Inhibition of kinin B1 receptors attenuates pulmonary hypertension and vascular remodeling.

This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hypertension, and whether its inhibition could reduce inflammation, pulmonary hypertension, vascular remodeling, and right heart dysfunction. Male Wistar rats underwent left pneumonectomy. Seven days later, the rats were injected subcutaneously with monocrotaline (60 mg/kg). The rats were then randomly assigned to receive treatment with vehicle or with BI113823 (a selective B1 receptor antagonist, 30 mg/kg, twice per day) via oral gavage from the day of monocrotaline injection to day 28. By day 28, BI113823-treated rats had significantly lower mean pulmonary artery pressure, less right ventricular hypertrophy, and pulmonary arterial neointimal formation than that of the vehicle-treated rats. Real-time polymerase chain reaction revealed that there was a significant increase in mRNA expression of B1 receptors in the lungs of monocrotaline-challenged pneumonectomized rats. Treatment with BI113823 significantly reduced macrophage recruitment, as measured via bronchoalveolar lavage. It also markedly reduced CD-68 positive macrophages and proliferating cell nuclear antigen positive cells in the perivascular areas, reduced expression of inducible nitric oxide synthase, matrix metalloproteinase 2 and 9, and B1 receptors compared with measurements in vehicle-treated rats. These findings demonstrate that kinin B1 receptors represent a novel therapeutic target for pulmonary arterial hypertension.

Cardioprotective effect of ornitho-kinin in an anesthetized, open-chest chicken model of acute coronary occlusion.

The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 microg/kg) reduced mean arterial pressure from 88 +/- 12 to 42 +/- 7 mmHg and increased heart rate from 335 +/- 38 to 402 +/- 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 microg/kg infused over a period of 5 min) from 35 +/- 3 to 10 +/- 2% of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.

Cardioprotective effect of ornitho-kinin in an anesthetized, open-chest chicken model of acute coronary occlusion

The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 µg/kg) reduced mean arterial pressure from 88 ± 12 to 42 ± 7 mmHg and increased heart rate from 335 ± 38 to 402 ± 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 µg/kg infused over a period of 5 min) from 35 ± 3 to 10 ± 2 percent of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.

Lipopolysaccharide activates the kallikrein-kinin system in mouse choroid plexus cell line ECPC4.

Regulation of the kallikrein-kinin system in cerebral inflammation is still unclear. Here, we used reverse-transcription polymerase chain reaction (RT-PCR) techniques to show that lipopolysaccharide (LPS) activates the kallikrein-kinin system by enhancing liberation of bradykinin (BK), and alters mRNA levels of kallikrein-kinin system components, including high molecular weight (H-) and low molecular weight (L-) kininogens, in ECPC4 cells, a cell line of mouse choroid plexus epithelium. LPS treatment increased liberation of immunoreactive bradykinin in the supernatant of ECPC4 cells, and addition of LPS (500 ng/ml) to cultures resulted in elevation of H- and L-kininogen mRNA levels in ECPC4 cells within 24-48 h. Furthermore, LPS treatment elevated bradykinin type 2 and type 1 receptor mRNA levels within 4h, but did not change tissue kallikrein or plasma kallikrein mRNA levels. On the other hand, expression of pro-inflammatory mediators interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cyclooxygenase-2 mRNA increased within 4-8h after addition of LPS to ECPC4 cells. The addition of IL-1beta and TNF-alpha to investigate the major mediator for kininogen expression in ECPC4 cells remarkably induced expression of H- and L-kininogen mRNAs in ECPC4 cells. These results suggest that LPS activates the kallikrein-kinin system in the choroid plexus via autocrine induction of IL-1beta and TNF-alpha.

Substrate specificity of two thrombin like enzymes (elegaxobin, elegaxobin II) from the venom of Trimeresurus elegans (Sakishima-habu), using neutralizing antibody.

We reported previously that elegaxobin and elegaxobin II cause the release of fibrinopeptide A alone from rabbit fibrinogen. Elegaxobin II is a thrombin-like enzyme that possesses kinin-releasing activity, and shows a characterization obviously different from elegaxobin. To study the substrate specificities of elegaxobin and elegaxobin II against fibrinogen, we investigated whether anti-elegaxobin or anti-elegaxobin II antibody counteracts those enzymatic activities. Anti-elegaxobin II antibody effectively counteracted the thrombin-like activity of elegaxobin and elegaxobin II in comparison to the anti-elegaxobin antibody. The anti-elegaxobin II antibody only counteracted the thrombin-like activity, whereas did not counteract TAME hydrolytic activity and weakly counteract the kinin-releasing activity. Furthermore, we investigated which part of elegaxobin II as an antigen this antibody connects with specifically, using M-peptides derived from digests with CNBr. As a result, anti-elegaxobin II antibody bound specifically to the M-peptide including C-terminal portion. In particular, the anti-elegaxobin II antibody connected to position 220-239 (AQPHEPGSYTNVFDHLDWIK), containing His(223).

The kinin system in the envenomation caused by the Tityus serrulatus scorpion sting.

Several lines of evidence in experimental animals indicate that the kinin system may participate in the pathogenesis of envenomation by the Tityus serrulatus (Ts) scorpion sting, but there are no studies in humans with regard to this system. In this study, we evaluated the plasma levels of high-molecular (HKg) and low-molecular (LKg) weight kininogens (detected by ELISA), the activities of plasma or tissue kallikreins and kininase II (enzymatic action upon selective substrates), and the Ts plasma venom levels (ELISA). A total of 27 patients (12 males) aged 12-72 were evaluated immediately at hospital admittance. According to the severity of envenomation, patients were classified as mild (n = 15), moderate (n = 8), and severe cases (n = 4). Controls were paired for age and sex. Plasma venom levels were associated with the severity of envenomation. Severe cases presented lower levels of LKg in relation to mild and controls. Inverse correlations were seen between LKg levels and the venom concentration. The results of this study suggested that the kinin system may participate in the pathogenesis of human Ts envenomation and knowledge about this system may be useful to develop new strategies to reduce the damage caused by scorpion envenomation.

Toll-like receptor stimulation induces airway hyper-responsiveness to bradykinin, an effect mediated by JNK and NF-kappa B signaling pathways.

Airway infections induce hyper-responsiveness in asthmatic patients. Toll-like receptors (TLR) mediate inflammatory responses to microbes. Occurrence and effects of TLR2, TLR3 and TLR4 were examined in a mouse organ culture model of asthma focusing on the smooth muscle responses to bradykinin. TLR2, TLR3 and TLR4 mRNA, and TLR2 and TLR4 immunoreactivity were detected in the tracheal muscle layer. Tracheal organ culture for 1 or 4 days with lipopolysaccharide (LPS; TLR2/4 agonist) or polyinosinic polycytidylic acid (poly-I-C; TLR3 agonist) enhanced bradykinin- and [des-Arg(9)]-bradykinin-induced contractions. Simultaneous LPS and poly-I-C treatment resulted in synergistic enhancement of bradykinin-induced contraction. In carbachol-pre-contracted segments TLR stimulation induced less potent relaxations to bradykinin and [des-Arg(9)]-bradykinin. The LPS and poly-I-C enhancement of bradykinin-induced contraction was inhibited by the transcriptional inhibitor actinomycin-D, dexamethasone, the proteasome inhibitor MG-132 and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. LPS and poly-I-C induced translocation of NF-kappa B p65 to the nucleus and up-regulation of kinin B(1) and B(2) receptor mRNA. In summary, TLR2, TLR3 and TLR4 are expressed in the mouse tracheal smooth muscle. Costimulation of these receptors results in NF-kappa B- and JNK-mediated transcription of B(1) and B(2) receptor, inducing hyper-responsiveness to bradykinin.

[Ecogenetic aspects of acute side effects caused by angiotensin converting enzyme inhibitors]. / Aspects écogénétiques des effets secondaires aigus dus aux inhibiteurs de l'enzyme de conversion de l'angiotensine.

Angiotensin converting enzyme inhibitors are currently used in the treatment of different cardiovascular diseases. Acute side effects of acei have been attributed to bradykinin. We have evidenced a decrease catabolism of des-arg9-bradykinin in the plasma of patients who presented such side effects. This anomaly is associated with a decreased activity of plasma aminopeptidase p which is, at least partially, of genetic origin.

Effects of angiotensin converting enzyme inhibitors on thrombotic mediators: potential clinical implications.

Angiotensin-converting enzyme inhibitors (ACE-I) were initially developed as therapeutic agents targeted for the treatment of hypertension. Since the initial application of these agents, several additional clinical indications have been identified such as coronary artery disease, stroke, congestive heart failure and prevention of diabetes-related complications. In addition to the blood pressure lowering effects, this class of agents has the ability to restore endothelial function, decrease oxidative stress and enhance endogenous fibrinolysis. Moreover, ACE-I possesses antiplatelet effects as well as antiproliferatory and antimigratory effects on smooth muscle cells. This article links the effects of ACE-I on thrombotic mediators to the potential clinical implications in the setting of coronary artery disease.

Cardiovascular properties of the kallikrein-kinin system.

All the components of the kallikrein-kinin system are located in the vascular smooth muscle as well as in the heart. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischaemia, myocardial infarction and left ventricular hypertrophy, have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental in the induction of cardiovascular-related diseases. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.

The region 1-11 of Alzheimer amyloid-beta is critical for activation of contact-kinin system.

Amyloid-beta protein (Abeta) has been implicated in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and its ability to trigger a local inflammatory response. In the present study using truncated Abeta peptides, we identified the region between residues 1 and 11 as critical for the activation of the contact system in vitro through an ionic interaction of Abeta with factor XII and/or kallikrein. Concomitant incubation of a small cationic peptide (lysine(4)) with Abeta abrogated its ability to trigger the cleavage of high molecular weight kininogen, indicating that Abeta's activity can be blocked by an inhibitory peptide. These findings could be clinically important, since there is evidence that the contact system is activated in AD brain. Thus, prevention of contact system activation, beside diminishing the recruitment of glial cells and microvascular permeability, can also decrease the activation of complement system and the release of IL6, both factors being considered to play an important role in the inflammatory reactions in AD brain.

Involvement of kinins, mast cells and sensory neurons in the plasma exudation and paw oedema induced by staphylococcal enterotoxin B in the mouse.

Intraplantar injection of staphylococcal enterotoxin B induces long-lasting oedema mediated by both cyclooxygenase and lipoxygenase products as well as by neuropeptides from sensory nerves. This study was undertaken to further clarify the role of peripheral primary afferent sensory nerves in staphylococcal enterotoxin B (25 microg/paw)-induced plasma extravasation and oedema formation. The tachykinin NK(1) receptor antagonist (S)-1-[2-[3-(3, 4-dichlorophenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azoniabicyclo [2.2.2]octane cloride (SR140333; 120 nmol/kg, s.c.+120 nmol/kg, i.v.) significantly inhibited plasma exudation and paw oedema evoked by staphylococcal enterotoxin B. The tachykinin NK(2) receptor antagonist (S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3, 4-dichlorophenyl)butyl]-benzamide (SR48968) had no effect on the staphylococcal enterotoxin B-induced responses. The bradykinin B(2) receptor antagonist D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (Hoe 140; 400 nmol/kg, i.v.) significantly reduced staphylococcal enterotoxin B-induced responses. The magnitude of the inhibition observed with Hoe 140 alone was similar to that caused by concomitant treatment of animals with SR140333 and Hoe 140, suggesting that there is a final common pathway. Additionally, SR140333 given alone reduced bradykinin (3 nmol/paw)-induced paw oedema. The vanilloid receptor antagonist N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7, 8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 100 micromol/kg) significantly reduced staphylococcal enterotoxin B-induced responses. The 5-HT receptor antagonist methysergide (10 mg/kg, i.v.) and the histamine H(1) receptor antagonist mepyramine (10 mg/kg, i.v.) produced a significant reduction in paw oedema whereas plasma exudation was reduced only by methysergide. In diabetic mice, exudation and oedema evoked by staphylococcal enterotoxin B were markedly reduced. Acute administration of insulin (20 UI/kg, s.c., 30 min before) did not restore the increased permeability induced by staphylococcal enterotoxin B. We conclude that plasma exudation and paw oedema in response to staphylococcal enterotoxin B are a consequence of a complex neurogenic response involving direct activation of vanilloid receptors on sensory nerves, release of kinins and subsequent activation of bradykinin B(2) receptors at a prejunctional level, and direct or indirect degranulation of mast cells.

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides.

The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikrein-kinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikrein-kinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

Bradykinin B2-receptor antagonism attenuates fatal cardiocirculatory breakdown induced by severe experimental pancreatitis.

OBJECTIVES: To investigate the impact of the long-acting bradykinin B2 receptor antagonist HOE 140 (Icatibant) on survival time in a model of severe porcine pancreatitis. DESIGN: Randomized, controlled intervention trial. SUBJECTS: Thirty domestic pigs of either gender anesthetized by intravenous application of piritramide, midazolam, and pancuronium and mechanically ventilated. INTERVENTIONS: Pancreatitis was induced by an injection of sodium taurocholate (5%, 1 mL/kg body weight [BW]) and enterokinase (10 U/kg BW). Control animals (group 1, n = 10) underwent the spontaneous course of the disease. In two treatment groups, Icatibant was administered either in a low (100 nmol/kg BW; group 2, n = 10) or in a high dosage (5000 nmol/kg BW; group 3, n = 10). MEASUREMENTS AND MAIN RESULTS: Mean survival time was significantly prolonged by Icatibant (controls, 6.6 hrs; group 2, 9.8 hrs; p = .022; group 3, 10.9 hrs; p = .007). Six hours postinduction, the decline of total peripheral resistance (52% of baseline) and cardiac index (92% of baseline) in controls was significantly improved by Icatibant, both in the low (16% and 44%; p < .05) and high (6% and 45%; p < .05) dosage. The concentrations of free, nonreceptor-bound kinin in plasma 6 hrs postinduction were significantly lower in controls than in groups 2 and 3 animals (111+/-50 vs. 208+/-40 and 237+/-52 fmol/mL, respectively). Six hours postinduction, the pretreatment with Icatibant was associated with significantly higher plasma concentrations of phospholipase A2 (controls, +1194%; group 2, +2000%; group 3, +2285% of baseline values) and interleukin-1 receptor antagonist (controls, 1900+/-800; group 2, 3100+/-800; group 3, 3600+/-800 pg/mL). In contrast, the increase of urinary trypsinogen activation peptides indicating local pancreatic damage (589+/-114 nmol/L in controls) was substantially attenuated by pretreatment with Icatibant (group 2, 467+/-102, NS; 352+/-91 nmol/L in group 3; p = .022 vs. controls). Systemic inflammatory reactions, however, as quantified by C-reactive protein and the extracellularly discharged neutrophil cytosolic inhibitor leukocyte neutral proteinase inhibitor were not influenced by the bradykinin B2-receptor antagonist. CONCLUSIONS: Pretreatment with the bradykinin B2 receptor antagonist Icatibant resulted in prolonged survival time and in delayed impairment of major macrocirculatory and pulmonary variables. Icatibant resulted in elevated concentrations of free, circulating kinin. This was associated with increased concentrations of phospholipase A2 and interleukin-1 receptor antagonist, suggesting that circulating kinins strengthen the activation of some mediator cascades, the association of which with the kinin metabolism requires further experimental clarification. Other variables indicating a systemic inflammatory response (C-reactive protein, leukocyte neutral proteinase inhibitor) remained unaffected by Icatibant. Bradykinin antagonism distinctly ameliorated the local pancreatic damage, indicated by increased urinary concentrations of trypsinogen activation peptides. It is concluded that the kinin metabolism plays an important role in the pathophysiology of systemic complications after severe experimental pancreatitis.

Kinin-degrading pathways in the human heart.

In experimental animals, kinins protect the myocardium from ischemia-reperfusion injuries and reduce left ventricular hypertrophy and progression of heart failure. This suggests that in humans, also, the presence of an intact kinin system is critical for the prevention of heart failure. In addition to the kinin-generating system, the concentration of kinins, and consequently the extent of their actions, is regulated by their degradation. In the vascular bed of the human heart, bradykinin (BK) is degraded by angiotensin-converting enzyme (ACE). In contrast, in the interstitium of the human heart, BK is degraded by neutral endopeptidase (NEP). For potentiating the beneficial effects of BK, one strategy is elevation of the BK concentration by inhibition of BK-degrading enzymes. An even more effective form of pharmacological control of BK elevation than inhibition of ACE alone might be the combined inhibition of ACE and NEP.

Interactions of angiotensin-converting enzyme, kinins and nitric oxide in circulation and the beneficial effects of ACE inhibitors in cardiovascular diseases.

Renin-angiotensin-aldosterone systems play a critical role in the development and progression of cardiovascular diseases, and inhibitors of angiotensin-converting enzyme have proven effective for the treatment of these diseases. Since angiotensin II receptor antagonists can inhibit the effects of angiotensin II via ACE-independent pathways, e.g., chymase, they were considered to be more effective than ACEIs. On the other hand, ACE inhibitors can increase bradykinin, and thus, nitric oxide, which may cause potent cardioprotection, inhibition of smooth muscle proliferation and attenuation of inflammation mechanisms. It appears that angiotensin II receptor antagonists and ACEIs may mediate cardioprotection in different ways. This is the rationale to explore the possibility of a combined administration of both drugs for the treatment of chronic heart failure and other cardiovascular pathology. In this review we try to analyze the role of ACE, kinins and chymase inhibition in the pathophysiology and treatment of cardiovascular diseases.

Pharmacology and cardiovascular implications of the kinin-kallikrein system.

Kinins are peptide hormones that can exert a significant influence on the regulation of blood pressure and vascular tone due to their vasodilatatory, natriuretic and growth modulating activity. Their cardiovascular involvement in physiological and pathophysiological situations has been studied intensively since inhibitors for angiotensin I-converting enzyme and selective receptor antagonists have become available for pharmacologically potentiating or inhibiting kinin-mediated reactions. Molecular biological analysis and the establishment of genetically modified animal models have also allowed newer information to be acquired on this subject. In this review, the components and cardiovascularly relevant mechanisms of the kinin-kallikrein system shall be described. Organ-specific effects concerning the kidneys, the vascular system, the heart and nervous tissue shall also be illustrated. On this issue, the physiological functions and pathophysiological implications of the kinin-kallikrein system should be clearly distinguished from the many, mostly endothelium-mediated protective effects which occur during ACE inhibition due to the potentiation of kinin effects. Finally, a view shall also be cast upon newly discovered targets of action, which could be exploited for therapeutically altering the kinin-kallikrein system.

Recombinant tumor necrosis factor receptor p75 fusion protein (TNFR:Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans.

The effects of inhibition of tumor necrosis factor (TNF) on cell and protease activation were evaluated in 18 normal volunteers given endotoxin (4 ng/kg, i.v.) after an infusion of low (10 mg/m2 i.v., n = 6) or high dose (60 mg/m2 i.v., n = 6) recombinant human dimeric TNF receptor protein (TNFR:Fc) or its vehicle (placebo n = 6). Activation of the coagulation system occurred by 2 h in the TNFR:Fc vehicle-placebo group manifested by decreased prekallikrein functional levels and increased levels of prothrombin F1+2 fragments (p < 0.0001). High or low dose TNFR:Fc delayed the fall in prekallikrein functional levels by 1 h and 4 h, respectively (p < 0.0002), but did not inhibit the increase in circulating levels of prothrombin F1+2 fragments. In contrast, endothelium activation, characterized by increased levels of tissue plasminogen activator, plasminogen activator inhibitor-1, and von Willebrand Factor antigen was blunted by both low and high dose TNFR:Fc (p < 0.001). While the endotoxin-associated decrease in platelet number was not altered, platelet-derived beta-thromboglobulin peak levels were blunted and delayed by TNFR:Fc (p < 0.02). Increased levels of neutrophil elastase were attenuated by low and high dose TNFR:Fc (p < 0.001). These results suggest that although TNF is functionally linked to the activation of endothelium, neutrophils, coagulation, and fibrinolysis, alternative pathways are present in vivo that result in activation of the kallikrein-kinin system after endotoxin-induced TNF release. These alternative pathways may limit some of the anti-inflammatory effects of TNFR:Fc.

Indian red scorpion (Buthus tamulus) venom-induced augmentation of cardiac reflexes is mediated through the mechanisms involving kinins in urethane anaesthetized rats.

The mechanism underlying the action of Indian red scorpion (Buthus tamulus; BT) venom on cardiac reflexes was examined in urethane anaesthetized adult albino rats of either sex. Intravenous injection of phenyldiguanide (PDG) produced reflex hypotension, bradycardia and apnea lasting for > 60 s. The PDG-induced reflex responses (blood pressure, heart rate and respiration) were augmented greatly (magnitude and time period) after exposure to BT venom (100 microg/kg, i.v., for 30 min). However, there were no great alterations in resting blood pressure, heart rate and respiratory rate. Pretreatment with kallikrein kinin inhibitor (aprotinin; 6000 kallikrein inactivating unit, i.v.) blocked the BT venom-induced augmentation of PDG reflex response. Further, pretreatment with indomethacin (prostaglandin synthetase inhibitor; 10 mg/kg) and heparin (1000 units/kg) also blocked the venom-induced potentiation of the reflex. Captopril (15 mg/kg), an agent known to increase endogenous kinins, also augmented the PDG induced-reflex to the same extent as in BT envenomed rats. The captopril-induced augmentation of the reflex was blocked by aprotinin and heparin, but not by indomethacin. The results indicate that kinins and prostaglandins are involved in the BT venom-induced augmentation of the cardiac reflexes.