icatibant and Pulmonary-Edema

Bradykinins are released from kininogen by kallikrein. They increase capillary lung permeability after their binding to β1 and especially β2 receptors before being metabolized by kininase enzyme. This study was performed to evaluate cardiopulmonary damages and inflammatory response on injected rats with Aah I toxin of scorpion venom and the involvement of Kallikrein-Kinin system in this pathogenesis. Obtained results revealed that Aah I toxin induces inflammatory cell infiltration accompanied by cellular peroxidase activities, a release of cytokine levels, pulmonary and myocardial damage, with altered metabolic activities and imbalanced redox status. Administration of aprotinin (bradykinin inhibitor) and especially icatibant (bradykinin β2 receptor antagonist) seemed to be able to protect animals against the toxicity of Aah I; nevertheless, the use of captopril (kininase II inhibitor) reduced partially some cardiac disorders. These findings indicate that the kallikrein-kinin system may contribute to the physiopathological effect and lung edema formation induced by toxin, which suggests a potential use of drugs with significant anti-kinin properties.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Bradykinin; Bradykinin B2 Receptor Antagonists; Bronchoalveolar Lavage Fluid; Capillary Permeability; Captopril; Cytokines; Eosinophil Peroxidase; Kallikreins; Leukocyte Count; Male; Peroxidase; Pulmonary Edema; Rats; Rats, Wistar; Scorpion Venoms

This study was performed to delineate the kinin (receptor)-dependent pathways in the Indian red scorpion (Mesobuthus tamulus; MBT) venom-induced pulmonary oedema as well as the augmentation of cardio-pulmonary reflexes evoked by phenyldiguanide (PDG).. In urethane-anaesthetized adult rats, the effect of venom on the PDG reflex responses (blood pressure, heart rate and respiration rate) and the pulmonary water content was ascertained using various antagonists(des- Arg, B(1) receptor antagonist; Hoe 140, B(2) receptor antagonist; N(omega)-nitro-l-arginine methyl ester (l-NAME), nitric oxide (NO) synthase inhibitor; methylene blue, soluble guanylate cyclase inhibitor; and glibenclamide, K(+)(ATP) channel blocker). The effect of phosphodiesterase V inhibitor (sildenafil citrate) on the reflex response and the pulmonary water content was also examined and compared with venom-induced responses.. Intravenous injection of PDG (10 microg kg(-1)) evoked apnoea, bradycardia and hypotension lasting >60 s. Exposure to MBT venom (100 microg kg(-1)) for 30 min augmented the PDG reflex responses by two times and increased the pulmonary water content, significantly. Hoe 140 blocked the venom-induced responses (augmentation of PDG reflex and increased pulmonary water content) whereas des-Arg did not. l-NAME, methylene blue or glibenclamide also blocked the venom-induced responses. Furthermore, sildenafil citrate (that increases cGMP levels) produced augmentation of PDG reflex response and increased the pulmonary water content as seen with venom.. The results indicate that venom-induced responses involve B(2) kinin receptors via the NO-dependent guanylate cyclase-cGMP pathway involving K(+)(ATP) channels.

Topics: Adrenergic beta-Antagonists; Animals; Biguanides; Bradykinin; Bradykinin B2 Receptor Antagonists; Enzyme Inhibitors; Glyburide; Guanosine Monophosphate; Heart; Hypoglycemic Agents; Lung; Male; Metabolic Networks and Pathways; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Piperazines; Pulmonary Edema; Purines; Rats; Receptor, Bradykinin B2; Reflex; Scorpion Venoms; Scorpions; Serotonin Receptor Agonists; Sildenafil Citrate; Sulfones

We investigated the effect of endogenous bradykinin on adrenaline-induced pulmonary edema (PE) by blocking bradykinin receptors. In preliminary experiments, a bolus injection of adrenaline (ADR; 10 microg/kg) solution (10 microg/ml) was determined to be an edematogenic dose for inducing PE. The lung body weight index (LBI) and incidence of PE (IPE) were determined. The IPE and LBI of the group pretreated with Des-Arg9-[Leu8]-Bradykinin (DA-BK, 50 microg/kg, 50 microg/ml) increased significantly compared with those of the control group (p<0.05). On the other hand, there were no remarkable changes in IPE and LBI in the groups pretreated with Hoe140 (D-Arginyl-[Hyp3, Thi5, D-Tic7, Oic8]-Bradykinin (100 microg/kg, 100 microg/ml), captopril (20 mg/kg, 20 mg/ml) or L-NAME (1 mg/kg, 1 mg/ml). Moreover, the IPE and LBI of the group co-treated with L-NAME and DA-BK decreased compared with the DA-BK group (p<0.05). Thus, bradykinin aggravates adrenaline-induced PE through activation of the B2 receptor by the kallikreins as a result of the ADR administration, although the precise mechanism is not known.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Chi-Square Distribution; Enzyme Inhibitors; Epinephrine; Kallikreins; Lung; Male; NG-Nitroarginine Methyl Ester; Organ Size; Phentolamine; Pulmonary Edema; Random Allocation; Rats; Rats, Wistar; Receptor, Bradykinin B2; Receptors, Bradykinin; Statistics as Topic; Vasoconstrictor Agents

Although prior studies suggest that hypoxia may increase pulmonary vascular permeability, the mechanisms responsible for that effect remain uncertain. Neprilysin (neutral endopeptidase) is a cell surface metallopeptidase that degrades several vasoactive peptides including substance P and bradykinin. We hypothesized that hypoxia could reduce lung neprilysin expression, leading to increased vascular leak. Weanling rats were exposed to normobaric hypoxia (inspired O(2) fraction = 0.1). Lung neprilysin activity was significantly decreased after 24 and 48 h of hypoxia (P < 0.006). The decrease in enzyme activity was associated with decreased lung neprilysin protein content and decreased lung neprilysin mRNA expression. Immunohistochemistry showed a predominantly perivascular distribution of neprilysin, with clear reductions in neprilysin immunoreactivity after exposure to hypoxia. Exposure to hypoxia for 24 h also caused marked increases in vascular leak (P = 0.008), which were reversed by the administration of recombinant neprilysin. The hypoxia-induced increase in leak was also reversed by substance P and bradykinin receptor antagonists. We conclude that in young rats hypoxia decreases lung neprilysin expression, which contributes to increased pulmonary vascular leak via substance P and bradykinin receptors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Gene Expression Regulation, Enzymologic; Hypoxia; Lung; Male; Methionine; Microcirculation; Neprilysin; Neurokinin-1 Receptor Antagonists; Oxygen; Piperidines; Protease Inhibitors; Pulmonary Edema; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; RNA, Messenger; Specific Pathogen-Free Organisms; Substance P; Water