Angiotensin II human

Angiotensin II human is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure.

CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression.[Pubmed:28292711]

Redox Biol. 2017 Aug;12:377-388.

Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47(phox), Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-kappaB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47(phox) translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-kappaB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.

Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes.[Pubmed:28374982]

Basic Clin Pharmacol Toxicol. 2017 Oct;121(4):239-245.

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti-inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50 ) of AA metabolism was losartan

miR-185/P2Y6 Axis Inhibits Angiotensin II-Induced Human Aortic Vascular Smooth Muscle Cell Proliferation.[Pubmed:28277742]

DNA Cell Biol. 2017 May;36(5):377-385.

The abnormal proliferation and apoptosis of human aortic vascular smooth muscle cells (HAVSMCs) play an important role in the pathogenesis of hypertension. Recent study revealed that angiotensin II (Ang II) could elicit HAVSMC dysfunction, to induce or aggravate hypertension. Purinergic receptor P2Y6, an inflammation-inducible G protein-coupled receptor, promoted Ang II-induced hypertension. In the present study, we revealed that Ang II induced HAVSMC proliferation and upregulated P2Y6 protein levels. After knockdown of P2Y6, the promotive effect of Ang II on HAVSMC proliferation was restored. microRNAs (miRNAs) involve in most biological processes. In this study, we scanned out seven candidate miRNAs, which were predicted to contain binding site of P2Y6's 3'-UTR by online tools. Among them, miR-185 was significantly downregulated by Ang II treatment. miR-185 reduced P2Y6 protein levels by direct binding to the 3'UTR of P2Y6. miR-185 overexpression suppressed HAVSMC proliferation; P2Y6 overexpression or Ang II treatment promoted HAVSMC proliferation, and restored the suppressive effect of miR-185 on HAVSMC proliferation. Besides, miR-185/P2Y6 axis also affected pERK1/2 protein levels. Taken together, the present study indicated that miR-185/P2Y6 axis might inhibit Ang II-induced HAVSMC proliferation through miR-185 negatively regulating P2Y6 expression and the downstream ERK pathway; rescuing miR-185 expression to inhibit P2Y6 may represent a therapeutic strategy against HAVSMC dysfunction and hypertension.

Activation of CB1 receptors by 2-arachidonoylglycerol attenuates vasoconstriction induced by U46619 and angiotensin II in human and rat pulmonary arteries.[Pubmed:28356298]

Am J Physiol Regul Integr Comp Physiol. 2017 Jun 1;312(6):R883-R893.

Recent evidence suggests that endocannabinoids acting via cannabinoid CB1 receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature. The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A2 analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct Gq/11 protein-coupled receptors (thromboxane, ANG II type 1, 5-HT2, and alpha1-adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB1 receptor antagonist AM251 (1 muM) and diacylglycerol lipase (2-arachidonoylglycerol synthesis enzyme) inhibitor RHC80267 (40 muM) enhanced contractions induced by U46619 in hPAs and rPAs and by ANG II in rPAs in an endothelium-dependent manner. AM251 did not influence vasoconstrictions induced by 5-HT or phenylephrine in rPAs. The monoacylglycerol lipase (2-arachidonoylglycerol degradation enzyme) inhibitor JZL184 (1 muM), but not the fatty acid amide hydrolase (anandamide degradation enzyme) inhibitor URB597 (1 muM), attenuated contractions evoked by U46619 in hPAs and rPAs and ANG II in rPAs. 2-Arachidonoylglycerol concentration-dependently induced relaxation of hPAs, which was inhibited by endothelium denudation or AM251 and enhanced by JZL184. Expression of CB1 receptors was confirmed in hPAs and rPAs using Western blotting and immunohistochemistry. The present study shows the protective interaction between the endocannabinoid system and vasoconstriction in response to U46619 and ANG II in the human and rat pulmonary circulation. U46619 and ANG II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB1 receptor-dependent and/or CB1 receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction.

Activation of brain neurons by circulating angiotensin II: direct effects and baroreceptor-mediated secondary effects.[Pubmed:10215161]

Neuroscience. 1999 May;90(2):581-94.

Circulating angiotensin II acts on neurons in circumventricular organs, leading to activation of central pathways involved in blood pressure regulation and body fluid homeostasis. Apart from this primary effect, an increase in the level of circulating angiotensin II may also activate brain neurons as a secondary consequence of the associated increase in blood pressure, which will stimulate arterial baroreceptors and thus activate central neurons that are part of the central baroreceptor reflex pathway. The aim of this study was to identify the population of neurons that are activated as a consequence of the direct actions of circulating angiotensin II on the brain, independent of secondary baroreceptor-mediated effects. For this purpose, we have mapped the distribution of neurons in the brainstem and forebrain that are immunoreactive for Fos (a marker of neuronal activation) following intravenous infusion of angiotensin II in conscious rabbits with chronically denervated carotid sinus and aortic baroreceptors. The distribution was compared with that evoked by the same procedure in two separate groups of barointact rabbits, in which angiotensin II was infused either at a rate similar to that in the barodenervated group, or at a rate approximately five times greater. In barodenervated rabbits, angiotensin II infusion evoked a significant increase in Fos expression, compared to control animals infused with the vehicle solution alone, in several forebrain nuclei (organum vasculosum of the lamina terminalis, subfornical organ, median preoptic nucleus, supraoptic nucleus, paraventricular nucleus, bed nucleus of the stria terminalis and suprachiasmatic nucleus), but little or no increase in Fos expression in any lower brainstem region. In barointact rabbits infused with angiotensin II at a similar rate to that in barodenervated rabbits, a similar degree of Fos expression was evoked in all of the above forebrain regions, but in addition a significantly greater degree of Fos expression was evoked in several medullary regions (nucleus tractus solitarius, area postrema, and ventrolateral medulla), even though the angiotensin II-evoked increase in mean arterial pressure (17 +/- 3 mmHg) was less than that evoked in the barodenervated rabbits (26 +/- 2 mmHg). In barointact rabbits infused with angiotensin II at the higher rate, the increase in mean arterial pressure was 29 +/- 3 mmHg. In these animals, the pattern of Fos expression was similar to that evoked in barointact rabbits infused at the lower rate, but the degree of Fos expression in all medullary regions and in some forebrain regions was significantly greater. The results of the present study, together with those of previous studies from our laboratory in which we determined the effects of phenylephrine-induced hypertension on brain Fos expression [Li and Dampney (1994) Neuroscience 61, 613-634; Potts et al. (1997) Neuroscience 77, 503-520], indicate that in conscious rabbits circulating angiotensin II activates primarily circumventricular neurons within the organum vasculosum of the lamina terminalis and subfornical organ, but not the area postrema, and this in turn leads to activation of neurons in other forebrain regions, including the median preoptic, supraoptic, paraventricular and suprachiasmatic nucleus as well as the bed nucleus of the stria terminalis. In contrast, the activation of neurons in medullary regions evoked by an increase in the level of circulating angiotensin II is primarily a secondary effect resulting from stimulation of arterial baroreceptors.

Effects of prostaglandins and nitric oxide on the renal effects of angiotensin II in the anaesthetized rat.[Pubmed:9723960]

Br J Pharmacol. 1998 Aug;124(7):1467-74.

1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation. 2. Intrarenal artery (i.r.a.) infusion of Ang II (1-30 ng kg(-1) min(-1)) elicited a dose-dependent decrease in renal vascular conductance (RVC; -38+/-3% at 30 ng kg(-1) min(-1); P < 0.01) and increase in filtration fraction (FF; +49+/-8%; P < 0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1-30 ng kg(-1) min(-1) (+6+/-17%, +11+/-17%, +22+/-23%, and -5+/-9%, respectively, at 30 ng kg(-1) min(-1)). At higher doses, Ang II (100 and 300 ng kg(-1) min(-1)) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV. 3. Pretreatment with indomethacin (10 mg kg(-1) i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (-25+/-7% vs -38+/-3% at Ang II 30 ng kg(-1) min(-1)). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (-38+/-10% at 30 ng kg(-1) min(-1)); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1-30 ng kg(-1) min(-1), and was not accompanied by any significant changes in Uv, UNaV or FENa (-21+/-12%, -18+/-16% and +36+/-38%, respectively). 4. Pretreatment with L-NAME (10 microg kg(-1) min(-1) i.v.) tended to reduce basal RVC (control -11.8+/-1.4, +L-NAME -7.9+/-1.8 ml min(-1) mmHg(-1) x 10(-2)), and significantly increased basal FF (control +15.9+/-0.8, +L-NAME +31.0+/-3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (-38+/-3% vs -35+/-13% at 30 ng kg(-1) min(-1)), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (-51+/-11%, -41+/-14% and -31+/-17%, respectively, at an infusion rate of Ang II, 30 ng kg(-1) min(-1)). When evaluated over the range of 1-30 ng kg(-1) min(-1), the effect of Ang II on GFR and Uv were statistically significant (P < 0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO. 5. In contrast to its effects after pretreatment with L-NAME alone, Ang II (1-30 ng kg(-1) min(-1)) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT1 receptor antagonist, GR117289 (1 mg kg(-1) i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT1 receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv. 6. In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.

Cardiovascular effects of microinjection of angiotensin II in the brainstem of renal hypertensive rats.[Pubmed:2213569]

J Pharmacol Exp Ther. 1990 Oct;255(1):374-81.

The cardiovascular effects of microinjection of angiotensin II (AII) into the area postrema (AP), nucleus of the solitary tract (NTS) and rostroventrolateral medulla were studied in urethane anesthetized sham-normotensive (NT) and two-kidney, one-clip renal hypertensive rats. Microinjection of AII (2-2000 ng) in the AP of renal hypertensive rats elicited a dose-dependent decrease in blood pressure, heart rate and renal sympathetic nerve activity. Similar effects were observed in the NTS. In the NT rats, low doses of AII (2 and 20 ng), either in the AP or NTS, were also depressor. High doses of AII (200-2000 ng) were needed to observe a modest pressor effect in the NT animals. A decrease in heart rate and renal sympathetic activity was observed with the pressor effect. The AII-antagonist, [Sar1,Val5,Ala8]-AII, into the NTS or AP increased blood pressure and heart rate and inhibited the cardiovascular effects of low doses of AII in both group of rats. In contrast, [Sar1,Val5,Ala8]AII did not affect the pressor action of high doses of AII in the NT group. While the microinjection of AII into the rostroventrolateral medulla did not produce any significant cardiovascular effect in the renal hypertensive group, it resulted in a modest pressor effect in the NT rats. These results indicate that acute activation of AII receptors in the AP or NTS does not contribute to the pressor effect of AII in renal hypertensive rats.

Angiotensin II human (Angiotensin II) is a vasoconstrictor that mainly acts on the AT1 receptor. Angiotensin II human stimulates sympathetic nervous stimulation, increases aldosterone biosynthesis and renal actions. Angiotensin II human induces growth of vascular smooth muscle cells, increases collagen type I and III synthesis in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis. Angiotensin II human also induces apoptosis.

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