[Hereditary angioedema: a case series and bibliographic update]. / Angioedema hereditario: serie de casos y actualización de la bibliografía.

BACKGROUND: Hereditary angioedema is an autosomal dominant inherited condition that is characterized by the local development of edema of the skin, subcutaneous tissue, and the walls of almost any organ, including the gastrointestinal and upper respiratory tracts. OBJECTIVE: To describe the clinical characteristics, diagnosis and treatment of six controlled patients with hereditary angioedema. PATIENTS AND METHODS: This paper presents clinical characteristics of six patients, four of them members of the same family, and two, isolated, non-family related cases. This contribution is a review of the latest literature related to diagnosis and treatment of hereditary angioedema. RESULTS: Hereditary angioedema is a rare clinical entity that has a complicated manifestation profile that requires to discard a wide series of differential diagnosis. Deeper knowledge of its genetics and physiopathology will allow us to explore new treatment alternatives in addition to those already available. CONCLUSIONS: By diffusion of isolated cases or familial cases series, as presented in this paper, the disease recognition and timely treatment will be reached.

Multifunctional drugs for head injury.

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.

Transvascular dissemination of Porphyromonas gingivalis from a sequestered site is dependent upon activation of the kallikrein/kinin pathway.

BACKGROUND AND OBJECTIVE: Epidemiological evidence implicates a connection between human periodontitis and systemic diseases. One possible mechanism involves the direct dissemination of periodontopathogens to the target organs through the circulation. The aim of this work was to define the mechanism used by Porphyromonas gingivalis for dissemination from a sequestered infection site. MATERIAL AND METHODS: BALB/c mice were subcutaneously infected with P. gingivalis via use of a mouse chamber model. Tissue fluids from various sites were collected and cultured to determine the presence of P. gingivalis. Evans Blue dye was used to measure the dissemination ability of P. gingivalis. Kinin-associated molecules were introduced into mice, and their effects on bacterial dissemination and mouse pathology were monitored. RESULTS: P. gingivalis strain A7436 caused remote lesions and septicemia with severe cachexia, resulting in animal death. Intrachamber challenge with A7436 resulted in vascular permeability enhancement (VPE), as measured by the systemic infiltration of Evans Blue dye into chamber fluids. VPE was blocked by kininase and kinin receptor antagonist and enhanced by exogenous bradykinin and kininase inhibitor. Live bacteria were recovered from the subcutaneous perichamber and abdominal spaces (spreading), and from the blood (disseminating) of infected mice. Both kininase and kinin receptor antagonist reduced animal mortality as a result of infection with strain A7436 and decreased the number of bacteria recoverable from the blood, but they were not associated with bacterial spreading. CONCLUSIONS: The results suggest that activation of the kinin system is involved in the breach of the vascular barrier that permits dissemination of P. gingivalis.

The kallikrein-kinin system: current and future pharmacological targets.

The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

Cloning of bradykinin precursor cDNAs from skin of Bombina maxima reveals novel bombinakinin M antagonists and a bradykinin potential peptide.

Bombinakinin M (DLPKINRKGP-bradykinin) is a bradykinin-related peptide purified from skin secretions of the frog Bombina maxima. As previously reported, its biosynthesis is characterized by a tandem repeats with various copy numbers of the peptide and sometimes co-expressed with other structure-function distinguishable peptides. At present study, two novel cDNAs encoding bombinakinin M and its variants were cloned from a cDNA library from the skin of the frog. The encoded two precursor proteins are common in that each contains three repeats of a novel 16-amino acid peptide unit and one copy of kinestatin at their N- and C-terminal parts, respectively. They differ in that the first precursor contains two copies of bombinakinin M and the second one contains one copy of a novel bombinakinin M variant. Bombinakinin M was found to elicit concentration-dependent contractile effects on guinea pig ileum, with an EC50 value of 4 nM that is four times higher than that of bradykinin (1 nM). Interestingly, the synthetic peptide (DYTIRTRLH-amide), as deduced from the 16-amino acid peptide repeats in the newly cloned cDNAs, possessed weak inhibitory activity on the contractile effects of bombinakinin M, but not on that of bradykinin. Furthermore, the newly identified bombinakinin M variant (DLSKMSFLHG-Ile1-bradykinin), did not show contractile activity on guinea pig ileum, but showed potentiation effect on the myotropic activity of bradykinin. In a molar ratio of 1:58, it augmented the activity of bradykinin up to two-fold.

The plasma and tissue kininogen-kallikrein-kinin system: role in the cardiovascular system.

Bradykinin and Lys-bradykinin are potent peptide mediators implicated in several physiopathological effects in mammals. They act through activation of G-protein-coupled constitutive B(2) or inducible kinin B(1) receptors linked to signaling pathways involving increased intracellular Ca(++) concentrations and/or release of mediators including arachidonic acid metabolites, NO and EDHF. In the cardiovascular system, the kallikrein-kinin system exerts a fine control of vascular smooth muscle tone and arterial blood pressure, and plays a significant cardioprotective effect. This has been lately confirmed in experimental studies employing transgenic mice overexpressing human tissue kallikrein and animals with knockout of kinin B(1) and B(2) receptor gene. Disturbances in this system are associated with arterial hypertension, myocardial ischaemia and other clinical complications. Inhibitors of kininase II (angiotensin-converting enzyme) have been prescribed successfully to patients with cardiovascular diseases, but there is still a great interest in developing drugs or pharmacological strategies that augment the activity of kininogen-kallikrein-kinin system in pathological conditions. Delivery of adenovirus vector containing the human tissue kallikrein gene (gene kallikrein therapy) has emerged as a great potential to satisfy these conditions. This review provides a summary of plasma and tissue kallikrein-kinin system, focusing on the pharmacological properties, kinin receptors and drugs reported to interfere with their actions. The modulatory effects of the kallikrein-kinin system on cardiovascular system, particularly in regulating smooth muscle tone and arterial blood pressure and in preventing myocardium ischaemia have also been explored in the review.

Mechanism of kinin release during experimental acute pancreatitis in rats: evidence for pro- as well as anti-inflammatory roles of oedema formation.

1 Kinin B(2) receptor antagonists or tissue kallikrein (t-KK) inhibitors prevent oedema formation and associated sequelae in caerulein-induced pancreatitis in the rat. We have now further investigated the mechanism of kinin generation in the pancreas. 2 Kinins were elevated in the pancreatic tissue already before oedema formation became manifest. Peak values (421+/-59 pmol g(-1) dry wt) were reached at 45 min and remained elevated for at least 2 h; a second increase was observed at 24 h. Pretreatment with the B(2) receptor antagonist icatibant abolished kinin formation, while post-treatment was ineffective. 3 Total kininogen levels were very low in the pancreas of controls, but increased 75-fold during acute pancreatitis. This increase was absent in rats that were pretreated with icatibant. 4 During pancreatitis, t-KK-like and plasma kallikrein (p-KK)-like activity in the pancreas, as well as trypsinogen activation peptide (TAP) increased significantly. Icatibant pretreatment further augmented t-KK about 100-fold, while p-KK was significantly attenuated; TAP levels remained unaffected. 5 Endogenous protease inhibitors (alpha(1)-antitrypsin, alpha(2)-macroglobulin) were low in normal tissues, but increased 45- and four-fold, respectively, during pancreatitis. This increase was abolished when oedema formation was prevented by icatibant. 6 In summary, oedema formation is initiated by t-KK; the ensuing plasma protein extravasation supplies further kininogen and active p-KK to the tissue. Concomitantly, endogenous protease inhibitors in the oedema fluid inhibit up to 99% of active t-KK. Our data thus suggest a complex interaction between kinin action and kinin generation involving positive and negative feedback actions of the inflammatory oedema.

Experimental treatments for asthma.

There has been increased recognition of the importance of inflammatory cells and their products in the pathogenesis of asthma. From this recognition has evolved a number of new approaches to treat the various components of the asthmatic inflammatory response. Nonselective anti-inflammatory agents such as cyclosporine and gold appear to decrease symptoms and allow a steroid-sparing effect in many cases, though side effects from cyclosporine often necessitate dose reduction. Novel oral compounds as the 5-lipoxygenase inhibitors have been effective in controlling asthma symptoms triggered by various stimuli, and the cysteinyl leukotriene receptor antagonists have shown promise in this regard as well. Neurokinin antagonists, inhaled loop diuretics, and lidocaine may play significant roles in asthma therapy through inhibition of neurogenic inflammation and possibly mast cell function. Inhibition of mast cell products by existing drugs such as heparin or the development of specific inhibitors of mast cell tryptase may also be effective agents, as are selective phosphodiesterase inhibitors, which appear to have anti-inflammatory properties. Finally, specific cytokine antagonists, agonists, inhibitors of T-cell function, selective inducible nitric oxide synthase inhibitors, and even gene-directed strategies may provide not only insights into the pathogenesis of asthma but also novel therapeutic approaches to treat the inflammation in this disease.

Tachykinin and kinin receptor antagonists: therapeutic perspectives in allergic airway disease.

The morbidity of allergic airway disease and the number of deaths resulting from it have not declined in the past ten years. The multiplicity of mediators released in the acute allergic reaction and our limited knowledge of the basic mechanisms that drive chronic inflammation have hampered the design of effective therapeutic regimens for this type of disease. In this article, Claude Bertrand and Pierangelo Geppetti summarize recent studies in which new, potent and selective tachykinin and kinin receptor antagonists demonstrate the involvement of tachykinins and kinins in airway anaphylaxis, and review how these antagonists might be of use in treating allergic asthma and rhinitis.

The kallikrein/kinin system and kinin antagonists in trauma.

These data and others indicate that the kallikrein/kinin system is activated in both systemic and central nervous system trauma and that specific kinin antagonists are active in animal models of systemic and CNS trauma. In addition, preliminary data in humans suggest that kinin antagonists may have a role in the management of traumatic brain injury. Clearly, further studies in these indications are indicated.

Role of synergistic action of PAF and kinin in bacterial endotoxin-induced hypotension in rats.

Involvement of PAF and kinin in the endotoxin (LPS)-induced hypotension was examined in the rat strains, Brown Norway (B/N);Kitasato (Normal) and B/N-Kitasato rats, intravenous injection of 10 mg/kg LPS caused a hypotension composed on two phases (15 min and 70 min after LPS injection). However in the kininogen-deficient B/N-Katholiek rats. LPS induced only the second phase. Pretreatment with bradykinin (BK) antagonist. Hoe 140 suppressed LPS-induced hypotension of normal rats to the level of Katholiek rats. TCV 309, a PAF-antagonist, suppressed the LPS-hypotension almost completely in the both strains. The reason why the PAF-antagonist showed almost complete inhibition, could be explained by a synergism. Because concomitant injection of a small amount of BK with PAF caused potentiation of the effect of the PAF action. These results suggest that formation of endogenous BK contributes mainly to the 1st phase of LPS-hypotension, and PAF contributes to both phases, by either direct and synergistic actions.

The agonist binding site on the bovine bradykinin B2 receptor is adjacent to a sulfhydryl and is differentiated from the antagonist binding site by chemical cross-linking.

Chemical cross-linking was used to analyze the binding sites for the agonist bradykinin (BK) and the antagonists NPC17731 and HOE140 on the bovine B2 bradykinin receptor. [3H]BK and [3H]NPC17731 bound with high affinity to the same B2 receptor in bovine myometrial membranes as determined by the total number of specific binding sites and pharmacological specificity of the binding of these two radioligands. Cross-linking experiments were done using a series of bifunctional reagents reactive either primarily to amines (homobifunctional) or reactive to amines in one end and to sulfhydryls in the opposite end (heterobifunctional). All the heterobifunctional reagents plus the homobifunctional arylhalide 1,5-difluoro-2,4-dinitrobenzene were effective in cross-linking the [3H]BK N terminus specifically to a sulfhydryl in the receptor, and this cross-linking occurred at 5-100 microM reagent. In contrast, the homobifunctional N-hydroxysuccinimide ester reagents, at < or = 1 mM, were only able to cross-link [3H]BK to membrane proteins nonspecifically. The sulfhydryl reagents N-ethylmaleimide, iodoacetamide, and phenylarsine oxide blocked cross-linking, whereas these reagents did not inhibit reversible specific [3H]BK binding. Immunoblotting with anti-BK antiserum revealed that low concentrations of BK (5-50 nM) were cross-linked to a receptor-specific species of 65 kDa. All cross-linking of [3H]NPC17731 was nonspecific with both homobifunctional and heterobifunctional reagents. The 65-kDa receptor-specific species was observed on anti-HOE140 immunoblots, but only when proteins were cross-linked with very high concentrations of HOE140 (> or = 500 nM). Our results provide direct biochemical evidence that the binding site for the agonist BK in the bovine B2 receptor is adjacent to a cysteine and is differentiated from the binding site(s) for the antagonists NPC17731 and HOE140.

Delineation of a region in the B2 bradykinin receptor that is essential for high-affinity agonist binding.

We have made mutations in the predicted sixth transmembrane segment of a rat B2 bradykinin receptor and analyzed the variant proteins by expressing them in COS-1 cells. Two amino acid substitutions reduced the affinity of the receptor for bradykinin (Phe261-->Val by 1600-fold; Thr265-->Ala by 700-fold) with comparatively little effect on the affinity for the bradykinin antagonists NPC17731 and D-Arg-[Hyp3,D-Phe7]bradykinin (where Hyp is hydroxyproline). Three other substitutions (Gln262-->Ala, Asp268-->Ala, and Thr269-->Ala) modestly reduced the affinity for bradykinin and for the antagonist D-Arg-[Hyp3,D-Phe7]bradykinin. Even the most dramatically affected mutated receptors were still able to couple, after bradykinin binding, to phosphatidylinositol turnover. The data suggest that bradykinin directly contacts the face of the sixth transmembrane helix formed by the residues Phe261, Gln262, Thr265, Asp268, and Thr269 or that this face of the helix is the site of intraprotein contacts that serve to stabilize the agonist-binding conformation of the receptor.

Water losses induced by heat exposure and the kinin system in the rat.

Normal Wistar rats, normal and kininogen-deficient Brown Norway rats were kept at ambiant temperatures of 26 degrees C, 36 degrees C or 40 degrees C for 3 to 5 hours. Their colonic temperatures and body weights were measured. At 26 degrees C, the changes in these parameters were similar in the three strains. At 36 degrees C, body weight loss was increased more in normal rats than in kininogen-deficient rats. At 40 degrees C, body temperature increased more quickly and body weight loss was less enhanced in kininogen-deficient rats than in normal rats. The water content of muscles was less reduced in kininogen-deficient rats than in normal rats. HOE 140, a bradykinin antagonist, reduced the weight loss of Wistar rats kept at 36 degrees C and 40 degrees C. Atropine or removal of submaxillary glands increased colonic temperature and reduced the weight loss of Wistar rats at 36 degrees C and 40 degrees C. HOE 140 did not modify the reduction of weight loss induced by atropine but increased colonic temperatures and decreased thermal tolerance of atropinized Wistar rats at 36 degrees C. These results indicate that the kallikrein-kinin system plays a role in salivary secretion and in heat exchange during a heat exposure.

Purification and characterization of endopeptidase H2, a kinin inactivating serine proteinase (kininase) from human urine

1. A kinin-inactivating chymotrypsin-like serine-endopeptidase was purified 202-fold from human urine by DEAE-cellulose chromatography, gel filtration, DEAE/HPLC chromatography and affinity chromatography. It hydrolyzed bradykinin at the Phe5-Ser6 peptide bond at a rate of 1.090 mumol min-1 mg protein-1 at pH 8.0 and 37 degrees C. The molecular weight of this endopeptidase H2, estimated by SDS-polyacrylamide gel electrophoresis and by gel filtration, was 60 kDa, and its optimum pH for bradykinin hydrolysis was near 8.5. 2. Bradykinin inactivating activity was inhibited 100 per cent by the serine-proteinase inhibitor PMFS (1 mM) and the chymotrypsin inhibitor TPCK (5 mM). Reagents such as 2-mercaptoethanol (3 mM) and pOH-mercuribenzoate (3 mM) inhibited the enzyme by 100 per cent and 67 per cent , respectively. 3. Endopeptidase H2 hydrolyzes the Phe-Ser bond of peptides related to bradykinin and its activity appears to be limited to peptide chains of < or = 18 amino acid residues since it does not hydrolyze BAM 22, peptide E or kininogen. 4. The molecular size and inhibition profile suggested that endopeptidase H2 differs from the serine-proteinases previously described in rat liver, rat hepatic endothelium, rat and rabbit brain. 5. The physiological role of endopeptidase H2 may be a link between the kinin and neuropeptide systems in the control of water-electrolyte balance

Antagonism of kinin effects on epithelial by Hoe 140: apparently competitive and non-competitive interactions.

1. Hoe-140, a potent kinin receptor antagonist, was investigated for its ability to inhibit the effects of lysylbradykinin (kallidin) on a cultured colonic epithelium, HCA-7 Colony 29, derived from a human adenocarcinoma. 2. Measurements of electrogenic chloride secretion (as short circuit current), and of intracellular Ca2+ (from Fura-2 fluorescence) were used to assess the action of lysylbradykinin in the absence and presence of Hoe 140. 3. From short circuit current data, Hoe 140 appeared to be a competitive antagonist with a Ki value of 5 nM. However, with measurements of intracellular Ca2+ Hoe 140 was apparently a non-competitive antagonist with a Ki of between 4-6 nM. 4. Because of the unexpected finding of non-competitive antagonism, measurements were made with a second antagonist pair, histamine and mepyramine. Mepyramine behaved as a competitive antagonist against responses to histamine with a Ki value of approximately 5 nM when short circuit current measurements were evaluated. However, when intracellular Ca2+ concentration was used as a measure mepyramine, 30 nM, produced a near parallel shift in the response curve, but at 100 nM the maximal response was depressed. 5. The reasons why the apparent type of antagonism depends upon the method of measurement is discussed, bearing in mind that the increase in intracellular Ca2+ is a signal which precedes the increase in short circuit current.

Evidence for renal kinins as mediators of amino acid-induced hyperperfusion and hyperfiltration in the rat.

This study examined the role of tissue kallikrein and kinins in renal vasodilation produced by infusion of amino acids (AA). In rats fed a 9% protein diet for 2 wk, intravenous infusion of a 10% AA solution over 60-90 min reduced total renal vascular resistance and increased glomerular filtration rate (GFR) by 25-40% and renal plasma flow (RPF) by 23-30% from baseline. This was associated with a two- to threefold increase in urinary kinin excretion rate. Acute treatment of rats with aprotinin, a kallikrein inhibitor, resulted in deposition of immunoreactive aprotinin in kallikrein-containing connecting tubule cells and inhibited renal kallikrein activity by 90%. A protinin pretreatment abolished the rise in urinary kinins and prevented significant increases in GFR and RPF in response to AA. In a second group of rats pretreated with a B2 kinin receptor antagonist, [DArg Hyp3, Thi5,8 D Phe7]bradykinin, AA infusion raised urinary kinins identically as in untreated controls, but GFR and RPF responses were absent. Aprotinin or the kinin antagonist produced no consistent change in renal function in rats that were not infused with AA.AA-induced increases in kinins were not associated with an increase in renal kallikrein activity. Notably, tissue active kallikrein level fell 50% in AA-infused rats. These studies provide evidence that kinins generated in the kidney participate in mediating renal vasodilation during acute infusion of AA.

Zinc metallopeptidase inhibitors. A novel antihypertensive treatment.

Inhibitors of two zinc metallopeptidases, angiotensin I converting enzyme (ACE) and neutral metalloendopeptidase-24.11 (EP-24.11), are antihypertensive agents. In this issue of Hypertension, Genden and Molineaux report that yet another peptidase inhibitor, metalloendopeptidase-24.15, EC 3.4.24.15 (EP-24.15), lowers blood pressure in normotensive rats. In this editorial we discuss the possible role of kinins as common mediators of part of the vasodepressor action of these peptidase inhibitors. Genden and Molineaux report that the marked fall in blood pressure caused by the EP-24.15 inhibitor is almost abolished by a kinin receptor antagonist, supporting the hypothesis that kinins play a role in the regulation of normal blood pressure. We have confirmed that the EP-24.15 inhibitor used by these investigators lowers blood pressure. Up to now, EP-24.15 has not been implicated in in vivo metabolism of kinins. Although a number of kininases have been identified, our own previous work indicated that the metabolic pathway responsible for clearing kinins from the circulation involves the action of kininase II (angiotensin I converting enzyme) and renal peptidases. Nevertheless, the main metabolic pathway involved some other unidentified enzyme, since in these experiments disappearance of kinins from the circulation was only marginally reduced by a "cocktail" of inhibitors of ACE, EP-24.11, and carboxypeptidase N. It could be that EP-24.15 is involved in kinin metabolism. However, a number of questions need to be answered with regard to the mechanism by which the EP-24.15 inhibitor lowers blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of bradykinin and kininogens in isolated rat kidney vasoconstricted by angiotensin II.

The hemodynamic and endocrine effects of bradykinin and kininogens were investigated using a closed-circuit isolated rat kidney perfused with angiotensin II (ANG II). ANG II induced vasoconstriction, stimulation of urinary kallikrein release, and inhibition of renin secretion. Bradykinin markedly increased renal perfusate flow (RPF) and produced a slight but significant diuresis and natriuresis. The inhibitory effect of ANG II on renin secretion was delayed. Urinary kallikrein secretion was unchanged. The effect of bradykinin was suppressed by the competitive kinin antagonist [DArg,Hyp3,Thi5,8,DPhe7]bradykinin. Kallikrein-sensitive rat high-molecular-weight kininogen produced a progressive rise in renal perfusate flow. Exocrine function and renin and kallikrein secretions were unchanged. Immunoreactive kinins, identified as bradykinin by high-pressure liquid chromatography, were liberated into the perfusate. Perfusate immunoreactive high-molecular-weight kininogen decreased in parallel as a result of consumption. The kalikrein-resistant T-kininogen was not hydrolyzed to release a kinin, had no effect on renal function, and its concentration in the perfusate remained constant. These results suggest that kinin can be produced in the renal circulation from kallikrein-sensitive circulating kininogens and can antagonize the vasoconstrictor effect of ANG II and alter renal hemodynamics. They provide evidence that the kallikrein-kinin system can participate with the renin-angiotensin system in the control of renal blood flow.