Bradykinin Levels Research Articles

Prospective crossover study for a standardized comparison of the dextrane sulfate whole blood and plasma apheresis system in patients with cardiovascular disease and severe dyslipidemia

Background and aimsThe objective of this study was a standardized comparison of the safety and effectiveness of the Kaneka (Kaneka Corporation, Osaka, Japan) whole blood (Liposorber DL-100) and plasma (Liposorber LA-15) lipoprotein apheresis (LA) system to optimize the individual therapy of patients with cardiovascular disease and severe dyslipidemia. MethodsSix chronic LA patients with a pre-treatment LDL-C < 6 mmol/l in steady state received a total of three treatments with the LA-15 device, followed by three treatments with the DL-100 device or vice versa. To achieve a standardized comparison the treated blood volume for any patient was kept identical for both procedures. Sampling points for total cholesterol, LDL-C, HDL-C, Lp(a), triglyceride, blood count, and bradykinin measurements were adjusted for both techniques. ResultsTotal cholesterol, LDL-C, HDL-C, Lp(a), and triglycerides were reduced by 59.2 ± 6.5%, 79.3 ± 6.9%, 7.1 ± 3.9%, 87.3 ± 3.1%, 22.5 ± 24.2% using the DL-100 system and by 51.4 ± 5.2%, 65.2 ± 3.7%, 2.2 ± 4.9%, 72.7 ± 2.2%, 46.5 ± 9.4% using the LA-15 system, showing that the DL-100 adsorber was significantly more effective for lowering total cholesterol (p = 0.044), LDL-C (p = 0.001), Lp(a) (p = 0.029), while triglycerides were reduced to a higher extent by the plasma system (p = 0.046) in this patient group. The regenerable LA-15 adsorber columns showed a higher removal capacity considering the difference between inflow and outflow concentrations. Bradykinin levels significantly increased up to 145 fold in the outflow lines using the plasma system (p = 0.028), but not systemically. There was no significant bradykinin generation using the whole blood adsorber. ConclusionIn conclusion, the whole blood system was faster and more effective in this LA patient group with pre apheresis LDL-C<6 mmol/l. Whether the regenerable plasma system is more effective in patients with higher LDL-C content should be evaluated in future standardized comparisons.

Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM), gadolinium (300 μM) and 2-aminoethyl diphenylborinate (0.1 μM). The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn) of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal normalized rate of contraction and relaxation of carbachol- and potential-induced smooth muscle contraction. Based on the results and previous investigations, the MX-1775 is a potential blocker of kinin B2-receptors. Effects obtained for other compounds require additional research.

Resetting of renal tissular renin-angiotensin and bradykinin-kallikrein systems after unilateral kidney denervation in rats.

The renal tissular renin-angiotensin and bradykinin-kallikrein systems control kidney function together with the renal sympathetic innervation but their interaction is still unclear. To further elucidate this relationship, we investigated these systems in rats 6days after left kidney denervation (DNX, n = 8) compared to sham-operated controls (CTR, n = 8). Plasma renin concentration was unchanged in DNX vs. CTR (p = NS). Kidney bradykinin (BK) and angiotensin (Ang) I and II concentrations decreased bilaterally in DNX vs. CTR rats (~20 to 40%, p < 0.05) together with Ang IV and V concentrations that were extremely low (p = NS). Renin, Ang III and dopamine concentrations decreased by ~25 to 50% and norepinephrine concentrations by 99% in DNX kidneys (p < 0.05) but were unaltered in opposite kidneys. Ang II/I and KA were comparable in DNX, contralateral and CTR kidneys. Ang III/II increased in right vs. DNX or CTR kidneys (40-50%, p < 0.05). Ang II was mainly located in tubular epithelium by immunocytological staining and its cellular distribution was unaffected by DNX. Moreover, the angiotensinergic and catecholaminergic innervation of right kidneys was unchanged vs. CTR. We found an important dependency of tissular Ang and BK levels on the renal innervation that may contribute to the resetting of kidney function after DNX. The DNX-induced peptide changes were not readily explained by kidney KA, renin or plasma Ang I generation. However, tissular peptide metabolism and compartmentalization may have played a central role. The mechanisms behind the concentration changes remain unclear and deserve further clarification.

Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa

BackgroundTraumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI.MethodsUsing a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings.ResultsWe show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model.ConclusionsStimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.

Effect of 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones on the bradykinin-induced smooth muscle contraction

Damage to tissue, inflammation and disruption of normal functioning of organs are often accompanied by pain. In pain perceptions, the kinin-kallikrein system with bradykinin as mediator is very important. Regulatory activity of the kinin-kallikrein system permits the control of inflammation, pain, vascular tone and other functions. A new group of substances that may used for this purpose are 3-substituted 1,4-benzdiazepinones. We analyzed the effect of 3-aryl amino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction of the stomach in the presence of calcium channel blockers verapamil (1 μM) and gadolinium (300 μM). The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in the incubation solution were 10–6 M. Data processing on the dynamics of contraction was performed according to the method of T. Burdyha and S. Kosterin. Statistically significant changes were found for MX-1828. This compound reduced the maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of Gd3+ and verapamil by 19.3% and 32.0%, respectively. Also, MX-1828 demonstrated effects similar to those of the competitive inhibitor bradykinin B2-receptor – des-Arg9-bradykinin-acetate, which is possible evidence of its interaction with the receptor or signal transduction pathways. MX-1828 additionally reduced the maximum normalized rate of relaxation by 6.2% in the presence of Gd3+. This effect was demonstrated for MX-1906 in the presence of verapamil with additional reduction of the maximal normalized rate of relaxation, which was 26.4%. The results suggest the presence of inhibitory interaction between MX-1828 and kinin-kallikrein system receptors or signal transduction pathways. The effects which were found for MX-1906 require further studies to clarify the mechanisms of influence on bradykinin-induced smooth muscle contraction.

Coagulation factor XII regulates inflammatory responses in human lungs.

Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis.

The role of bradykinin in lung ischemia-reperfusion injury in a rat lung transplantation model.

To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin β2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.

Lysosomal Cathepsin A Plays a Significant Role in the Processing of Endogenous Bioactive Peptides.

Lysosomal serine carboxypeptidase Cathepsin A (CTSA) is a multifunctional enzyme with distinct protective and catalytic function. CTSA present in the lysosomal multienzyme complex to facilitate the correct lysosomal routing, stability and activation of with beta–galactosidase and alpha-neuraminidase. Beside CTSA has role in inactivation of bioactive peptides including bradykinin, substances P, oxytocin, angiotensin I and endothelin-I by cleavage of 1 or 2 amino acid(s) from C-terminal ends. In this study, we aimed to elucidate the regulatory role of CTSA on bioactive peptides in knock-in mice model of CTSAS190A. We investigated the level of bradykinin, substances P, oxytocin, angiotensin I and endothelin-I in the kidney, liver, lung, brain and serum from CTSAS190A mouse model at 3- and 6-months of age. Our results suggest CTSA selectively contributes to processing of bioactive peptides in different tissues from CTSAS190A mice compared to age matched WT mice.

Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: Seven case series and discussion

Background and aimsFor patients with homozygous familial hypercholesterolemia (HoFH), atherogenic lipoprotein changes and increased stress on cardiovascular system during pregnancy may pose substantial risk for both the mother and her fetus. Although lipoprotein apheresis (LA) is reported as the most effective therapy to control LDL-C levels during pregnancy in HoFH patients, only case reports have been published, and there is no guidance for management. MethodsWe report twelve pregnancies and ten deliveries in seven patients with HoFH, and compare the clinical outcomes between patients who received LA during pregnancy and those who did not. ResultsOne patient who refused LA during pregnancy died from acute myocardial infarction after delivery. Another patient whose adherence to LA was poor also died of myocardial infarction during pregnancy. One patient who initiated LA at the age of 18 had to discontinue LA due to severe symptoms of angina pectoris during pregnancy. Another had symptoms of nausea, hypotension, and bradycardia with increased levels of serum bradykinin during a dextran sulfate cellulose absorption-based LA procedure. Although two of the other three patients had already had coronary artery disease by the time of pregnancy, early initiation of LA from childhood and good adherence to it during pregnancy resulted in the delivery of healthy infants without adverse effects. ConclusionsLA is essential for managing pregnancy safely in patients with HoFH. Increasing numbers of documented cases, including ours, will be helpful to guide future therapeutic decisions.

Visceral Angioedema: A Rare Complication of ACE Inhibitors Causing Chronic Diarrhea

Isolated visceral angioedema due to angiotensin converting enzyme inhibitors (ACEi) is a rare and under-recognized phenomenon. It is an adverse effect that should be considered when presented with a case of gastrointestinal symptoms of unclear etiology. We provide a case of a female presenting solely with a month long history of diarrhea and unremarkable diagnostic findings, only found to have relief after discontinuing her ACEi. Drug re-challenge lead to recurrence of her symptoms, thus confirming our diagnosis. A 68-year-old female presented to the hospital for non-bloody diarrhea occurring for the last one month, which failed outpatient therapy. Her medical history included mesenteric ischemia with partial small bowel resection and hypertension. Initial findings on exam were significant for blood pressure of 85/60 mmHg and left lower quadrant abdominal tenderness. Laboratory work was significant for acute renal injury and metabolic acidosis. Stool was negative for - C.difficile toxin AB, lactoferrin, occult blood, Giardia/Cryptosporidium antigens, Ova/Parasites, Shiga toxin, Salmonella, Shigella, or Campylobacter species. Computed tomography (CT) showed diffuse non-obstructive distention of the small bowel, confirmed by CT enterography. Colonoscopy showed normal appearing ileal and colonic mucosa with unremarkable biopsies. Lisinopril was held due to acute kidney injury, but with the differential of ACEi-induced visceral angioedema, it was discontinued at the time of discharge. Three weeks follow up at PCP'S office, patient reported of complete symptom resolution. Three years later lisinopril was restarted by patient's cardiologist which lead to recurrence of diarrhea. Thus confirming the diagnosis. Angioedema, a rare but potentially fatal side effect of ACEi, occur in about 0.1-0.7% of patients affecting the face, mouth, and upper airways. This is due to the higher levels of bradykinin resulting in the vasodilation and increased vascular permeability in the skin and mucous membranes. Even less recognized is visceral angioedema, with only a handful of cases involving the small intestine and one including the stomach. Patients tend to have nausea, vomiting, abdominal pain, diarrhea, and occasionally ascites. Our patient presented with complaints of diarrhea and urgency with unremarkable imaging and stool studies. Visceral angioedema was confirmed with symptom resolution when the ACEi was discontinued and recurrence with drug re-challenge.Figure 1

ACE Inhibitor-Induced Angioedema of the Small Bowel

Angiotensin-converting enzyme (ACE) inhibitors are routinely prescribed for patients with hypertension, coronary artery disease (CAD), heart failure with systolic dysfunction, diabetes and chronic kidney disease (CKD). This category of medications is also the leading cause of drug-induced angioedema, occurring in 0.1% to 0.7% of patients. A 49-year-old female presented for evaluation of worsening abdominal pain with nausea, vomiting, and severe bloating, worsening over the next 12 months. Her past medical history included hypertension, depression, hiatal hernia, and an abdominal hysterectomy 20 years prior. Her only medication was Lisinopril 20 mg daily which she had been on for two years. Work up included an EGD and colonoscopy which showed no abnormalities, laboratory workup were all normal except for mildly elevated CRP of 21 and lipase of 73, and the only abnormality seen on imaging came from the CT which showed borderline thickening of distal small bowel loops. She continued to experience symptoms for a total of 15 months, at which point her ACE-inhibitor was stopped. Her symptoms resolved shortly afterwards and did not return, suggesting angioedema caused by her ACE inhibitor. This was likely seen on her initial abdominal CT as the cause for the borderline wall thickening of the small bowel loops. This case demonstrates the angioedema may be exclusive to the GI tract with no overt evidence of swelling elsewhere. We recommend consideration of ACE inhibitor-induced angioedema in any patient using ACE inhibitors presenting with non-specific abdominal complaints without evidence of other causes. Practice recommendations would include reviewing medications while considering ACE inhibitor induced angioedema, checking bradykinin levels which may be elevated with ACE inhibitor use, and a trial off of the ACE inhibitor to see if symptoms resolve. We also recommend discussion of angioedema, including GI symptoms, with patients prior to starting ACE inhibitors.Figure 1Figure 2

Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series

BackgroundThere is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (TB) in order to predict treatment outcomes. Exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (BK) and its metabolite desArg9-bradykinin (DABK) to induce inflammation and innate immune responses. We hypothesized that serum BK and DABK levels might act as sensitive immune response signatures for changes in Mycobacterium tuberculosis (Mtb) burden, and therefore examined how serum levels of these markers corresponded with anti-TB therapy in a small cohort of active TB cases. MethodsNanotrap Mass-Spectrometry (MS) was used to analyze serial blood specimens from 13 HIV-negative adults with microbiologically confirmed active TB who were treated with first-line anti-TB chemotherapy. MS signal for BK (m/z 1060.5) and DABK (m/z 904.5) serum peptides were evaluated at multiple time-points (before, during, and after treatment) to evaluate how BK and DABK levels corresponded with disease status. ResultsSerum BK levels declined from pretreatment baseline levels during the early stage anti-TB therapy (induction phase) and tended to remain below baseline levels during extended treatment (consolidation phase) and after therapy completion. BK levels were consistent with induction phase sputum culture conversions indicative of decreased Mtb burden reflecting good treatment responses. Serum DABK levels tended to increase during the induction phase and decrease at consolidation and post-therapy time points, which may indicate a shift from active disease to chronic inflammation to a disease free state. Elevated BK and DABK levels after treatment completion in one patient may be related to the subsequent recurrent TB disease. ConclusionsOur pilot data suggests that changes in the circulating BK and DABK levels in adult TB patients can be used as potential surrogate markers of the host response both early and late in anti-TB treatment for both pulmonary and extrapulmonary TB patients. We will further exploit these host-response signatures in the future as biomarkers in combination with other clinical and microbiologic tools which may improve treatment efficacy and facilitate the development of host-directed therapy.

Alu insertion/deletion of ACE gene polymorphism might not affect significantly the serum bradykinin level in hypertensive patients taking ACE inhibitors

BackgroundAngiotensin I-converting enzyme (ACE) has two homologous catalytic domains, the N- and C-domains. Our previous study suggested that Alu insertion (I allele) in the intron 16 of ACE resulted in premature codon termination. The I allele has only one active site in the N-domain while the Alu deletion (D allele) still has two active sites of ACE. Therefore the effect of I/D polymorphism of ACE on the enzyme’s ability to catalyse bradykinin is still not widely known. AimsThis study aimed to examine the serum bradykinin level in hypertensive patients with I/D polymorphism of ACE, who were treated with ACE inhibitor. Subjects and methodsThe serum bradykinin and I/D polymorphism have been detected in 64 hypertensive patients taking ACE inhibitor (lisinopril or captopril) for at least eight weeks with good medication adherence. The binding affinity of ACE with its receptor was calculated by molecular docking. ResultsThe findings show that genotype II is more frequent in the population the researchers observed (53.12%) compared to ID (23.44%) and DD (23.44%) variances. On the other hand, the bradykinin level is not affected by genotype of the ACE genes on the population. Bradykinin increases in patients with genotype II who are given captopril, but decreases in patients treated with lisinopril. Nevertheless, there is no statistically significant difference. ConclusionThis study suggests that the polymorphism might not significantly affect the serum bradykinin level in hypertensive patients taking ACE inhibitors.

ISH NIA PS 01-05 Cardioprotection by aliskiren, valsartan and their combination in rats with chronic myocardial infarction

Objective: Aliskiren is a renin inhibitor approved for the treatment of hypertension. Aliskiren increases cardiac tissue kallikrein and bradykinin levels, both of which are important for cardioprotection. We showed previously that aliskiren reduces myocardial ischemia-reperfusion injury via a bradykinin B2 and angiotensin AT2 receptor-mediated mechanism. In the present study, we investigated the effects of aliskiren on cardiac remodeling and hemodynamics post myocardial infarction (MI). Design and Method: Female Sprague-Dawley rats were subjected to either sham MI or MI produced by permanent ligation of the left anterior descending coronary artery. MI rats were then divided into 4 treatment groups at 2 days post-MI: vehicle, aliskiren (10 mg/kg/day s.c.), valsartan (30 mg/kg/day p.o.), or the combination of aliskiren and valsartan. Cardiac function was assessed by echocardiography and in vivo pressure-volume loop analysis of hemodynamics at 28 days post-MI. Results: Vehicle-treated MI rats developed left ventricular dilation, with higher end-diastolic volumes (530 ± 60 μl c.f. 370 ± 30 μl) and end-systolic volumes (300 ± 50 μl c.f. 120 ± 10 μl) when compared with sham MI rats. Compared to sham MI rats, vehicle-treated MI rats had reduced ejection fraction (EF; 47 ± 4% c.f. 69 ± 2%), fractional area change (FAC; 35 ± 4% c.f. 59 ± 5%) and fractional shortening (FS; 21 ± 2% c.f. 43 ± 3%). Treatment with valsartan or the combination of aliskiren and valsartan improved EF to 58 ± 3% or 55 ± 3%, respectively, and a similar trend was observed in aliskiren-treated rats (56 ± 3%; P = 0.056). FAC was improved in valsartan-treated rats (44 ± 3%) but not in aliskiren- (39 ± 3%) or combination-treated (37 ± 3%) rats. FS improved significantly with aliskiren (to 31 ± 3%), valsartan (to 31 ± 3%) and with the combination of aliskiren and valsartan (to 26 ± 2%). Apart from a lowering of systolic blood pressure with valsartan and the combination of aliskiren and valsartan, there were no effects of treatment on hemodynamics. Conclusions: In rats with chronic myocardial infarction, aliskiren and valsartan were similarly cardioprotective with no additional benefit from their combination.

Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Prothrombotic Processes and Myocardial Infarction Risk

Acute ischemic events occur most frequently at dawn and in the early hours of the morning. The development of these severe clinical events exhibits a temporal relationship with changes in various hemodynamic, prothrombotic, and hormonal processes. The authors highlight not only these relationships but also the potential protective effect of increased bradykinin levels and the inhibition of different angiotensin II (AT-II) receptors (AT2, AT4) against unfavorable prothrombotic influences, which—based on studies to date—decreases the risk of acute cardiovascular events. Comparisons are presented between the different effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on factors that influence thrombus formation and myocardial infarction risk.

Therapeutic modulation of tissue kallikrein expression.

The kallikrein kinin system has cardioprotective actions and mediates in part the cardioprotection produced by angiotensin converting enzyme inhibitors and angiotensin type 1 receptor blockers. Additional approaches to exploit the cardioprotective effects of the kallikrein kinin system include the administration of tissue kallikrein and kinin receptor agonists. The renin inhibitor aliskiren was recently shown to increase cardiac tissue kallikrein expression and bradykinin levels, and to reduce myocardial ischemia-reperfusion injury by bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. Thus, aliskiren represents a prototype drug for the modulation of tissue kallikrein expression for therapeutic benefit.

Review of hereditary angioedema

Hereditary angioedema (HAE) is a rare disease caused by deficiency of C1 esterase inhibitor (C1-INH). It is an autosomal dominant disease caused by a variety of mutations in the C1-INH gene. C1-INH is an important regulator of several pathways. One pathway it affects is the kallikrein–kinin pathway, which results in the generation of bradykinin. Bradykinin is an important mediator of edema. Diagnosis is based on low levels of C1-INH. HAE with normal C1-INH is also recognized in the literature and the pathophysiology is due to another aspect of the pathway being affected leading to increased bradykinin level. Bradykinin results in intermittent swelling of the cutaneous and mucosal surfaces. The swelling usually evolves over several hours and lasts a few days. Location of the swelling can involve any part of the body including fatal laryngeal edema. Newer treatments exist to treat acute attacks and reduce the frequency of future attacks. Earlier diagnosis and treatment of hereditary angioedema can prevent HAE-associated mortality. Statement of novelty: New treatments are used to treat these attacks. These treatments are aimed at patients having a more normal life with hereditary angioedema.

Protective effect of soybean oil- or fish oil-rich diets on allergic airway inflammation.

BackgroundThe increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets rich in n-6 fatty acids (FAs) and poor in n-3 FAs. This study aimed to analyze the prophylactic effects of treatment with a soybean oil-rich diet (rich in n-6) or fish oil (rich in n-3) in an allergic airway inflammation model on lung inflammation score, leukocyte migration, T-helper cell (Th)-2 (interleukin [IL]-4, IL-5) and Th1 (interferon [IFN]-γ, tumor necrosis factor-α) cytokines, lipoxin A4, nitric oxide, bradykinin, and corticosterone levels in bronchoalveolar lavage (BAL) or lungs.MethodsMale Wistar rats fed with soybean oil- or fish oil-rich diet or standard rat chow were sensitized twice with ovalbumin–alumen and challenged twice with ovalbumin aerosol. The BAL and lungs were examined 24 hours later.ResultsBoth diets, rich in n-6 or n-3 FAs, impaired the allergic lung inflammation and reduced leukocyte migration, eosinophil and neutrophil percentages, and IL-4/IL-5/bradykinin levels in BAL and/or lungs, as well as increased the nitric oxide levels in BAL. The soybean oil-rich diet additionally increased the levels of lipoxin A4 and corticosterone in the lungs.ConclusionData presented demonstrated that the n-6 FA-rich diet had protective effect upon allergic airway inflammation and was as anti-inflammatory as the n-3 FA-rich diet, although through different mechanisms, suggesting that both diets could be considered as complementary therapy or a prophylactic alternative for allergic airway inflammation.

High-molecular-weight kininogen and its cleavage product bradykinin are critical in the pathogenesis of autoantibody-induced arthritis

Abstract High-molecular-weight kininogen (HK) is a major component of plasma kallikrein-kinin system (KKS), the activation of which mediates HK cleavage to release bradykinin (BK). BK is a nonapeptide with potent proinflammatory and vasoactive activities. Although patients with rheumatoid arthritis (RA) exhibits the activation of the KKS and the cleavage of HK in plasma, the role of HK in arthritis pathogenesis has never been characterized. In this study we evaluated the phenotype of our newly-generated HK-deficient (Kng1−/−) mice in arthritis. To induce autoantibody-induced arthritis, two groups of Kng1+/+ and Kng1−/− mice were injected intraperitoneally with anti-type II collagen antibody cocktail (4 mg) on day 0 and lipopolysaccharide (LPS, 50 μg) on day 3. Although wild-type (WT) mice developed severe arthritis, the Kng1−/− mice exhibited significantly attenuated disease severity as evaluated by joint diameter change and clinical scores (p&amp;lt;0.0001). Compared with WT mice, Kng1−/− mice displayed reduced synovial hyperplasia and cartilage erosions, and decreased protein and mRNA levels of IL-1b and IL-6 in joint tissue (p&amp;lt;0.001). BK level and kallikrein activity in Kng1−/− plasma were significantly lower than that of WT mice. Incubation with collagen-anti-collagen antibody complex mediated BK production in human plasma. Consistent with the phenotype of Kng1−/− mice, the mice lacking BK receptors also displayed a reduced arthritis severity, as well as a decrease in IL-1b and IL-6 production in joint tissue. Our study provides the first genetic evidence indicating an important role of HK in the pathogenesis of arthritis, and the blockade of HK cleavage to prevent BK production might be a novel therapeutic strategy for RA treatment.

Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein-kinin system in vascular endothelial cells.

Vascular farnesoid X receptor (FXR) ligands have been shown previously to regulate vascular tension. This study investigated whether FXR activation regulates vasoreactivity via the angiotensin II (Ang II) type 2 receptor (AT2 R) and the kallikrein-kinin system in rat aortic vascular endothelial cells (RAECs). Protein abundances of Ang II type 1 receptor (AT1 R), AT2 R, bradykinin type 1/2 receptor (B1 R, B2 R), small heterodimer partner-1 (SHP-1) and the endothelial and inducible NO synthases (eNOS/iNOS) were analysed by Western blotting. Real-time quantitative polymerase chain reaction was performed to analyse expression of eNOS and iNOS mRNA. Kallikrein activity and bradykinin content were assayed using spectrophotometry and a bradykinin assay kit, respectively. Aortic vasoconstriction and vasodilation were also investigated following FXR activation in the presence or absence of AT2 R and B2 R blockade. It was found that the FXR agonists GW4064 and INT-747, in a dose-dependent manner, increased the protein abundance of AT2 R, B2 R and SHP-1 and decreased that of AT1 R. AT2 R blockade with PD123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP-1, B2 R and bradykinin. Moreover, it was found that GW4064 and INT-747 upregulated expression of eNOS and enhanced NOS activity, which attenuated vasoconstriction and induced vasodilation, respectively. These effects were partially reversed by PD123319 and by B2 R blockade with HOE140. The current work suggests that FXR regulates vascular tension by controlling the eNOS-NO system via activation of a pathway mediated by AT2 R-B2 R pathway in RAECs.