatment of cardiac myocytes. Phosphorylation of Stat5a and Stat5b proteins was rapid and sustained (30-60 min), and Jak2 kinase co-immunoprecipitated with activated Stat5 proteins. In cardiac myocytes, Stat5 proteins co-immunoprecipitated with the AT1 receptor. Selective inhibition of Jak2 kinase with AG-490 blocked formation of prolactin-inducing factor (PIF) complexes by Ang II, suggesting that Jak2 kinase was required for the tyrosine phosphorylation of Stat5 in cardiac myocytes.
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PMID:Angiotensin II activates Stat5 through Jak2 kinase in cardiac myocytes. 960 24

The renin-angiotensin system plays an important role in myocardial ischemia-reperfusion injury. Angiotensin II (Ang II) contributes to the evolution of ischemic coronary events through its hemodynamic, hemostatic and mitogenic effects. Angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor antagonists have been shown to be cardioprotective in experimental animal models, with ischemia-reperfusion injury and in patients with congestive heart failure. Ang II receptors include at least two different subtypes, AT1 and AT2. Both AT1 and AT2 are expressed in the rat heart. Myocardial AT1 receptor density increases in association with ACE expression, and AT1 receptor activation is related to collagen formation following myocardial infarction in rats. Studies from the authors' laboratory have shown significant myocardial dysfunction in association with a concurrent increase in AT1 receptor expression in the rat myocardium immediately following a brief period of ischemia and reperfusion. Application of antisense oligodeoxynucleotides (AS-ODN) directed at AT1 receptor messenger RNA and AT1 receptor antagonist, losartan, significantly attenuates myocardial dysfunction induced by ischemia-reperfusion in the isolated rat heart. These observations suggest that myocardial AT1 receptor expression is involved in myocardial dysfunction following ischemia-reperfusion. Unlike losartan, which upregulates the plasma Ang II level, administration of AS-ODN does not affect plasma Ang II level. Although the reason for this is not clear, the difference in plasma Ang II levels implies that AS-ODN may be, at least theoretically, more beneficial than losartan in limiting ischemia-reperfusion-induced cardiac dysfunction. Apoptosis, or programmed cell death, also contributes to the outcome of myocardial ischemia-reperfusion injury. Recent studies from the authors' laboratory have demonstrated that Ang II induces apoptosis in cultured human coronary artery endothelial cells via activation of AT1 receptors and this can be blocked by losartan. These observations collectively underscore the importance of myocardial AT1 receptor expression in ischemia-reperfusion injury.
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PMID:Myocardial angiotensin II receptor expression and ischemia-reperfusion injury. 979 75

The effects of N-type calcium channel inhibition with omega-conotoxin GVIA (omega-CTX) on cardiovascular parameters and vagally mediated autonomic reflexes and the role of the renin-angiotensin system were assessed in conscious rabbits. Omega-CTX (10 microg/kg, i.v.) resulted in hypotension, tachycardia, and attenuation of the sympathetic and vagal components of the baroreceptor-heart rate reflex (baroreflex). In the control group (no pretreatment), the peak decrease in mean arterial pressure (MAP) of 13 +/- 3 mm Hg from 72 +/- 2 mm Hg occurred after 33 +/- 3 min, with a corresponding tachycardia of 80 +/- 20 beats/min (n = 6). The tachycardia was due to vagal withdrawal, as a similar increase in heart rate (84 +/- 8 beats/min) after omega-CTX was observed after pretreatment with the beta-adrenoceptor antagonist, propranolol (n = 6). Angiotensin-converting enzyme (ACE) inhibition with enalaprilat revealed a larger, more rapid decrease in MAP in response to omega-CTX (-19 +/- 4 mm Hg from 65 +/- 1 mm Hg after 18 +/- 2 min; n = 6) compared with the control group. Similar larger decreases in MAP were also observed in the presence of the AT1-receptor antagonist, losartan, or the bradykinin B2 receptor antagonist, HOE-140 (n = 5-6). Pretreatment with enalaprilat, losartan, or HOE-140 caused a 50% decrease in the reflex tachycardia after omega-CTX compared with that observed in the control group, and omega-CTX caused a greater attenuation of the vagal component of the baroreflex and a decrease in the bradycardia evoked by the Bezold-Jarisch-like reflex. Also, there was a significant decrease in the bradycardia induced by the nasopharyngeal reflex after omega-CTX in the presence of ACE inhibition and HOE-140. Thus in the conscious rabbit, angiotensin II and bradykinin have a role in attenuating and slowing the hypotensive effect of N-type calcium channel inhibition. Vagolytic effects of omega-CTX on the baroreflex are augmented, and on other vagal reflexes are unmasked, via inhibition of the renin-angiotensin system. The complexity and mechanism of the interaction between N-type calcium channels and the renin-angiotensin system remain to be elucidated.
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PMID:Endogenous angiotensin II and bradykinin delay and attenuate the hypotension after N-type calcium channel blockade in conscious rabbits. 986 1


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