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Endogenous bradykinin and B1-B5 during angiotensin-converting enzyme inhibitor-associated angioedema.
Hubers SA, Kohm K, Wei S, Yu C, Nian H, Grabert R, Sexton DJ, Brown NJ
(2018) J Allergy Clin Immunol 142: 1636-1639.e5
MeSH Terms: Aged, Angioedema, Angiotensin-Converting Enzyme Inhibitors, Bradykinin, Enalapril, Female, Humans, Kininogen, High-Molecular-Weight, Lisinopril, Male, Middle Aged, Peptide Fragments, Quinapril
Added November 7, 2018
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13 MeSH Terms
A randomized trial of a 6-week course of celecoxib on proteinuria in diabetic kidney disease.
Sinsakul M, Sika M, Rodby R, Middleton J, Shyr Y, Chen H, Han E, Lehrich R, Clyne S, Schulman G, Harris R, Lewis J
(2007) Am J Kidney Dis 50: 946-51
MeSH Terms: Aged, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Celecoxib, Creatinine, Cross-Over Studies, Cyclooxygenase Inhibitors, Diabetic Nephropathies, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Humans, Middle Aged, Models, Statistical, Pilot Projects, Proteinuria, Pyrazoles, Quinapril, Sulfonamides, Tetrahydroisoquinolines
Show Abstract · Added March 25, 2014
BACKGROUND - Preclinical data suggest that cyclooxygenase 2 inhibitors decrease proteinuria and preserve glomerular structure in animal models of diabetic nephropathy. The objective of this study is to compare the efficacy and safety of celecoxib with placebo for decreasing proteinuria in patients with diabetic nephropathy.
STUDY DESIGN - Placebo-controlled double-blinded crossover design.
SETTING & PARTICIPANTS - 24 patients with type 1 or 2 diabetes mellitus, proteinuria with protein of 500 mg/d or greater, and serum creatinine level of 3.0 mg/dL or less.
INTERVENTION - Patients were randomly assigned to: (1) 6 weeks of celecoxib followed by a 3-week washout period, followed by 6 weeks of placebo followed by another 3-week washout; or (2) 6 weeks of placebo followed by a 3-week washout, followed by 6 weeks of celecoxib followed by another 3-week washout period. All patients were administered quinapril, 20 to 40 mg/d, or irbesartan, 150 to 300 mg/d. All patients were administered aspirin, 81 mg/d.
OUTCOMES & MEASUREMENTS - Proteinuria was assessed by means of protein-creatinine ratio. Data were analyzed using the mixed-effect statistical model.
RESULTS - There was no significant difference in urinary proteinuria after 6 weeks of treatment with placebo or celecoxib (proteinuria ratio, celecoxib versus placebo, 1.041; 95% confidence interval, 0.846 to 1.282). Celecoxib had no significant effect on potassium or estimated glomerular filtration rate. Frequencies of adverse events were similar between the placebo and celecoxib treatments.
LIMITATIONS - This pilot study was not designed to evaluate the safety or long-term clinical effects of celecoxib.
CONCLUSIONS - Celecoxib, 200 mg/d, for 6 weeks did not alter proteinuria. Few adverse events were noted in this high-risk population.
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20 MeSH Terms
Inhibition of aminopeptidase P potentiates wheal response to bradykinin in angiotensin-converting enzyme inhibitor-treated humans.
Kim KS, Kumar S, Simmons WH, Brown NJ
(2000) J Pharmacol Exp Ther 292: 295-8
MeSH Terms: Adult, Aminopeptidases, Angiotensin-Converting Enzyme Inhibitors, Bradykinin, Dose-Response Relationship, Drug, Drug Synergism, Female, Humans, Inflammation, Isoquinolines, Male, Peptides, Protease Inhibitors, Quinapril, Tetrahydroisoquinolines, Time Factors, Urticaria
Show Abstract · Added December 10, 2013
Bradykinin is a nonapeptide that contributes to the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors. During ACE inhibition, an increased proportion of bradykinin is degraded through non-ACE pathways. Studies in animals suggest that aminopeptidase P (EC 3.4.11.9) may contribute to the metabolism of bradykinin. The purpose of the present study was to determine the contribution of aminopeptidase P to the degradation of bradykinin in humans in the presence and absence of ACE inhibition. To do this, we measured the wheal response to intradermal injection of bradykinin (0, 1, or 10 nicrog) in the presence or absence of intradermal administration of the specific aminopeptidase P inhibitor apstatin (5 or 10 microg) and oral administration of the ACE inhibitor quinapril (10 mg) in six healthy subjects. Both bradykinin (ANOVA; F = 101.18, P <.001) and apstatin alone (F = 7.01, P =.049) caused a wheal of dose-dependent size. There was no significant interaction between apstatin and bradykinin (F = 4.94, P =.175). Pretreatment with 10 mg of quinapril significantly shifted the dose-response curve for bradykinin to the left (effect of quinapril; F = 77.96, P <.001) and there was significant interaction between quinapril and bradykinin (F = 7.82, P =.041). The effect of quinapril was significantly potentiated by coinjection of 10 microg of apstatin (effect of apstatin; F = 21.60, P =.006), such that there was significant interactive effect of quinapril and apstatin (F = 20.83, P =.006) on the wheal response to bradykinin. Collectively, these data suggest that aminopeptidase P plays a minor role in the degradation of bradykinin in human skin in the absence of ACE inhibition but contributes significantly to the degradation of bradykinin in the presence of ACE inhibition.
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17 MeSH Terms
Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans.
Brown NJ, Agirbasli M, Vaughan DE
(1999) Hypertension 34: 285-90
MeSH Terms: Adult, Aldosterone, Angiotensin II, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Data Interpretation, Statistical, Diet, Sodium-Restricted, Female, Fibrinolysis, Heart Rate, Humans, Isoquinolines, Losartan, Male, Plasminogen Activator Inhibitor 1, Quinapril, Renin, Renin-Angiotensin System, Tetrahydroisoquinolines, Tissue Plasminogen Activator
Show Abstract · Added December 10, 2013
Angiotensin-converting enzyme (ACE) inhibition significantly decreases plasminogen activator inhibitor-1 (PAI-1) without altering tissue plasminogen activator (tPA) during activation of the renin-angiotensin-aldosterone system in humans. Because ACE inhibitors and angiotensin II type 1 (AT(1)) receptor antagonists differ in their effects on angiotensin II formation and bradykinin degradation, the present study compared the effect of equivalent hypotensive doses of an ACE inhibitor and AT(1) antagonist on fibrinolytic balance. Plasma PAI-1 antigen, tPA antigen, plasma renin activity, and aldosterone were measured in 25 normotensive subjects (19 white, 6 black; 14 men, 11 women; mean age 38.5+/-1.8 years; mean body mass index 25.3+/-0.7 kg/m(2)) during low salt intake alone (10 mmol Na/d), low salt intake + quinapril (40 mg PO bid), and low salt intake + losartan (50 mg PO bid). Compared with low salt alone (systolic blood pressure [BP] 118.8+/-2.2 mm Hg), both quinapril (106.3+/-2.5 mm Hg, P<0.001) and losartan (105.4+/-2. 8 mm Hg, P<0.001) reduced BP. No statistical difference was found between quinapril and losartan in their BP lowering effect. Losartan (P=0.009), but not quinapril, lowered heart rate. Both drugs significantly lowered aldosterone (P<0.001 versus low salt alone for each); however, this effect was significantly greater for quinapril than for losartan (P<0.001 for quinapril versus losartan). Treatment with quinapril, but not with losartan, was associated with a decrease in both PAI-1 antigen (P=0.03) and activity (P=0.018). PAI-1 activity was lower during treatment with quinapril than with losartan (P=0.015). The average PAI-1 antigen concentration was 13. 0+/-2.0 ng/mL during low salt alone, 10.5+/-1.6 ng/mL during quinapril treatment, and 12.3+/-2.1 ng/mL during losartan treatment. In contrast, plasma tPA antigen concentrations were reduced during treatment with losartan (P=0.03) but not with quinapril. This study provides the first evidence that ACE inhibitors and AT(1) antagonists differ in their effects on fibrinolytic balance under conditions of activation of the renin-angiotensin-aldosterone system. Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences.
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22 MeSH Terms
Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1.
Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE
(1998) Hypertension 32: 965-71
MeSH Terms: Adult, Aldosterone, Angiotensin-Converting Enzyme Inhibitors, Catecholamines, Circadian Rhythm, Creatinine, Diet, Sodium-Restricted, Fibrinolysis, Hemodynamics, Humans, Hydrocortisone, Isoquinolines, Male, Plasminogen Activator Inhibitor 1, Quinapril, Renin, Renin-Angiotensin System, Sodium, Supine Position, Tetrahydroisoquinolines, Tissue Plasminogen Activator
Show Abstract · Added December 10, 2013
Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P<10(-7)) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6. 7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7+/-4.6 versus 16. 1+/-3.3 and 16.3+/-3.7 ng/mL, respectively; P<0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1.
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21 MeSH Terms
Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin.
Brown NJ, Nadeau JH, Vaughan DE
(1997) Thromb Haemost 77: 522-5
MeSH Terms: Analysis of Variance, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Bradykinin, Captopril, Female, Humans, Hypertension, Isoquinolines, Male, Plasminogen Activator Inhibitor 1, Quinapril, Randomized Controlled Trials as Topic, Tetrahydroisoquinolines, Tissue Plasminogen Activator
Show Abstract · Added December 10, 2013
Angiotensin converting inhibitors (ACEI) not only decrease angiotensin II (Ang II) but also potentiate the effects of bradykinin. Bradykinin is a potent stimulus to tissue type plasminogen activator (t-PA) secretion in animal models. In this study, we tested the hypothesis that bradykinin increase t-PA levels in humans. Bradykinin was infused in seventeen hypertensive patients randomized to treatment with the ACEIs captopril and quinapril or with placebo. Bradykinin caused a significant decrease in mean arterial pressure (MAP) (p = 0.014) and increase in pulse (p < 0.001). ACEI significantly potentiated the hemodynamic effect of bradykinin (p < 0.05). Although baseline t-PA antigen levels were similar in the ACEI-treated (6.85 +/- 0.85 ng/ml) and placebo-treated (7.85 +/- 0.68 ng/ml) subjects, bradykinin caused a significant (p < 0.01) increase in t-PA antigen levels (to 19.3 +/- 8.2) only in the ACEI-treated patients. This increase in t-PA was independent of activation of the sympathetic nervous system. Bradykinin had no effect on PAI-1 antigen levels. These in vivo data suggest that infusion of bradykinin results in an increase in circulating t-PA levels without an effect on PAI-1.
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16 MeSH Terms