UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin converting enzyme (ACE) inhibitors inhibit the degradation of bradykinin and contribute to accumulation of bradykinin and NO, both of which may be beneficial for diseased hearts. To test this idea, we administered imidaprilat and cilazaprilat, respectively to the canine ischemic myocardium. In the open chest dogs with low constant coronary perfusion pressure (CPP, from 104 +/- 3 to 42 +/- 3 mmHg), coronary blood flow (CBF, 91 +/- 1 to 32 +/- 2 ml/100 g/min), fractional shortening (FS), and lactate extraction ratio (LER) decreased. Either imidaprilat or cilazaprilat increased CBF, FS, and LER with increases in cardiac bradykinin and NO levels. The beneficial effects of ACE inhibitors were blunted by either L-NAME (an inhibitor of NO synthase) and HOE140 (an inhibitor of bradykinin receptors), respectively. ACE inhibitors, on the other hand, are reported to attenuate the severity of myocardial stunning, which effect is partially attributable to bradykinin- and NO-dependent mechanisms. Further, ACE inhibitors limited infarct size following coronary occlusion and reperfusion. This infarct size-limitation was blunted by either L-NAME and IBTX (the antagonist of K(Ca) channels). Bradykinin is also reported to close K(Ca) channels. Thus, we concluded that ACE inhibitors attenuate both reversible and irreversible myocardial cellular injury via bradykinin/NO-dependent mechanisms. In experimental and clinical settings, the cardioprotective effects of ACE inhibitors on the diseased heart may be attributable to these mechanisms.
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PMID:Cellular mechanisms of cardioprotection afforded by inhibitors of angiotensin converting enzyme in ischemic hearts: role of bradykinin and nitric oxide. 1082 Nov 35

Kinin B(1)-receptors are inducible-receptors. They are absent under basal conditions but expressed following pathophysiological stresses. This study was designed to examine a possible role of nitric oxide (NO) in the mechanism underlying B(1)-receptor induction after heat stress (HS). Rats were divided into six groups, subjected or not to HS (42 degrees C internal temperature, 20 min) without or with treatment with nitro-L-arginine-methylester (L-NAME), a nonselective inhibitor of NO synthase (NOS) isoforms, or L-N(6)-(1-imino-ethyl)lysine (L-NIL), a selective inhibitor of the inducible NOS. Twenty-four hours after HS, rats were injected with bradykinin and [des-Arg(9)]-bradykinin and hypotensive responses were recorded. In six additional groups, B(1)-receptor mRNAs were detected in aorta 5 h after HS or sham treatment. Bradykinin, a B(2)-receptor agonist, induced a hypotension of a similar magnitude in all the groups studied. [des-Arg(9)]-bradykinin, a B(1)-receptor agonist, induced no response in sham rats. In rats previously subjected to hyperthermia, this agonist induced a hypotensive response, which was, respectively, decreased and increased by pretreatment with L-NAME and with L-NIL prior to hyperthermia. RT-PCR results confirmed these in vivo observations. In conclusion, this study suggests a role for NO in B(1)-receptor induction after HS as well as a possible interaction between NOS isoforms.
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PMID:Nitric oxide and its role in the induction of kinin B(1)-receptors after heat stress in the rat. 1082 88

We have previously shown that NO production by tissues following stimulation with bradykinin or other agonists can regulate oxygen consumption in skeletal muscle, heart and kidney. From those studies and from those using agonists, which classically release NO from blood vessels and which are unable to regulate tissue oxygen consumption in heart from ecNOS knockout mice, we concluded that vascular NO production is capable of regulating tissue oxygen consumption. The goal of these studies was to directly address the concept that NO production by blood vessels can regulate tissue oxygen consumption using a classical transfer paradigm. Microvessels, capable of producing NO, were prepared from canine hearts using a sieving technique, cardiac tissue was taken from mice lacking the ability to produce NO from ecNOS (ecNOS -/- mice) and tissue oxygen consumption measured in vitro using a Clark type electrode in a sealed chamber. Bradykinin (10(-7)to 10(-4)M) had no effect on tissue oxygen consumption when administered to heart from ecNOS -/mice as expected and no effect on oxygen consumption by isolated canine coronary microvessels (0+/-5% at 10(-5)M). However when coronary microvessels were co-incubated with heart from ecNOS -/- mice, bradykinin caused a dose dependent reduction in tissue oxygen consumption reaching a maximum of 44+/-10% at 10(-4)M. The effects of bradykinin were entirely abolished by L -NAME. The calculated concentration range for NO in these studies was 2.9 to 293 n M, within estimated physiologic range for the activity of NO on cytochrome oxidase. These data indicate that coronary microvessels can regulate cardiac oxygen consumption through a NO dependent mechanism.
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PMID:Canine coronary microvessel NO production regulates oxygen consumption in ecNOS knockout mouse heart. 1086 Jul 58

1. Bradykinin (BK) effect on the [Ca(2+)](i) response to 1 nM angiotensin II was examined in muscular juxtamedullary efferent arterioles (EA) of rat kidney. 2. BK (10 nM) applied during the angiotensin II-stimulated [Ca(2+)](i) increase, induced a [Ca(2+)](i) drop (73+/-2%). This drop was prevented by de-endothelialization and suppressed by HOE 140, a B2 receptor antagonist. It was neither affected by L-NAME or indomethacin, nor mimicked by sodium nitroprusside, 8-bromo-cyclic GMP or PGI(2). The BK effect did not occur when the [Ca(2+)](i) increase was caused by 100 mM KCl-induced membrane depolarization and was abolished by 0.1 microM charybdotoxin, a K(+) channel blocker. 3. Although proadifen prevented the BK-caused [Ca(2+)](i) fall, more selective cytochrome P450 inhibitors, 17-octadecynoic acid (50 microM) and 7-ethoxyresorufin (10 microM) were without effect. 4. Increasing extracellular potassium from 5 to 15 mM during angiotensin II stimulation caused a [Ca(2+)](i) decrease (26+/-4%) smaller than BK which was charybdotoxin-insensitive. Inhibition of inward rectifying K(+) channels by 30 microM BaCl(2) and/or of Na(+)/K(+) ATPase by 1 mM ouabain abolished the [Ca(2+)](i) decrease elicited by potassium but not by BK. 5. A voltage-operated calcium channel blocker, nifedipine (1 microM) did not prevent the BK effect but reduced the [Ca(2+)](i) drop. 6. These results indicate that the BK-induced [Ca(2+)](i) decrease in angiotensin II-stimulated muscular EA is mediated by an EDHF which activates charybdotoxin-sensitive K(+) channels. In these vessels, EDHF seems to be neither a cytochrome P450-derived arachidonic acid metabolite nor K(+) itself. The closure of voltage-operated calcium channels is not the only cellular mechanism involved in this EDHF-mediated [Ca(2+)](i) decrease.
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PMID:Bradykinin attenuates the [Ca(2+)](i) response to angiotensin II of renal juxtamedullary efferent arterioles via an EDHF. 1115 28

Serine proteinases elicit profound cellular effects in various tissues mediated by activation of proteinase-activated receptors (PAR). In the present study, we investigated the vascular effects of cathepsin G, a serine proteinase that is present in the azurophil granules of leukocytes and is known to activate several cells that express PARs. In prostaglandin F2alpha (3 microM)-precontracted rings from porcine pulmonary arteries with intact endothelium, cathepsin G caused concentration-dependent relaxant responses (pEC(50)=9.64+/-0.12). The endothelium-dependent relaxant effect of cathepsin G could also be demonstrated in porcine coronary arteries (pEC(50)=9.23+/-0.07). In pulmonary arteries the cathepsin G-induced relaxation was inhibited after blockade of nitric oxide synthesis by L-NAME (200 microM) and was absent in endothelium-denuded vessels. Bradykinin- and cathepsin G-induced relaxant effects were associated with a 5.7 fold and 2.4 fold increase in the concentration of cyclic GMP, respectively. Compared with thrombin and trypsin, which also produced an endothelium-dependent relaxation in pulmonary arteries, cathepsin G was 2.5 and four times more potent, respectively. Cathepsin G caused only small homologous desensitization. In cathepsin G-challenged vessels, thrombin was still able to elicit a relaxant effect. The effects of cathepsin G were blocked by soybean trypsin inhibitor (IC(50)=0.043 microg ml(-1)), suggesting that proteolytic activity is essential for induction of relaxation. Recombinant acetyl-eglin C proved to be a potent inhibitor (IC(50)=0.14 microg ml(-1)) of the cathepsin G effect, whereas neither indomethacin (3 microM) nor the thrombin inhibitor hirudin (5 ATU ml(-1)) elicited any inhibitory activity. Due to their polyanionic structure defibrotide (IC(50)=0.11 microg ml(-1)), heparin (IC(50)=0.48 microg ml(-1)) and suramin (IC(50)=1.85 microg ml(-1)) diminished significantly the relaxation in response to the basic protein cathepsin G. In conclusion, like thrombin and trypsin, cathepsin G is able to induce endothelium-dependent vascular relaxation. It can be released from activated leukocytes at sites of vascular injury and inflammation and, therefore, sufficiently high concentrations might be reached locally in the vascular space to induce vasodilatation.
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PMID:Endothelium-dependent relaxation induced by cathepsin G in porcine pulmonary arteries. 1137 59

Bradykinin is an important endogenous mediator exerting acute protective effects in the ischemic myocardium. The aims of this study were to investigate whether exogenously administered bradykinin could evoke delayed myocardial protection and to determine whether any protection observed might be dependent on nitric oxide (NO) generation. Conscious rats received bradykinin (40 microg/kg iv) or saline, preceded 15-20 min earlier by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg ip) or saline. Twenty-four hours later, hearts were Langendorff perfused and subjected to 35 min of regional ischemia and 120 min of reperfusion. Infarct size was assessed using tetrazolium staining and expressed as a percentage of the risk zone. Bradykinin pretreatment reduced the infarct-to-risk ratio from 53.5 +/- 3.2% to 29.1 +/- 4.7% (P < 0.01). The administration of L-NAME before bradykinin abrogated the delayed protection (infarct size 52.3 +/- 5.0%) but alone did not influence infarct size (53.5 +/- 4.8%). These results are the first to demonstrate that bradykinin can evoke a delayed ("second window") enhancement of myocardial tolerance to ischemia, an action that is dependent on the early generation of NO.
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PMID:Bradykinin elicits "second window" myocardial protection in rat heart through an NO-dependent mechanism. 1151 19

Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT(1) receptor. To elucidate the direct effects of the AT(2) receptor on the AT(1) receptor in VSMCs, we transfected AT(2) receptor gene into cultured rat VSMCs. Overexpression of AT(2) receptor significantly decreased expression of AT(1a) receptor at both the mRNA and protein levels in the presence and absence of Ang II in VSMCs. Overexpression of AT(2) receptor increased expression of bradykinin and inducible NO in the presence and absence of Ang II in VSMCs. Bradykinin B(2) receptor antagonist HOE-140 and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) inhibited the decreases in AT(1a) receptor expression by the overexpression of AT(2) receptor in VSMCs. L-Arginine augmented the decrease in AT(1a) receptor expression. Overexpression of AT(2) receptor suppressed basal DNA synthesis and proliferation of VSMCs and abolished response of DNA synthesis to Ang II in VSMCs. Our results demonstrate that overexpression of the AT(2) receptor downregulates AT(1a) receptor expression in rat VSMCs in a ligand-independent manner that is mediated by the bradykinin/NO pathway. Downregulation of AT(1a) receptor is a novel mechanism by which the AT(2) receptor regulates growth and metabolism of VSMCs.
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PMID:Angiotensin II type 2 receptor gene transfer downregulates angiotensin II type 1a receptor in vascular smooth muscle cells. 1201 86

We investigated the effect of endogenous bradykinin on adrenaline-induced pulmonary edema (PE) by blocking bradykinin receptors. In preliminary experiments, a bolus injection of adrenaline (ADR; 10 microg/kg) solution (10 microg/ml) was determined to be an edematogenic dose for inducing PE. The lung body weight index (LBI) and incidence of PE (IPE) were determined. The IPE and LBI of the group pretreated with Des-Arg9-[Leu8]-Bradykinin (DA-BK, 50 microg/kg, 50 microg/ml) increased significantly compared with those of the control group (p<0.05). On the other hand, there were no remarkable changes in IPE and LBI in the groups pretreated with Hoe140 (D-Arginyl-[Hyp3, Thi5, D-Tic7, Oic8]-Bradykinin (100 microg/kg, 100 microg/ml), captopril (20 mg/kg, 20 mg/ml) or L-NAME (1 mg/kg, 1 mg/ml). Moreover, the IPE and LBI of the group co-treated with L-NAME and DA-BK decreased compared with the DA-BK group (p<0.05). Thus, bradykinin aggravates adrenaline-induced PE through activation of the B2 receptor by the kallikreins as a result of the ADR administration, although the precise mechanism is not known.
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PMID:The involvement of bradykinin in adrenaline-induced pulmonary edema in rats. 1216 Feb 18

We assessed whether pregnancy results in enhanced nitric oxide (NO)-mediated control of myocardial oxygen consumption. Rats were studied before (C), at 1 wk (1w) or 2 wk (2w) of pregnancy, and at 4 days after giving birth (-4d). Left ventricular endothelial NO synthase (eNOS) protein expression was determined by immunoblotting. Oxygen consumption of left ventricular tissue samples was measured in vitro in response to increasing doses of bradykinin with or without addition of the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Echocardiography indicated an increased cardiac output during pregnancy. Myocardial eNOS protein expression significantly increased by 46 +/- 9 and 39 +/- 8% at 1w and 2w, respectively, and returned to control levels at -4d. Bradykinin (10(-4) M) decreased cardiac oxygen consumption in a NO-dependent manner by 17 +/- 2% at C, by 21 +/- 2% at 1w, by 24 +/- 2% at 2w (P < 0.05 vs. C and -4d), and by 18 +/- 1% at -4d. Myocardial eNOS protein expression is transiently increased during pregnancy in rats, and this increase is associated with enhanced NO-dependent control of myocardial oxygen consumption at a time when cardiac output is increased.
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PMID:Role of cardiac eNOS expression during pregnancy in the coupling of myocardial oxygen consumption to cardiac work. 1218 Nov 52

Bradykinin (BK) mimics ischemic preconditioning by generating reactive oxygen species (ROS). To identify intermediate steps that lead to ROS generation, rabbit cardiomyocytes were incubated in reduced MitoTracker Red stain, which becomes fluorescent after exposure to ROS. Fluorescence intensity in treated cells was expressed as a percentage of that in paired, untreated cells. BK (500 nM) caused a 51 +/- 16% increase in ROS generation (P < 0.001). Coincubation with either the BK B2-receptor blocker HOE-140 (5 microM) or the free radical scavenger N-(2-mercaptopropionyl)glycine (1 mM) prevented this increase, which confirms that the response was receptor mediated and ROS were actually being measured. Closing mitochondrial ATP-sensitive K+ (mitoKATP) channels with 5-hydroxydecanoate (5-HD, 1 mM) prevented increased ROS generation. BK-induced ROS generation was blocked by Nomega-nitro-m-arginine methyl ester (m-NAME, 200 microM), which implicates nitric oxide as an intermediate. Blockade of guanylyl cyclase with 1-H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ, 10 microM) aborted BK-induced ROS generation but not that from diazoxide, a direct opener of mitoKATP channels. The protein kinase G (PKG) blocker 8-bromoguanosine-3',5'-cyclic monophosphorothioate (25 microM) eliminated the effects of BK. Conversely, direct activation of PKG with 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate (100 microM) increased ROS generation (39 +/- 15%; P < 0.004) similar to BK. This increase was blocked by 5-HD. Finally, the nitric oxide donor S-nitroso-N-acetylpenicillamine (1 microM) increased ROS by 34 +/- 6%. This increase was also blocked by 5-HD. In intact rabbit hearts, BK (400 nM) decreased infarction from 30.5 +/- 3.0 of the risk zone in control hearts to 11.9 +/- 1.4% (P < 0.01). This protection was aborted by either 200 microM m-NAME or 2 microM ODQ (35.4 +/- 5.7 and 30.4 +/- 3.0% infarction, respectively; P = not significant vs. control). Hence, BK preconditions through receptor-mediated production of nitric oxide, which activates guanylyl cyclase. The resulting cGMP activates PKG, which opens mitoKATP. Subsequent release of ROS triggers cardioprotection.
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PMID:Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection. 1295 31

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