Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT2 receptors, we examined the possible contribution of AT2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK+/+) and in tissue kallikrein-deficient mice (TK-/-) in which the presence of AT2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK+/+, whereas it had no effect in TK-/- mice. In both groups, blockade of AT1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT2 receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice. Combining PD123319 with the bradykinin B2 receptor antagonist HOE-140 had no additional effect to AT2 receptor blockade alone in TK+/+ arteries. Flow-dependent-dilation was also impaired in AT2 receptor deficient mice (AT2-/-) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT2+/+, but not in AT2-/- mice. In conclusion, this study demonstrates that the presence of functional AT2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.
 ...
PMID:Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors. 1513 Oct 8

It has been suggested that low concentrations of angiotensin II cause vasoconstriction, whereas high concentrations evoke vasodilation. Thus, this work aimed to characterize functionally the mechanisms underlying angiotensin II-induced relaxation, at high concentration, in isolated rat aortic rings. Vascular reactivity experiments, using standard muscle bath procedures, showed that angiotensin II (1-30 microM) concentration-dependently induces relaxation of phenylephrine-precontracted rings with intact or denuded endothelium. The relaxation was not altered in the presence of ethylenediamine tetraacetic acid (EDTA), a nonselective inhibitor of metalloprotease. The selective antagonist of AT2 receptors, PD123319, inhibited angiotensin II-induced relaxation. Conversely, losartan or A-779, selective AT1 and Ang1-7 receptor antagonists, respectively, did not alter the relaxation induced by angiotensin II. HOE-140, a selective antagonist of the bradykinin B2 receptor, and amiloride, a Na+/H+ exchanger inhibitor, abolished angiotensin II-induced relaxation. Administration of exogenous bradykinin on precontracted tissues produced concentration-dependent relaxation, which was also inhibited by HOE-140. Preincubation of denuded-rings with NG-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), indomethacin, or tetraethylammonium (TEA) reduced angiotensin II-induced relaxation. The combination of L-NAME, indomethacin, and TEA completely abolished the relaxation induced by angiotensin II. 4-Aminopyridine (4-AP) as well as charybdotoxin reduced angiotensin II-induced relaxation. On the other hand, neither apamin nor glibenclamide altered the relaxation induced by angiotensin II. The major new finding of this work is that it demonstrated functionally the existence of AT2 receptors located on smooth muscle of rat aortic rings that mediated vasorelaxation via stimulation of B2 receptors by bradykinin, which in turns results in the activation of the NO-cGMP pathway, vasodilator cyclooxygenase product(s), and voltage-dependent and Ca+-activated large-conductance K+ channels.
 ...
PMID:Mechanisms underlying the endothelium-independent relaxation induced by angiotensin II in rat aorta. 1565 62

Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system [TGR(ASrAOGEN)680]. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.
 ...
PMID:Central angiotensin II controls alcohol consumption via its AT1 receptor. 1612 15

Recent study demonstrated that duodenal HCO3- secretion is affected by modulation of the renin-angiotensin system. We examined the effects of enalapril (angiotensin-converting enzyme (ACE) inhibitor) or losartan (angiotensin AT1 receptor antagonist) on duodenal HCO3- secretion in rats and investigated the mechanisms involved in the renin-angiotensin system-related HCO3- response. A proximal duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. Enalapril increased the HCO3- secretion in a dose-dependent manner, with a decrease in arterial blood pressure (MBP), and these effects were significantly attenuated by pretreatment with indomethacin, L-NAME and FR172357 (a selective bradykinin B2 receptor antagonist). Although losartan alone did not affect the HCO3- secretion, despite reducing MBP, the agent dose-dependently increased the HCO3- secretion in the presence of angiotensin II, and this response was totally antagonized by prior administration of FR172357, indomethacin and L-NAME. Bradykinin also dose-dependently increased the HCO3- secretion with no change in MBP, though transient, and again the effects were blocked by indomethacin, L-NAME and FR172357. Both prostaglandin (PG) E2 and the nitric oxide (NO) donor NOR-3 also increased the HCO3- secretion, the latter effect being inhibited by indomethacin. These results suggest that both an ACE inhibitor and AT1 antagonist (in the presence of angiotensin II) increase duodenal HCO3- secretion via a common pathway, involving bradykinin, NO and PGs. It is also assumed that bradykinin releases NO locally, which in turns stimulates HCO3- secretion mediated by PGs.
 ...
PMID:ACE inhibitor and AT1 antagonist stimulate duodenal HCO3- secretion mediated by a common pathway - involvement of PG, NO and bradykinin. 1620 62

The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin. In the current experiments, we found that exogenous ACE added to vascular smooth muscle cell culture strongly induces and upregulates the genes of bradykinin receptors B1 and B2. This transcriptional regulatory property of ACE was shown to be unrelated to its known enzymatic properties. Indeed, ACE at 3.75 microg/ml added in the culture medium of vascular smooth muscle cells was found to cause marked upregulation of the mRNA expression of the genes for the B1 and B2 receptors of bradykinin by 22- and 11-fold, respectively. This phenomenon was not altered by the addition of specific angiotensin II antagonists for the AT1 or AT2 receptors. Moreover, the ACE inhibitor captopril, which inhibited ACE enzymatic activity, did not block its effect at the bradykinin receptor gene transcription level. Expression of both receptor genes was completely abolished by actinomycin D. Furthermore, transcriptional upregulation was inhibited by curcumin, suggesting involvement of different transcriptional factors in this phenomenon. Electrophoretic mobility shift assay revealed increase in NF-kappaB and activator protein-1 protein binding for consensus sequences, between ACE-treated cells versus untreated cells. The data indicate a novel biological function of the ACE unrelated to its well-known enzymatic function as a peptidyl dipeptidase.
 ...
PMID:Angiotensin-converting enzyme regulates bradykinin receptor gene expression. 1621 9

With inhibition or absence of the bradykinin B2 receptor (B2R), B1R is upregulated and assumes some of the hemodynamic properties of B2R, indicating that both participate in the maintenance of normal vasoregulation or to development of hypertension. Herein we further evaluate the role of bradykinin in normal blood pressure (BP) regulation and its relationship with other vasoactive factors by selectively blocking its receptors. Six groups of Wistar rats were treated for 3 wk: one control group with vehicle alone, one with concurrent administration of B1R antagonist R-954 (70 microg x kg(-1) x day(-1)) and B2R antagonist HOE-140 (500 microg x kg(-1) x day(-1)), one with R-954 alone, one with HOE 140 alone, one with concurrent administration of both R-954 and HOE-140 plus the angiotensin antagonist losartan (5 mg x kg(-1) x day(-1)), and one with only losartan. BP was measured continuously by radiotelemetry. Only combined administration of B1R and B2R antagonists produced a significant BP increase from a baseline of 107-119 mmHg at end point, which could be partly prevented by losartan and was not associated with change in catecholamines, suggesting no involvement of the sympathoadrenal system. The impact of blockade of bradykinin on other vasoregulating systems was assessed by evaluating gene expression of different vasoactive factors. There was upregulation of the eNOS, AT1 receptor, PGE2 receptor, and tissue kallikrein genes in cardiac and renal tissues, more pronounced when both bradykinin receptors were blocked; significant downregulation of AT2 receptor gene in renal tissues only; and no consistent changes in B1R and B2R genes in either tissue. The results indicate that both B1R and B2R contribute to the maintenance of normal BP, but one can compensate for inhibition of the other, and the chronic inhibition of both leads to significant upregulation in the genes of related vasoactive systems.
 ...
PMID:Role of bradykinin B1 and B2 receptors in normal blood pressure regulation. 1650 3

Preeclampsia is a hypertensive disorder that is unique to pregnancy, with consistent involvement of the kidney. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of preeclampsia. In the gravid state, in addition to the RAS in the kidney, there is a tissue-based RAS in the uteroplacental unit. Increased renin expression in human preeclampsia and in transgenic mouse models with a human preeclampsia-like syndrome shows that activation of the uteroplacental RAS, with angiotensin II entering the systemic circulation, may mediate the pathogenesis of preeclampsia. Vascular maladaptation in preeclampsia with increased vasomotor tone, endothelial dysfunction, and increased sensitivity to angiotensin II and norepinephrine in manifest preeclampsia may be explained on the basis of angiotensin II-mediated mechanisms through angiotensin receptor type I (AT1) activation. Recently, novel angiotensin II-related biomolecular mechanisms have been described in preeclampsia. These include AT1 and bradykinin B2 receptor heterodimerization and the production of autoantibody against AT1. Various organ systems with predilection for involvement in preeclampsia are sites of tissue-based RAS. Angiotensin II-mediated mechanisms may explain the primary clinicopathologic features of preeclampsia. In this review, these various aspects are critically examined and an integrated concept on the role of RAS in preeclampsia is presented.
 ...
PMID:The role of RAS in the pathogenesis of preeclampsia. 1667 48

We have recently described, in the mouse aorta, the vasodilator effect of angiotensin-(1-7) (Ang-(1-7)) was mediated by activation of the Mas Ang-(1-7) receptor and that A-779 and D-Pro7-Ang-(1-7) act as Mas receptor antagonists. In this work we show pharmacological evidence for the existence of a different Ang-(1-7) receptor subtype mediating the vasodilator effect of Ang-(1-7) in the aorta from Sprague-Dawley (SD) rats. Ang-(1-7) induced an endothelium-dependent vasodilator effect in aortic rings from SD rats which was inhibited by removal of the endothelium and by L-NAME (100 microM) but not by indomethacin (10 microM). The Ang-(1-7) receptor antagonist D-Pro7-Ang-(1-7) (0.1 microM) abolished the vasodilator effect of the peptide. However, the other specific Ang-(1-7) receptor antagonist, A-779 in concentrations up to 10 microM, did not affect vasodilation induced by Ang-(1-7). The Ang II AT1 and AT2 receptors antagonists CV11974 (0.01 microM) and PD123319 (1 microM), respectively, the bradykinin B2 receptor antagonist HOE 140 (1 microM) and the inhibitor of ACE captopril (10 microM) did not change the effect of Ang-(1-7). Our results show that in the aorta of SD rats, the vasodilator effect of Ang-(1-7) is dependent on endothelium-derived nitric oxide. This effect is mediated by the activation of Ang-(1-7) receptors sensitive to D-Pro7-Ang-(1-7), but not to A-779, which suggests the existence of a different Ang-(1-7) receptor subtype.
 ...
PMID:Evidence for a new angiotensin-(1-7) receptor subtype in the aorta of Sprague-Dawley rats. 1712 38

Ischemia/reperfusion (I/R) in post-arterior post-capillary venules induces an acute inflammatory response, characterized by increased adherence and emigration of leukocytes and vascular permeability, all of which play important roles in cardiovascular disease. The aim of this study was to determine the roles of angiotensin II and AT1 receptor blockade in microvascular I/R injury in rats. Rats were anesthetized and intubated, then the peritoneum was opened and the mesentery was revealed. Small post-capillary venules were examined by in vivo fluorescence microscopy. The flow of erythrocytes and leukocytes was observed under the microscope and video recorded for later dynamic analyses. The superior mesenteric artery (SMA) was ligated with polyethylene tubing and released to induce I/R (20 min of ischemia/60 min of reperfusion). Subsequently, leukocyte adhesion, emigration and albumin leakage were compared with those of non-I/R controls. I/R injury was significantly suppressed by superfusing tissues with the AT1 receptor antagonist losartan (LO; 10 microM). The beneficial effects of LO were inhibited by topical application of either the bradykinin B2 receptor antagonist HOE140 (10 nM) or nitric oxide (NO) synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME 10 microM). The effects of LO were lost in the presence of AT2 receptor blocker PD 123319 (PD). In conclusion, LO suppressed and protected against I/R injuries. The possible interaction between AT1 and AT2 receptors was also suggested.
 ...
PMID:AT1 receptor blockade prevents microvascular dysfunction induced by ischemia/reperfusion injury. 1714 51

Bradykinin (BK) and angiotensin II (AngII) often have opposite roles in cardiovascular diseases. Our aim here was to construct hybrid receptors which bind AngII but signal as BK. Various sequences of the intracellular face of the AngII type I receptor, AT1R, were replaced with corresponding sequences from the bradykinin B2 receptor (BKB2R). The hybrids demonstrated a number of signaling characteristics of the BKB2R. For example, the hybrids demonstrated BK as opposed to AngII like phosphorylation of Akt and JNK. The hybrids containing the BKB2R intracellular loop 2 (IC2) displayed minimal G-protein, Galphai/Galphaq, linked signaling. Computer based molecular models suggested that Ser-Met-Gly from the IC2 of the BKB2R is detrimental for the Galphai/Galphaq coupled functions of this hybrid. The return of Lys-Ser-Arg of the AT1R to this hybrid led to almost full recovery of Galphai and Galphaq activation. The design and production of AT1/BKB2 hybrid receptors is a potential approach in the treatment of hypertension related diseases where the presence of AngII, its AT1 receptor and the consequent signal transduction has proven detrimental.
 ...
PMID:Activation of ERK, JNK, Akt, and G-protein coupled signaling by hybrid angiotensin II AT1/bradykinin B2 receptors expressed in HEK-293 cells. 1721 59


<< Previous 1 2 3 4 Next >>