Plasma Bradykinin Concentrations Research Articles

Plasma bradykinin concentrations during septic shock determined by a novel LC-MS/MS assay

BackgroundBradykinin is an important mediator of inflammation and vascular permeability and could have an important role in the development of septic shock. Measurement of bradykinin by immunological methods may suffer from interference and lack of specificity. We developed and validated a liquid chromatography mass spectrometry assay (LC-MS/MS) for plasma bradykinin. MethodsWe used plasma samples from healthy volunteers (n = 19) and patients with septic shock (n = 47). Stable isotope bradykinin internal standard was added to samples before solid-phase extraction and quantification by LC-MS/MS. Stability of bradykinin was studied for 12 months. ResultsOur assay has good sensitivity (0.1 nmol/l) and a wide linear range (0.1–1000 nmol/l). Bradykinin added to plasma was stable for 12 months at −20 °C when a mixture of protease inhibitors was added at sampling but degraded during repeated freezing and thawing. Bradykinin concentration in plasma from septic shock patients (<0.1–0.6 nmol/l) did not change significantly during shock and recovery but differed slightly from that in healthy individuals (0.5–1.1 nmol/l). ConclusionsOur bradykinin assay was successfully used to determine bradykinin concentrations in plasma samples. Intensive care unit patients with septic shock had low concentrations of plasma bradykinin during both shock and recovery phases.

Lactotripeptides Inhibiting ACE1 Elevate the Plasma Bradykinin Concentration Acutely in a Placebo-Controlled, Double-Blind, Cross-Over, 4-Week Trial in Healthy Volunteers

This placebo-controlled, double-blind, cross-over intervention with twelve normotensive healthy volunteers tested the effects of milk products containing either 5 or 50 mg of ACE1-inhibitory lactotripeptides (isolecine-proline-proline, Ile-Pro-Pro, and valine-proline-proline, Val-Pro-Pro) and placebo milk drink (with similar taste) on plasma bradykinin levels. The subjects consumed one of the three test products in a random order, double-blinded, and four-week trial. On the first day (day 1) and on the last day (day 29) i.e. after four weeks’ treatment with one of the products, the acute effect with the same single dose was assayed. Other markers of the renin-angiotensin-aldosterone system (RAAS) were measured from plasma four times on the same days when we also assessed daytime urinary excretion of biomarkers of endothelial function. Neither acute nor prolonged administration of the ACE-1 inhibiting peptide drinks significantly lowered blood pressure of the normotensive subjects. The most important finding was the dose-dependent, and linear increase in plasma bradykinin concentrations after acute dosing on the first day; it was nearly statistically significant also on the day 29 (p 0.06). Other indicators of RAAS or endothelial function did not differ from those of placebo after the acute or prolonged treatments. Our results suggest that even weak inhibitors of ACE-1, such as the lactotripeptides Ile-Pro-Pro and Val-Pro-Pro, are able to diminish the breakdown of bradykinin and therefore increase plasma bradykinin levels. This may partly explain the blood pressure lowering and vasodilatory effects of lactotripeptides, shown by us earlier in mildly hypertensive subjects.

Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus.

ObjectiveTo examine the association of bradykinin and related peptides with the development of diabetic nephropathy lesions in 243 participants with type 1 diabetes (T1D) from the Renin-Angiotensin System Study who, at baseline, were normoalbuminuric, normotensive and had normal or increased glomerular filtration rate (GFR).DesignPlasma concentrations of bradykinin and related peptides were measured at baseline by quantitative mass spectrometry. All participants were randomly assigned at baseline to receive placebo, enalapril or losartan during the 5 years between kidney biopsies. Kidney morphometric data were available from kidney biopsies at baseline and after 5 years. Relationships of peptides with changes in morphometric variables were assessed using multiple linear regression after adjustment for age, sex, diabetes duration, HbA1c, mean arterial pressure, treatment assignment and, for longitudinal analyses, baseline structure.ResultsBaseline median albumin excretion rate of study participants was 5.0 μg/min, and mean GFR was 128 mL/min/1.73 m2. After multivariable adjustment, higher plasma concentration of bradykinin (1–8) was associated with greater glomerular volume (partial r = 0.191, P = 0.019) and total filtration surface area (partial r = 0.211, P = 0.010), and higher bradykinin (1–7) and hyp3-bradykinin (1–7) were associated with lower cortical interstitial fractional volume (partial r = -0.189, P = 0.011; partial r = -0.164, P = 0.027 respectively). In longitudinal analyses, higher bradykinin was associated with preservation of surface density of the peripheral glomerular basement membrane (partial r = 0.162, P = 0.013), and for participants randomized to losartan, higher hyp3-bradykinin (1–8) was associated with more limited increase in cortical interstitial fractional volume (partial r = -0.291, P = 0.033).ConclusionsHigher plasma bradykinin and related peptide concentrations measured before clinical onset of diabetic nephropathy in persons with T1D were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic nephropathy.

Changes in Plasma Bradykinin Concentration and Citric Acid Cough Threshold at High Altitude

Altitude-related cough is a troublesome condition of unknown etiology. Inhaled tussive agents are used to quantify cough, and the citric acid cough threshold has been shown to fall on ascent to altitude. Cough can occur in patients taking angiotensin-converting enzyme inhibitors due to stimulation of airway sensory receptors by increased levels of bradykinin. We hypothesized that increased levels of bradykinin could be responsible for the decrease in citric acid cough threshold on exposure to altitude and a possible etiologic factor in altitude-related cough. Twenty healthy volunteers underwent baseline tests at 700 m before a 2-week stay at 3800 m. Angiotensin-converting enzyme activity and plasma bradykinin were measured at baseline and altitude. Citric acid cough threshold and nocturnal cough frequency were measured at baseline and throughout the 2 weeks at altitude. Citric acid cough threshold fell from 3.7 g/dL at baseline to 2.1 g/dL on the second day at 3800 m (geometric mean difference 1.8, 95% CIs 1.0-5.0, P = .025) and remained reduced throughout the stay at altitude. Nocturnal cough frequency was unchanged compared to baseline. Plasma bradykinin fell from 0.43 ng/mL at baseline to 0.08 ng/mL at altitude (geometric mean difference 5.7, 95% CIs 2.1-15.5, P = .002), but angiotensin-converting enzyme activity was unchanged (mean difference 0.06, 95% CIs -2.7-2.8, P = .97). There was no correlation between plasma bradykinin and citric acid cough threshold. Increased levels of bradykinin are unlikely to be a significant factor in the increased sensitivity to citric acid seen in hypobaric hypoxia. Further studies are required to elucidate the etiology of altitude-related cough.

Pain on injection with microemulsion propofol

To evaluate the incidence and severity of injection pain caused by microemulsion propofol and lipid emulsion propofol in relation to plasma bradykinin generation and aqueous free propofol concentrations. Injection pain was evaluated in 147 patients. Aqueous free propofol concentrations in each formulation, and in formulation mixtures containing agents that reduce propofol-induced pain, were measured by high-performance liquid chromatography. Plasma bradykinin concentrations in both formulations and in their components mixed with blood sampled from six volunteers were measured by radioimmunoassays. Injection pain caused by 8% polyethylene glycol 660 hydroxystearate (PEG660 HS) was evaluated in another 10 volunteers. The incidence of injection pain [visual analogue scale (VAS) >30 mm] caused by microemulsion and lipid emulsion propofol was 69.7 and 42.3% (P < 0.001), respectively. The median VAS scores for microemulsion and lipid emulsion propofol were 59 and 24 mm, respectively (95% confidence interval for the difference 12.5, 40.0). The aqueous free propofol concentration of microemulsion propofol was seven times higher than that of lipid emulsion propofol. Agents that reduce injection pain did not affect aqueous free propofol concentrations. Microemulsion propofol and 8% PEG660 HS enhanced plasma bradykinin generation, whereas lipid emulsion propofol and lipid solvent did not. PEG660 HS did not cause injection pain. Higher aqueous free propofol concentrations of microemulsion propofol produce more frequent and severe pain. The plasma kallikrein-kinin system may not be involved, and the agents that reduce injection pain may not act by decreasing aqueous free propofol concentrations.

Kallikrein kinin system activation in post-exercise hypotension in water running of hypertensive volunteers

Previous studies demonstrated a reduction in blood pressure level immediately after different types of exercises, like running, cycling and resistance training, a phenomenon called post-exercise hypotension (PEH). Since PEH can persist for hours it could be suggested as a non-pharmacological therapy for hypertensive individuals. Unfortunately, usually running is not recommended due to the high impact caused by its practice. Therefore running in water treadmill should be a better option, since the environment is completely different and causes lower impact. However it is not known whether PEH occurs in this situation. The objective of this work was to evaluate the existence of PEH after water running and to compare PEH promoted by running in two different environments. In addition, changes in plasmatic concentrations of the kallikrein kinin system (KKS) components were also evaluated. Sixteen hypertensive subjects were submitted to two exercise sessions, conventional running and water running, in two different occasions. The pattern of heart rate, blood pressure and plasmatic concentrations of KKS components immediately after and one hour after exercise were investigated. Results showed a maximal reduction in systolic and diastolic blood pressure 30 min after both exercise models (P<0.001), indicating that moderate water running promotes PEH with similar magnitude as compared to conventional running. Plasma kallikrein activity and bradykinin concentration increased immediately after exercise (P<0.05), but these parameters were not different in both exercise models. In conclusion, our findings show that water running, similarly to conventional running, can also provoke PEH and alterations in the KKS components.

Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant)

In hereditary angioedema, bradykinin is assumed to be the most important mediator of edema formation. To assess whether the selective bradykinin receptor-2 antagonist Icatibant is effective in acute edema attacks of hereditary angioedema. In this uncontrolled pilot study, 15 patients with 20 attacks were treated with Icatibant. The attacks were analyzed by using a standardized and validated visual analog scale measurement and compared with historical data of untreated attacks. Plasma bradykinin concentration was measured before and 4 hours after intravenous Icatibant treatment. Symptom intensity decreased within 4 hours after administration of Icatibant; the median time to onset of symptom relief was 1.50, 1.42, and 1.13 hours in the intravenous groups and 0.58 and 0.45 hours in the subcutaneous groups, respectively. The median difference in the 10-cm visual analog scale 4 hours after start of treatment was 4.11 cm (95% CI, 1.72-6.07). Compared with untreated attacks, Icatibant treatment reduced the mean (SD) time to onset of symptom relief by 97% from 42 +/- 14 to 1.16 +/- 0.95 hours (all groups combined). Median bradykinin concentration was 7-fold above the norm during acute attacks at 48.5 pmol/L and decreased to 18.0 pmol/L 4 hours after Icatibant infusion or injection. Icatibant was effective in treating acute attacks of hereditary angioedema. This is the first report demonstrating the clinical usefulness of antagonizing bradykinin binding to bradykinin receptor-2 in hereditary angioedema.

Increase in kinins on post-exercise hypotension in normotensive and hypertensive volunteers

Post-exercise hypotension is an important event for blood pressure regulation, especially in hypertensive individuals. Although post-exercise hypotension is a well-known phenomenon, the mechanism responsible is still unclear. The kallikrein-kinin system is involved in blood pressure control, but its role in post-exercise hypotension has not yet been investigated. Thus, the purpose of this study was to investigate the involvement of the vasodilators bradykinin and des-Arg(9)-BK and kallikrein activity in post-exercise hypotension promoted by 35 min of cycle ergometer (CE) or circuit weight-training (CWT) bouts in normotensive and hypertensive individuals. A significant decrease in mean arterial pressure at 45 and 60 min after CE and 45 min after CWT was observed in normotensive individuals. Hypertensive values of mean arterial pressure were significantly reduced at 45 and 60 min after CE and at 60 min after CWT. Before exercise, plasma bradykinin concentrations and kallikrein activity were higher in hypertensive compared to normotensive volunteers. Kinin levels increased in the groups evaluated at the end of the training period and 60 min post-exercise. These data suggest that the kallikrein-kinin system may be involved in post-exercise hypotension in normotensive and hypertensive individuals subjected to CE and CWT bouts.

Long-Term Treatment With Imidapril but Not With Nifedipine Enhances Plasma NOx Concentration in Patients With Essential Hypertension

We investigated whether long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor imidapril or the calcium channel antagonist nifedipine increases systemic nitric oxide (NO) production in patients with essential hypertension. Twenty-nine patients with essential hypertension were randomly divided into two groups, and they were treated with either imidapril or nifedipine once daily p.o. for 4 weeks. Long-term treatment with imidapril significantly decreased blood pressure and increased plasma NOx concentration. Long-term treatment with nifedipine also caused a comparable extent of significant decrease in blood pressure, but failed to alter plasma NOx levels. The imidapril treatment significantly inhibited serum ACE activity and increased plasma bradykinin concentration. Furthermore, the extent of inhibition of serum ACE activity and the extent of increase in plasma bradykinin concentration in response to the imidapril treatment were both significantly correlated with the extent of increase in plasma NOx concentration. In contrast, no such changes were noted after the nifedipine treatment. These results provide the first evidence that long-term treatment with imidapril enhances plasma NOx concentration in patients with essential hypertension. This effect does not seem to be due to the decrease in blood pressure. The increase in bradykinin concentration may be involved in the enhancing effect of the ACE inhibitor on NOx production in vivo.

Putative contribution of prostaglandin and bradykinin to muscle reflex hyperactivity in patients on Ace-inhibitor therapy for chronic heart failure.

In patients with chronic heart failure (CHF), an overactive muscle ergoreceptor reflex (chemo-afferents sensitive to the products of muscle work) is thought to play an important role in the origin of dyspnoea. We sought to investigate whether raised intra-muscular prostaglandins (PG) and bradykinin, as estimated by levels within the venous effluent from exercising skeletal muscle may be involved in symptom generation through the stimulation of the ergoreflex. In 19 stable CHF patients and 12 normal controls, cardiopulmonary exercise capacity (peak O2 consumption [peak VO2]) and the ergoreflex contribution to ventilation (post-handgrip regional circulatory occlusion method) were measured. Venous resting and exercise plasma PGE2, PGF1alpha and bradykinin concentrations were assessed. Eleven patients on angiotensin converting enzyme inhibitors and 10 controls were challenged with ketoprofen infusion (to inhibit PG synthesis and bradykinin activity). Patients vs. controls presented lower exercise tolerance (peak VO2 15.9+/-0.7 vs. 33.0+/-1.3 mL/kg/min), an increased ventilatory response to exercise (VE/VCO2 slope 43+/-2 vs. 27+/-0.9) (p<0.0001 for all comparisons). The overactive ergoreflex of CHF (5.1+/-1.3 vs. 0.1+/-0.3 L/min) was significantly related to the increase in PGF1alpha (adjusted R2=0.34, p<0.005) but not PGE2 (adjusted R2=0.16, p>0.05). The increased PG and bradykinin productions both at rest and during exercise in CHF were attenuated after ketoprofen infusion, associated with ergoreflex reduction (-5.1+/-2.2 L/min, p<0.05 vs. saline). In CHF, overactive muscle ergoreflex is associated with elevated blood concentration of PG and bradykinin. Modulation of these metabolite concentrations acutely reduces the muscle ergoreflex activity, which suggests a causative role in triggering and/or mediating the ergoreflex response.

Contact-system activation in children with vasculitis

The contact system triggers the kallikrein-kinin cascade, liberating bradykinin from high-molecular-weight kininogen. Effectors of the contact system have proinflammatory and vasoactive properties. Vasculitis is a condition characterised by inflammation around vessel walls, leading to secondary tissue damage for which the underlying molecular mechanisms are poorly understood. Our aim was to investigate contact-system activation in children with vasculitis. We compared 17 children, aged 4-19 years, with vasculitis, engaging the skin, joints, intestines, or kidneys, with 21 controls, aged 2-18 years. We analysed proteolysis of high-molecular-weight kininogen by immunoblotting. Plasma bradykinin concentrations were quantified by ELISA. Kidney and skin biopsies were stained in situ for kinins. Concentrations of heparin binding protein (HBP) were quantified by ELISA. We noted extensive proteolysis of high-molecular-weight kininogen in the plasma of 13 of 17 patients, but in only one of 21 controls (p<0.0001). Bradykinin concentrations were higher in the patients' plasma (median 320 ng/L, range <1-19680) than in plasma from controls (11 ng/L, <1-304; p=0.0004). Patients had local release of kinins at sites of inflammation in kidney and skin biopsies. HBP values were raised in patients (17.4 microg/L, 5.4-237.6) compared with controls (6 microg/L, 2.5-43.4; p=0.008). Activation of the contact system could play a part in the pathogenesis of vasculitis, and explain the inflammation, pain, vasodilatation, and oedema seen in patients.

Long-Term Treatment With Perindopril Ameliorates Dobutamine-Induced Myocardial Ischemia in Patients With Coronary Artery Disease

The present study was designed to examine whether long-term blockade of angiotensin-converting enzyme (ACE) with perindopril ameliorates dobutamine-induced myocardial ischemia in patients with coronary artery disease (CAD). Twelve patients with proven CAD were randomly divided in two groups; one group received perindopril (8 mg/day, p.o.) for 3 months and another group served as a control. To evaluate anti-ischemic effects of perindopril, dobutamine stress echocardiography was performed before and 3 months after the treatment in a double-blind manner. Long-term treatment with perindopril significantly ameliorated the dobutamine-induced myocardial ischemia, as evaluated by time to the onset of symptoms, magnitude of electrocardiographic ST-segment changes, and left ventricular wall motion score (all P<0.05). The treatment significantly decreased serum ACE activities (P<0.01) and increased plasma bradykinin concentrations (P<0.05). The extent of reduction of left ventricular wall motion score by perindopril was closely correlated with that of inhibition of serum ACE activities (P<0.01) and with that of increase in plasma bradykinin concentrations (P<0.05). By contrast, no such beneficial changes were noted in the control group. These results provide the first evidence that long-term treatment with perindopril exerts anti-ischemic effects on the myocardial ischemia induced by increased myocardial oxygen demand in patients with CAD.

No relation between angiotensin-converting enzyme (ACE) inhibitor-induced cough and ACE gene polymorphism, plasma bradykinin, substance P and ACE inhibitor concentration in Japanese patients

Persistent dry cough is well known as the most common side-effect of angiotensin-converting enzyme (ACE) inhibitors. We examined the relationship between a cough and ACE gene polymorphism, plasma bradykinin (BK), substance P (SP) and ACE inhibitor concentrations in patients with hypertension or chronic nephritis. First, ACE genotyping was carried out in 96 patients, 42 with coughs and 54 without coughs, which had been treated with various kinds of ACE inhibitors. However, no significant difference in the ACE genotypes was observed between the two groups. Second, the plasma concentrations of BK, SP and ACE inhibitor were measured in 12 patients, which were treated with trandolapril at a daily dose of 1 mg for 4-33 weeks. In 3 patients, the cough was induced during the trandolapril therapy, while it was induced not in 9 patients. The plasma levels of BK and SP did not significantly change after trandolapril administration in the patients with and without coughs. Between the two groups, there were no significant differences in the plasma levels of BK and SP either before or after the trandolapril therapy. Also the plasma concentrations of trandolapril and trandolaprilat, the active metabolite of trandolapril, did not significantly differ between the two groups. These results suggest that there is no significant relationship between the ACE inhibitor-induced cough and ACE gene polymorphism, plasma BK, SP and ACE inhibitor concentrations in patients with hypertension or chronic nephritis.

Plasma bradykinin levels in human chronic congestive heart failure

Induction of congestive heart failure by high-frequency pacing has been reported to increase plasma levels of immunoreactive kinins in dogs. In the present study, we evaluated plasma bradykinin levels in human heart failure. Utilizing a recently developed method, we specifically measured plasma levels of bradykinin-(1-9) nonapeptide in 21 patients with chronic congestive heart failure [New York Heart Association (NYHA) stages III and IV). At the same time, we measured plasma atrial natriuretic peptide levels and plasma renin activity, and, as a marker of inflammation, plasma levels of tumour necrosis factor. In addition, 18 healthy subjects matched for gender and age served as normal controls. Plasma bradykinin concentrations were not higher in patients with chronic congestive heart failure (median 2.1 fmol/ml) than in healthy subjects (2.6 fmol/ml). In contrast, plasma atrial natriuretic peptide levels were clearly higher (patients, 63 fmol/ml; controls, 24 fmol/ml; P<0.0001), despite diuretic treatment and in the presence of high plasma renin activity (patients, 13.0 ng x h(-1) x ml(-1); controls, 0.3 ng x h(-1) x ml(-1); P<0.0001). Tumour necrosis factor was elevated in heart failure patients in NYHA class IV only (27 pg/ml, compared with 21 pg/ml in controls; P=0.013). Bradykinin, atrial natriuretic peptide and plasma renin activity levels were not correlated with the severity of the disease, as assessed by NYHA classification. These results indicate that a rather selective cytokine activation, without concomitant stimulation of the kallikrein-kinin system, occurs in human chronic congestive heart failure.

Activation of the kallikrein-kinin system in hemodialysis: Role of membrane electronegativity, blood dilution, and pH

The kallikrein-kinin system activation by contact with a negatively charged surface has been promulgated to be responsible for hypersensitivity reactions. However, to explain the low frequency and heterogeneity of hypersensitivity reactions, we hypothesized that not only the electronegativity of the membrane, but also other physicochemical parameters could influence the activation of the contact phase system of plasma assessed by the measurement of kallikrein activity and bradykinin concentration. Plasma kallikrein activity using chromogenic substrate (S2302) and plasma bradykinin concentration (enzyme immuno assay) were measured during the perfusion of human plasma (2.5 ml/min) through minidialyzers mounted with six different membranes [polyacrylonitrile (PAN) from Asahi (PANDX) and from Hospal (AN69), polymethylmethacrylate (PMMA) from Toray, cellulose triacetate (CT) from Baxter, cuprophane (CUP) from Akzo and polysulfone (PS) from Fresenius]. A direct relationship was shown between the electronegativity of the membrane assessed by its zeta potential and the activation of plasma during the first five minutes of plasma circulation. With the AN69 membrane, the detection of a kallikrein activity in diluted plasma but not in undiluted samples confirmed the importance of a protease-antiprotease imbalance leading to bradykinin release during the first five minutes of dialysis. With PAN membranes, the use of citrated versus heparinized plasma and the use of various rinsing solutions clearly show a dramatic effect of pH on the kallikrein activity and the bradykinin concentration measured in plasma. Finally, increasing the zeta potential of the membrane leads to a significant increase of plasma kallikrein activity and bradykinin concentration. Our in vitro experimental approach evidences the importance of the control of these physicochemical factors to decrease the activation of the contact system.

Plasma bradykinin in angio-oedema

Bradykinin is believed to be the main mediator of symptoms in hereditary (HA) and acquired (AA) angio-oedema due to C1 esterase inhibitor deficiency, as well as in angio-oedema that complicates treatment with inhibitors of angiotensin-converting enzyme (ACE). Difficulties in the measurement of kinin concentrations, however, have so far precluded the demonstration of an incontrovertible change in plasma bradykinin concentrations in these disorders. By developing a reliable assay we have been able to follow bradykinin concentrations during attacks and during remission in HA and in AA, and also in a patient treated with an ACE-inhibitor. Liquid-phase extraction, high-performance liquid chromatography, and RIA were used for specific measurement of plasma bradykinin concentrations in 22 patients with HA and in 22 healthy volunteers of similar age and sex distribution. Four patients with AA and one hypertensive patient treated with the ACE inhibitor captopril were also studied. Among the healthy volunteers plasma bradykinin concentration was inversely proportional to age. The geometric mean plasma bradykinin concentration in the healthy volunteers was 2.2 fmol/mL (SD 2.2), compared with 3.9 fmol/mL (3.7) among patients with HA during remission (p=0.095). Bradykinin was also high in the patients with AA (10.4 fmol/mL [1.6]). During acute attacks of oedema, in both HA and AA, plasma bradykinin rose to two to 12 times the upper limit of normal. Infusion of C1-esterase inhibitor (the deficient factor in both HA and AA) immediately lowered bradykinin concentrations. In the patient receiving the ACE-inhibitor captopril, bradykinin concentration was very high at 47 fmol/mL during an acute attack of angio-oedema, but normal at 3.2 fmol/mL in remission after withdrawal of the drug. A sensitive method for measurement of plasma bradykinin provided the means to show that concentrations of this peptide decrease with age in healthy people. Although the differences between patients in remission and healthy controls did not reach statistical significance, there were substantial rises in bradykinin during acute attacks of hereditary, acquired, or captopril-induced angio-oedema.

The involvement of plasma kinins in the cardiovascular effects of Leiurus quinquestriatus scorpion venom in anaesthetised rabbits

The present study was undertaken to investigate the involvement of kinins in the cardiovascular and respiratory effects of LQQ venom. Blood pressure, heart rate, electrocardiogram (ECG) and respiration were studied in anaesthetised rabbits, in the presence and absence of aprotinin and icatibant, a B 2 bradykinin antagonist. Plasma bradykinin concentrations were also measured following venom injection. LQQ venom caused a triphasic effect on blood pressure comprising an immediate fall, a pronounced rise and a progressive decline until death. Bradycardia, myocardial damage, arrhythmias, respiratory distress and pulmonary oedema were also exhibited. Pretreatment with aprotinin attenuated the venom-induced hypotension, bradycardia, ECG and respiratory changes and prolonged survival. Pretreatment of atropinized animals with icatibant gave similar protection. In animals treated with LQQ venom, plasma bradykinin was significantly higher than controls, although there was considerable inter-animal variation in plasma kinin concentrations and the elevation was seen relatively late after venom administration. The data provides some support for the hypothesis that kinins are involved in the cardiovascular and lethal effects of LQQ venom in rabbits.

Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: bradykinin may improve insulin resistance in dogs and humans

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol · kg−1) or orally (5.0 mmol · kg−1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol · kg−1) and oral administration of either delapril or enalapril (5.0 mmol · kg−1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-α-adamantaneacetyl-d-Arg-[Hyp3, Thi5,8,d-Phe7]-bradykinin) (0.5 nmol · kg−1 · min−1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol · kg−1 · min−1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol · kg−1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group. Bradykinin may also possibly be involved in the mechanism underlying the improvement in insulin sensitivity associated with ACE-inhibition.

Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: Bradykinin may improve insulin resistance in dogs and humans

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol.kg-1) or orally (5.0 mmol.kg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol.kg-1) and oral administration of either delapril or enalapril (5.0 mmol.kg-1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-alpha-adamantane-acetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]-b bradykinin) (0.5 nmol.kg-1 x min-1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol.kg-1 x min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol.kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Bradykinin in Anaphylactoid Reactions during Hemodialysis with AN69 Dialyzers

In vitro experiments have related anaphylactoid reactions in patients treated with angiotensin-converting enzyme (ACE) inhibitors during dialysis with AN69 membranes to excessive bradykinin generation using this negatively charged dialysis membrane. In the present clinical trial plasma bradykinin levels were followed during the early phase of dialysis in 10 patients, not being treated with ACE inhibitors, using AN69, cuprophane, and polysulfone membranes. Bradykinin was measured after extraction by radioimmunoassay. During this study one episode of anaphylaxis occurred during dialysis with the AN69 membrane. Blood samples were collected during the first 5 min of the adverse reaction and showed a more than 100-fold increase in the venous effluent of the AN69 dialyzer (baseline 40 +/- 3 vs. 4,900 +/- 130 fmol/ml after 5 min). Even though none of the patients received ACE inhibitors, there were 4 more asymptomatic individuals who displayed a more than two-fold increase in their plasma bradykinin concentrations in the venous effluent of the AN69 dialyzer. When these patients were treated either with cuprophane or with polysulfone dialyzers, no significant bradykinin formation was detected, nor were there any adverse events. Taken together, these findings show that anaphylactoid reactions with the AN69 membrane are due to excessive bradykinin generation which even may occur in the absence of ACE inhibitors.