Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The aim of the present study was to determine the effects of the metalloendopeptidase (EP) 24.15 and 24.16 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA-2) on haemodynamics and renal function in conscious rabbits with two-kidney, two-wrapped hypertension. We have also examined the role of endogenous bradykinin in the maintenance phase of this form of renovascular hypertension and whether inhibition of bradykinin degradation contributes to any potential effects of JA-2. 2. In two preliminary operations, rabbits were equipped with transit-time ultrasound flow probes for measuring cardiac output (CO) and renal blood flow (RBF) and had both kidneys wrapped in cellophane. Starting 4 weeks after the last operation, rabbits underwent four studies (3-5 days apart), during which they were treated with combinations of the bradykinin B2 receptor antagonist icatibant or its vehicle (1 mL/kg bodyweight 0.9% w/v NaCl) and JA-2 or its vehicle (1 mL/kg of a 5% w/v 2-hydroxypropyl-beta-cyclodextrin, 2.5% v/v dimethylsulphoxide solution). Renal function was monitored using standard renal clearance methods. 3. Icatibant (10 microg/kg) had no significant effects on systemic haemodynamic variables (mean arterial pressure, heart rate or CO), renal haemodynamic variables (RBF or glomerular filtration rate), urine flow or sodium excretion. At 5 mg/kg plus 3 mg/kg per h, JA-2 also did not affect any of these variables, either after icatibant vehicle treatment or after icatibant treatment. 4. Our data do not support major roles for endogenous bradykinin or bradykinin degradation by EP 24.15/24.16 in the control of systemic and renal haemodynamics or renal excretory function in two-kidney, two-wrapped hypertension in rabbits.
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PMID:Metalloendopeptidases EC 3.4.24.15 and EC 3.4.24.16 and bradykinin B2 receptors do not play important roles in renal wrap hypertension in rabbits. 1155 25

To investigate the genetic susceptibility associated with cough related to angiotensin-converting enzyme inhibitor (ACEI) therapy in patients with type 2 diabetes, 189 non-insulin-dependent diabetes mellitus (NIDDM) patients with proteinuria or hypertension treated with perindopril were studied. Cough was considered to be present if the patients had been bothered by a cough during treatment and if they had had related symptoms for at least 2 weeks without an identifiable cause. Polymerase chain reaction (PCR) coupled with single-strand conformation polymorphism (SSCP) was used to detect polymorphisms of ACE and bradykinin B2-receptor genes. After 8 weeks of treatment, 49.2% (93 of 189) of our NIDDM patients were found to be suffering from ACEI-related cough. ACEI-related cough was mainly associated with female patients, with 71.7% (76 of 106) of female and only 20.5% (17 of 83) of male patients experiencing cough after ACEI treatment. There was a significant association of ACE II genotype with ACEI-related cough. The genotype frequencies were 58.2% for II, 47.8% for ID, and 16.7% for DD in patients with ACEI-associated cough and 41.8% for II, 52.2% for ID, and 83.3% for DD in subjects without ACEI-associated cough (chi(2) = 10.268; df = 2, P =.006). As female patients made up the majority of the subjects suffering from ACEI-related cough, we further analyzed the association of ACE I/D genotype with ACEI-related cough separately by sex. Male patients with ACEI-related cough were not associated with ACE I/D genotype distribution, while female patients were strongly associated with ACE I/D genotype polymorphism (chi(2) = 16.12; df = 2; P <.001). There was no association between the bradykinin B2 receptor gene -58T/C polymorphism with ACEI-related cough. In conclusion, our results indicate that Chinese diabetic female subjects are susceptible to ACEI-related cough, and this susceptibility may be genetically predetermined.
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PMID:Angiotensin-converting enzyme gene insertion/deletion, not bradykinin B2 receptor -58T/C gene polymorphism, associated with angiotensin-converting enzyme inhibitor-related cough in Chinese female patients with non-insulin-dependent diabetes mellitus. 1169 55

Bradykinin evokes endothelium-dependent relaxation in some vascular beds; on the other hand, the possibility has been demonstrated that in certain organs, such as the adrenal medulla or atria, bradykinin may enhance transmitter release from the sympathetic nerves. We hypothesized that bradykinin may also enhance postganglionic sympathetic neurotransmission in blood vessels. To test this hypothesis, we recorded excitatory junction potentials (EJPs), a measure of sympathetic purinergic neurotransmission, in rat mesenteric resistance arteries with a conventional microelectrode technique. EJPs were elicited by repetitive perivascular nerve stimulation (1 Hz, 20 to 50 V, 30 to 60 micros, 11 pulses). In this preparation, bradykinin (10(-7) or 10(-6) mol/L) significantly enhanced the amplitude of EJPs without altering the resting membrane potential. This effect of bradykinin was blocked by Hoe 140, a bradykinin B2 receptor antagonist, but not by des-Arg(9),[Leu(8)]-bradykinin, a bradykinin B1 receptor antagonist. The cyclooxygenase inhibitor indomethacin or NO synthase inhibitor N(G)-nitro-L-arginine did not alter the effect of bradykinin. Captopril, an ACE inhibitor, but not candesartan, an angiotensin II type 1 receptor antagonist, enhanced the action of a low concentration (10(-8) mol/L) of bradykinin on EJPs. These findings suggest that in rat mesenteric resistance arteries, bradykinin enhances sympathetic purinergic neurotransmission, presumably through presynaptic bradykinin B2 receptors. The clinical relevance of the present findings remains unclear; however, the fact that the ACE inhibitor, but not the angiotensin II type 1 receptor antagonist, enhanced the action of bradykinin on sympathetic neurotransmission may warrant further investigation.
Hypertension 2002 Jan
PMID:Bradykinin enhances sympathetic neurotransmission in rat blood vessels. 1179 74

Obstructive sleep apnea syndrome (OSAS), a disorder characterized by episodic hypoxia (EH) during sleep, is associated with systemic hypertension. We used proteomic analysis to examine differences in rat kidney protein expression during EH, and their potential relationship to EH-induced hypertension. Young male Sprague-Dawley rats were exposed to either EH or sustained hypoxia (SH) for 14 (EH14/SH14) and 30 (EH30/SH30) days. Mean arterial blood pressure was significantly increased only in EH30 (p < 0.0002). Kidney proteins were resolved by two-dimensional-PAGE and were identified by MALDI-MS. Renal expression of kallistatin, a potent vasodilator, was down-regulated in all animals. Expression of alpha-1-antitrypsin, an inhibitor of kallikrein activation, was up-regulated in EH but down-regulated in SH. Western blotting showed significant elevation of B(2)-bradykinin receptor expression in all normotensive animals but remained unchanged in hypertensive animals. Proteins relevant to vascular hypertrophy, such as smooth muscle myosin and protein-disulfide isomerase were up-regulated in EH30 but were down-regulated in SH30. These data indicate that EH induces changes in renal protein expression consistent with impairment of vasodilation mediated by the kallikrein-kallistatin pathway and vascular hypertrophy. In contrast, SH-induced changes suggest the kallikrein- and bradykinin-mediated compensatory mechanisms for prevention of hypertension and vascular remodeling. To test the hypothesis suggested by the proteomic data, we measured the effect of EH on blood pressure in transgenic hKLK1 rats that overexpress human kallikrein. Transgenic hKLK1 animals were protected from EH-induced hypertension. We conclude that EH-induced hypertension may result, at least in part, from altered regulation of the renal kallikrein system.
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PMID:Proteomic analysis reveals alterations in the renal kallikrein pathway during hypoxia-induced hypertension. 1212 87

Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[3H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.
Hypertension 2002 Sep
PMID:ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. 1221 75

Recently, we demonstrated that the heptapeptide angiotensin-(1-7) (Ang-[1-7]) exhibits a favorable kinetic of nitric oxide (NO) release accompanied by extremely low superoxide (O2-) production. In this report we describe AVE 0991, a novel nonpeptide compound that evoked effects similar to Ang-(1-7) on the endothelium. AVE 0991 and unlabeled Ang-(1-7) competed for high-affinity binding of [125I]-Ang-(1-7) to bovine aortic endothelial cell membranes with IC50 values of 21+/-35 and 220+/-280 nmol/L, respectively. Stimulated NO and O2- release from bovine aortic endothelial cells was directly and simultaneously measured on the cell surface by selective electrochemical nanosensors. Peak concentrations of NO and O2- release by AVE 0991 and Ang-(1-7) (both 10 micromol/L) were not significantly different (NO: 295+/-20 and 270+/-25 nmol/L; O2-: 18+/-2 and 20+/-4 nmol/L). However, the released amount of bioactive NO was approximately 5 times higher for AVE 0991 in comparison to Ang-(1-7). The selective Ang-(1-7) antagonist [D-Ala(7)]-Ang-(1-7) inhibited the AVE 0991-induced NO and O2- production by approximately 50%. A similar inhibition level was observed for the Ang II AT1 receptor antagonist EXP 3174. In contrast, the Ang II AT2 receptor antagonist PD 123,177 inhibited the AVE 0991-stimulated NO production by approximately 90% but without any inhibitory effect on O2- production. Both NO and O2- production were inhibited by NO synthase inhibition ( approximately 70%) and by bradykinin B2 receptor blockade (approximately 80%). AVE 0991 efficiently mimics the effects of Ang-(1-7) on the endothelium, most probably through stimulation of a specific, endothelial Ang-(1-7)-sensitive binding site causing kinin-mediated activation of endothelial NO synthase.
Hypertension 2002 Dec
PMID:AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. 1246 68

We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT2 receptors in cardiomyocytes attenuates Ang II-induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT2 receptor relative to AT1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by approximately 45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (approximately 2.6-fold, P<0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B2 receptors were present in fibroblasts. These results suggest that stimulation of AT2 receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting.
Hypertension 2003 Jan
PMID:Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. 1251 37

The use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension has recently increased. However, their use is associated with a persistent dry cough in a significant percentage of such patients. The present study was designed to assess the contribution of polymorphisms as a genetic marker of ACE-inhibitor-related cough in a Japanese hypertensive population. Genotyping was carried out in 190 patients, 70 with cough and 120 without cough, who had been treated with ACE inhibitors. Polymorphisms of ACE insertion/deletion (I/D), angiotensin II type 1 receptor (1166A/C), type 2 receptor (3123C/A), and bradykinin B2 receptor (-58T/C, exon 1, I/D), were analyzed in these subjects. The TT genotype and T allele of bradykinin B2 receptor (-58T/C) were identified at a significantly higher frequency in the cough (+) patients than in the cough (-) patients. This difference was even more pronounced in women. However, there was no significant relationship between polymorphisms of ACE, angiotensin II receptors, or bradykinin B2 receptor exon 1, and occurrence of ACE-inhibitor-related cough. The transcriptional activity of the bradykinin B2 receptor promoter is involved in the occurrence of cough, and this new marker may provide a valuable tool to detect patients at risk of developing this side effect of ACE inhibitors. In conclusion, Susceptibility to develop cough is associated with a genetic variant of the bradykinin B2 receptor promoter; thus, it may be possible to identify those patients who will develop this adverse reaction to ACE inhibitors in advance.
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PMID:Association of polymorphisms of the renin-angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough. 1252 67

1. Angiotensin-converting enzyme (ACE) inhibitor treatment leads to beneficial effects on kidney function. The aim of the present study was to determine whether ACE inhibition at high or low doses affects glomerular capillary surface area and length, glomerular number or total renal filtration surface area in rats with established hypertension and, if so, to determine whether these effects are mediated through bradykinin potentiation. 2. Spontaneously hypertensive rats (SHR) were treated with the ACE inhibitor perindopril at either 3 or 0.1 mg/kg per day (high and low doses, respectively) from 16 to 24 weeks of age. Some rats were concomitantly treated with the bradykinin B2 receptor antagonist S16118 (10 nmol/kg per day). Blood pressure was measured twice weekly during the treatment period. At 24 weeks of age, rats were perfusion fixed at 140 mmHg, the kidneys removed, embedded in resin and examined stereologically to estimate glomerular number and volume, length and surface area of glomerular capillaries and total renal filtration surface area. 3. High- and low-perindopril treatment significantly reduced systolic blood pressure compared with control SHR. However, the rats treated with low-dose perindopril were still considered hypertensive. Neither low-dose nor high-dose perindopril treatment had any observable effect on glomerular number (23 876 +/- 1201 vs 26 240 +/- 1465 glomeruli/kidney, respectively) or volume (2.25 +/- 0.21 and 1.96 +/- 0.06 x 10-3 mm3, respectively) compared with controls (glomerular number 25866 +/- 1210 glomeruli/kidney; glomerular volume 2.24 +/- 0.21 x 10-3 mm3). As a result, there was no significant difference in total renal filtration surface area between any of the experimental groups (8161.6 +/- 550.9, 8699.7 +/- 427.6, 9081.9 +/- 453.6, 8830.2 +/- 521.2 and 8559.4 +/- 341.4 mm2 for SHR, SHR low-dose perindopril, SHR low-dose perindopril + B2 antagonist, SHR high-dose perindopril and SHR high-dose perindopril + B2 antagonist, respectively). Coadministration of the bradykinin antagonist had no observable effect on any of the parameters studied. 4. In conclusion, because neither high-dose nor low-dose perindopril had any effect on total renal filtration surface area, the observed beneficial effects of ACE inhibition on kidney function are not the result of enhancement in glomerular capillary surface area.
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PMID:Angiotensin-converting enzyme inhibition in adult hypertensive rats: a stereological study of renal filtration surface area. 1254 57

We have examined whether exogenous human tissue kallikrein exerts pharmacological actions via the bradykinin B2 receptor; specifically, whether the protease can bind to, cleave, internalize, and/or activate a fusion protein composed of the rabbit B2 receptor conjugated to the green fluorescent protein (B2R-GFP). The enzyme partially digested the fusion protein at 1 micromol/L, but not 100 nmol/L, and promoted B2R-GFP endocytosis in HEK 293 cells (> or =50 nmol/L). Trypsin and endoproteinase Lys-C, but not plasma kallikrein, also cleaved B2R-GFP. Phospholipase A2 was activated by 50 nmol/L tissue kallikrein in HEK 293 cells expressing B2R-GFP, and this was mediated by the receptor, as shown by the effect of a B2 receptor antagonist and by the lack of response in untransfected cells. However, 500 nmol/L kallikrein elicited a strong receptor-independent activation of phospholipase A2. Tissue kallikrein competed for [3H]bradykinin binding to B2R-GFP only at 1 micromol/L. A simulation involving kallikrein treatment of HEK 293 cells, pretreated or not with human plasma, evidenced the formation of immunoreactive bradykinin. The enzyme (50 nmol/L) contracted the rabbit isolated jugular vein via its endogenous B2 receptors, but the effect was tachyphylactic, and there was no cross-desensitization with bradykinin effects. Aprotinin prevented all pharmacological responses to tissue kallikrein, indicating that the enzyme activity is required for its effect. The local generation of kinins is a plausible mechanism for the pharmacological effects of lower concentrations of tissue kallikrein (50 to 100 nmol/L); higher levels (0.5 to 1 micromol/L) can not only initiate the degradation of rabbit B2 receptors but also exert nonreceptor-mediated effects.
Hypertension 2003 Mar
PMID:Tissue kallikrein actions at the rabbit natural or recombinant kinin B2 receptors. 1283 33


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