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

Angiotensin II plays a central role in the pathogenesis of hypertension and of related cardiovascular disorders by binding to and activating angiotensin II receptors (AT1 receptors). Sensitization to the vasopressor response of angiotensin II is a key feature in many cardiovascular disorders. However, underlying mechanisms responsible for angiotensin II hypersensitivity are barely understood. Because angiotensin II responsiveness of AT1 receptors can be specifically modified by AT1/B2 receptor dimerization, we determined the AT1 receptor dimerization status in an experimental model of hypertension. AT1/B2 receptor heterodimers were abundant on renal mesangial cells isolated from spontaneously hypertensive rats compared with that on cells from normotensive controls. Heterodimerization of AT1 with B2 receptors was correlated with high levels of B2 receptor protein on kidneys and on mesangial cells of hypertensive rats, as determined in immunoblot with receptor-specific antibodies. Specific inhibition of AT1/B2 receptor heterodimers revealed that these receptor heterodimers mediated an enhanced angiotensin II-stimulated Galphaq/11 activation and an increased endothelin-1 secretion of mesangial cells from hypertensive rats. Thus, AT1/B2 receptor heterodimerization contributes to angiotensin II hyperresponsiveness of mesangial cells in experimental hypertension.
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PMID:Mesangial AT1/B2 receptor heterodimers contribute to angiotensin II hyperresponsiveness in experimental hypertension. 1601 92

The effect of angiotensin IV (AngIV) was studied in freshly isolated rat basilar arteries (BAs) perfused at a constant rate. AngIV had no effect on basal BA perfusion pressure, but induced a marked concentration-dependent contraction in vessels precontracted by a 50-mM KCl solution (EC50=44.5+/-16 nM). This contraction was unaffected by the angiotensin AT1 receptor antagonist candesartan or the angiotensin AT2 receptor blocker PD123319, but was markedly inhibited by two different specific AT4 receptor antagonists, Nle1-Leu3 yen(CH2-NH2)3-4-AngIV and divalinal-AngIV. Removal of the endothelium abolished the contractile response to AngIV, and pretreatment of endothelium-intact arteries with the endothelin ETA/ETB receptors inhibitor PD142893 blocked the AngIV-induced contraction to the same extent. In BA pretreated with endothelin-1 (ET-1; 0.01 microM), AngIV-induced a concentration-dependent contraction, shifted to the left, compared with that observed with KCl precontraction, unaffected by candesartan but completely abolished by Nle1-Leu3 yen(CH2-NH2)3-4-AngIV. The contractile effect was not affected by endothelium removal in the presence of exogenous ET-1, in contrast to KCl pretreated BA, suggesting that endothelium was mandatory to unmask the effect of AngIV as a source of endogenous ET-1 release. Taken together, these results indicate that low (nanomolar) concentrations of AngIV exert a constrictive effect mediated by its specific binding site AT4 in the rat BA, and that this vasoactive effect is indirect and involves endogenous endothelin(s).
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PMID:Vasoconstrictive effect of angiotensin IV in isolated rat basilar artery independent of AT1 and AT2 receptors. 1625 39

We investigated the implication of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the proliferation stimulated by angiotensin II (Ang II) and endothelin-1 (ET-1) in cultured rabbit gingival fibroblasts (CRGF). Ang II stimulated activation of ERK1/2 and the activation was inhibited by CV-11974, an AT1 antagonist, and saralasin, an AT1/AT2 antagonist, but not by PD123,319, an AT2 antagonist in the CRGF. Ang II-stimulated proliferation was inhibited by PD98059 or U0126, selective MEK inhibitors. Furthermore, ET-1 stimulated proliferation via G-protein-coupled ETA receptors, which were identified by Western blot analysis of membrane protein from the CRGF. ET-1 also stimulated activation of ERK1/2 and the activation was inhibited by BQ-123, an ETA inhibitor, and TAK044, an ETA/ETB inhibitor, but not by BQ-788, an ETB inhibitor. ET-1-stimulated proliferation was inhibited by PD98059 or U0126. These findings suggest that ERK1/2 play a role in the signaling process leading to proliferation stimulated by Ang II and ET-1 via G-protein-coupled receptors, AT1 and ETA in CRGF.
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PMID:Inhibition of angiotensin II- and endothelin-1-stimulated proliferation by selective MEK inhibitor in cultured rabbit gingival fibroblastsdagger. 1631 80

Our present study aimed to characterize the effects of lipopolysaccharide (LPS) on the expression of the bradykinin B2-receptor in the mouse heart, which may have a role in cardiac depression during sepsis. We found that LPS induced the up-regulation of B2-receptor mRNA in the heart in vivo and in cultured cardiac myocytes in vitro. Like LPS, tumor necrosis factor-alpha (TNF-alpha) but not interleukin (IL)-1-beta, IL-6 or endothelin-1 stimulated B2-receptor expression in cultured myocytes. The effect of LPS on the expression of B2-receptor mRNA was also mimicked in cardiac myocytes by Ang II via Ang II type 1 (AT1-) receptor. Losartan, an AT1-receptor antagonist, inhibited about 50% of the LPS-induced up-regulation of B2-receptor mRNA in the heart in vivo and in cultured cardiac myocytes in vitro. Furthermore, the up-regulation of B2-receptor mRNA by either LPS or Ang II in cultured myocytes was abolished by anti-TNF-alpha antibody. These results suggest that the up-regulation of cardiac B2-receptor expression by LPS is mediated through TNF-alpha, which is produced in the myocardium by two different mechanisms in an AT1-receptor-dependent and independent manners, implying the role of the cardiac kallikrein-kinin system in the development of cardiac dysfunction during sepsis.
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PMID:The lipopolysaccharide-induced up-regulation of bradykinin B2-receptor in the mouse heart is mediated by tumor necrosis factor-alpha and angiotensin II. 1675 7

Chronic ventricular pressure overload states, such as hypertension, and elevated levels of neurohormones (norepinephrine, angiotensin II, endothelin-1) initiate cardiac hypertrophy and dysfunction and share the property of being able to bind to Gq-coupled 7-transmembrane receptors. The goal of the current study was to determine the role of endogenous cardiac myocyte Gq signaling and its role in cardiac hypertrophy and dysfunction during high blood pressure (BP). We induced renal artery stenosis for 8 weeks in control mice and mice expressing a peptide inhibitor of Gq signaling (GqI) using a 2 kidney, 1 clip renal artery stenosis model. 8 weeks following chronic high BP, control mice had cardiac hypertrophy and depressed function. Inhibition of cardiomyocyte Gq signaling did not reverse cardiac hypertrophy but attenuated increases in a profile of cardiac profibrotic genes and genes associated with remodeling. Inhibition of Gq signaling also attenuated the loss of cardiac function. We determined that Gq signaling downstream of angiotensin II receptor stimulation negatively impacted beta-adrenergic receptor (AR) responses and inhibition of Gq signaling was sufficient to restore betaAR-mediated responses. Therefore, in this study we found that Gq signaling negatively impacts cardiac function during high BP. Specifically, we found that inhibition of AT1-Gq signaling augmented betaAR mediated effects in a renal artery stenosis model of hypertension. These observations may underlie additional, beneficial effects of angiotensinogen converting enzyme (ACE) inhibitors and angiotensin receptor antagonists observed during times of hemodynamic stress.
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PMID:Inhibition of angiotensin II Gq signaling augments beta-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure. 1893 63

As angiotensin II may underlie the deleterious effects of some vascular diseases, we have examined the role of this peptide on the cerbrovascular endothelin-1 action after ischemia-reperfusion. In anesthetized goats, 1 hour-occlusion followed by 1 hour-reperfusion of the left middle cerebral artery (MCA) was induced, and then segments 3-mm in length from branches of the right MCA (control) and the left MCA (ischemic) were obtained for isometric tension recording. Endothelin-1 (10(-11)-10(-7) M) produced a contraction that was higher in ischemic than in control arteries, and in control but not in ischemic arteries this contraction was potentiated by angiotensin II (10(-7) M). Losartan (3 x 10(-6) M), antagonist of AT1 receptors, did not affect the response to endothelin-1 in control arteries, but reduced it both in ischemic arteries and angiotensin II-treated control arteries. PD123,319 (3 x 10(-6) M), antagonist of AT2 receptors, or the inhibitor of nitric oxide synthesis L-NAME (10(-4) M) did not alter the arterial effects of endothelin-1. Therefore, angiotensin II may potentiate the constriction to endothelin-1 in normal cerebral arteries by activating AT1 receptors. The observed cerebrovascular increased response to endothelin-1 after ischemia-reperfusion might be related in part to activation of AT1 receptors under this condition.
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PMID:Role of angiotensin II in the response to endothelin-1 of goat cerebral arteries after ischemia-reperfusion. 1913 74

We investigated the role of angiotensin II and endothelin-1 using the angiotensin AT1 receptor antagonist losartan and the endothelin ETA receptor antagonist atrasentan, in malignant hypertension and renal failure and damage induced by nitric oxide (NO) synthase inhibition in Harlan Sprague-Dawley (SD) rats. We also evaluated whether the protective effects of losartan go beyond the blood pressure reduction. Within only 3 weeks of treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), Harlan SD rats developed malignant hypertension with renal failure and injuries. The latter were comprised of fibrinoid necrosis of small arteries and glomerular and tubular necrosis. Although both losartan and atrasentan attenuated the development of hypertension and renal failure, losartan only prevented the renal damage. In contrast to antrasentan, the vasodilator hydralazine reduced blood pressure and prevented the renal injuries similar to losartan. However, when these treatments were prolonged to 5 weeks, losartan, but not hydralazine, was still effective in reducing renal failure and damage, despite a marked increase in blood pressure. Our results indicate that angiotensin II and endothelin-1 play a differential role in the pathogenesis of malignant hypertension and in vascular and renal damage induced by L-NAME in Harlan SD rats. Although the protective effects of atrasentan may depend on the reduction of blood pressure, which was shown to retard the development of renal injury using hydralazine, those of losartan go beyond the blood pressure reduction. Hence, tissue protective effects of angiotensin AT1 receptor blockade may be pivotal for long-term vascular and renal protection.
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PMID:Protective effects of angiotensin AT1 receptor blockade in malignant hypertension in the rat. 1932 69

Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca(2+)](i)) in a dose-dependent manner and activated the L-type Ca(2+) channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca(2+)](i) elevation was abolished in the presence of the ET(A) receptor blocker BQ123, but was not affected by the ET(B) receptor blocker BQ788. ET-1-induced an increase in [Ca(2+)](i), which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 micromol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca(2+)](i) increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca(2+) channel current and an increase of open-state probability (NPo) of an L-type single Ca(2+) channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca(2+) channel activation and Ca(2+)-induced Ca(2+) release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.
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PMID:Endothelin-1 induces intracellular [Ca2+] increase via Ca 2+ influx through the L-type Ca2+ channel, Ca 2+ -induced Ca2+ release and a pathway involving ET A receptors, PKC, PKA and AT1 receptors in cardiomyocytes. 1938 62

Inflammation plays a major role in pathological conditions leading to cardiovascular events. Administration of lipopolysaccharide to animals decreases arterial blood flow, in contrast to the dilatations that occur in microvessels. The purpose of the present study was to determine whether or not lipopolysaccharide, in vivo, evokes arterial constriction and if so the underlying mechanisms. Rabbits were anaesthetized, blood pressure monitored and femoral artery diameter continuously recorded with an echotracking device. Lipopolysaccharide induced leucopenia, thrombocytopenia, acidosis and a progressive hypotension with a decrease in femoral artery diameter (-30.7+/-2.4% after 3 h) and an increase in arterial rigidity. Three hours after lipopolysaccharide administration, the arterial dilatations to acetylcholine, arachidonic acid and iloprost were inhibited while that to sodium nitroprusside was not altered; the constrictions to norepinephrine, angiotensin II, U46619 (thromboxane analog) and serotonin were not modified. Under control conditions endothelin-1 produced an endothelin ET(B) dependent dilatation, reversed after lipopolysaccharide to an endothelin ETA dependent constriction. The thromboxane TP receptor antagonist S 18886 partially blocked the constriction; the angiotensin AT1 receptor antagonist candesartan prevented it. S 18886 normalized the impaired dilatations to acetylcholine, antagonists of 5-HT-receptors partially restored them while candesartan was ineffective. Antagonists of the endothelin or the histamine receptors had no effect. The present data show that lipopolysaccharide-induced inflammation causes 1) a strong constriction of the femoral artery in which activation of both thromboxane and angiotensin AT1 receptors is involved 2) a reduction of the endothelium-dependent dilatation to acetylcholine attributed to the activation of thromboxane TP receptors.
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PMID:Role of thromboxane TP and angiotensin AT1 receptors in lipopolysaccharide-induced arterial dysfunction in the rabbit: an in vivo study. 2020 67

The number of patients suffering from heart failure is constantly increasing. One of its main causes is coronary artery disease, especially myocardial infarction. Progression of heart failure depends both on the extent of ischaemic injury and the course of subsequent adaptive processes. Genetic methods may help to find individuals at high risk of developing heart failure. There are multiple genes influencing circulatory system, some of their alleles may potentially affect progression of the disease. Among the most promising targets are genes of the renin-angiotensin-aldosterone system: insertion/deletion (L/D) polymorphism of angiotensin converting enzyme gene, polymorphisms of angiotensinogen, angiotensin receptors (AT1 and AT2) and aldosterone syntase genes. Other genetic factors, which may affect are different gene variants of adrenergic receptors (beta1, beta2, alpha2C), AMP deaminase-1, endothelin-1, endothelial nitric oxide syntase, precursors of natriuretic peptides and inflammatory factors (TNF-alpha, IL-6, MCP-1, TGF, MMP-2). Furthermore, the response to drugs may depend on genetic background, that is why pharmacogenetics creates new possibilities to tailor the best therapy for each patients with heart failure. Therefore research in the field of genetic factors affecting the development of heart failure has not only scientific, but also practical value.
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PMID:[Development of heart failure in the course of coronary artery disease--the role of genetic factors]. 2052 99


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