Lysyl-bradykinin Research Articles

Secretory effects of kinins on colonic epithelium in relation to prostaglandins released from cells of the lamina propria.

1. Sheets of muscle-stripped rat and rabbit colon with epithelium intact or removed were mounted in Ussing-type chambers for recording of transepithelial p.d., resistance and short circuit current (Isc), and measurement by radioimmunoassay (RIA) of the release of prostaglandins into serosal and mucosal bathing solutions. 2. In epithelial-intact preparations prostaglandin E2 (PGE2), PGE1, PGF2 alpha, U46619 and prostacyclin (10(-7)-10(-6) M) caused increases in Isc and transepithelial p.d., in (approximate) descending order of potency. Epithelial-removed preparations did not exhibit any transepithelial p.d. 3. In epithelial-intact preparations, lysyl-bradykinin (LBk) applied serosally but not mucosally caused increased p.d. and release of PGE2 (and to a lesser extent other prostaglandins) into serosal but not mucosal bathing solutions. In epithelial-removed tissues, responsiveness to LBk was maintained, but it did not exhibit 'sidedness', i.e. LBk was effective when applied on either side and PGE2 release occurred into both compartments. 4. Indomethacin and other non steroidal anti-inflammatory drugs (NSAIDs) abolished the LBk-induced p.d. and reduced PGE2 release if applied serosally but not mucosally in epithelial-intact preparations. In epithelial-removed tissues, indomethacin added to either side abolished prostaglandin release into both compartments. 5. Calcium removal from serosal but not mucosal bathing solution (Ca2+-free EGTA Krebs) abolished p.d. generation by LBk in epithelial-intact preparations, and reduced PGE2 release in rabbit but not rat colon. Similarly, in epithelial-removed preparations, calcium removal did not affect kinin-induced PGE2 generation in rat but strongly attenuated it in rabbit colon. 6. We conclude that (i) kinins activate the arachidonate cascade principally by interactions with cells in the subepithelial (lamina propria) layer, rather than with the epithelial cells themselves, (ii) PGE2 contributes substantially to the kinin-induced increase of transepithelial p.d. as a messenger released from kinin-responsive subepithelial cells and acting on the basolateral pole of the epithelial cells, (iii) the apparent sidedness of colonic epithelium in terms of responses to kinins, NSAIDs and calcium removal is due to the barrier properties of the epithelial cell layer, and (iv) there are differences in calcium sequestration and apparent calcium dependence of prostaglandin biosynthesis between rat and rabbit colonic subepithelial cells.

Identification of [Hydroxyproline 3]-lysyl-bradykinin released from human plasma protein by kallikrein

[Hydroxyproline 3]-lysyl-bradykinin ([Hyp 3]-Lys-BK), a new kinin was isolated, besides lysyl-bradykinin (Lys-BK), from the reaction mixture of human plasma protein Cohn's fraction IV-4 with hog pancreatic kallikrein. The liberated kinins were isolated by procedures including ethanol extraction, Sephadex G-15, CM cellulose and reverse-phase high performance liquid chromatography (HPLC) and quantitated by radioimmunoassay. On HPLC, two peaks of immunoreactive kinins emerged. Peak 1, an unknown kinin proceeded to Peak 2 which had an identical retention time to that of Lys-BK. The amino acid sequence of the unknown Peak 1 proved to be Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg, or [Hyp 3]-Lys-BK, and Peak 2 Lys-BK. The ratio of the amounts of two kinins thus formed were [Hyp 3]-Lys-BK 25±4% and Lys-BK 75±4%. The existence of [Hyp 3]-Lys-BK suggests a presence of a new kininogen, containing [Hyp 3]-Lys-BK in human plasma protein, possibly undergone post-translational modifications.

Antagonistic effect of Mandevilla velutina extract on kinin-induced contractions of guinea-pig and cat ileum longitudinal smooth muscle

1. 1. The effect of aqueous/alcoholic extract of Mandevilla velutina on bradykinin (BK), lysyl-bradykinin (L-BK), methionyl-lysyl-bradykinin (M-L-BK), acetylcholine (Ach) and histamine (Hist)-induced contractions in the isolated muscle from guinea-pig and cat lieum was analysed. 2. 2. In the presence of atropine and pyrilamine, the extract (0.5–2 mg/ml) caused a parallel and concentration-dependent rightward displacement to all three kinins dose-response curves. Schild plots yielded nominal PA 2 values (g/ml) of 3.2, 3.3 and 3.8 respectively, but slopes of BK and M-L-BK were different from unity. 3. 3. M. velutina extract (1 and 2 mg/ml) also concentration-dependently inhibited the contractile response evoked by BK in the isolated cat ileum and produced only slight depressions of the Ach and His-contractions (<20%) suggesting some selectivity towards kinin receptors. 4. 4. These findings and those previously reported indicate that the active principles present in the crude extract of M. velutina competitively antagonizes kinin-induced contractions in several smooth muscle preparations.

Kinin antagonist activity of compounds from Mandevilla velutina in the rat isolated uterus.

The effect of four semi-purified compounds obtained from Mandevilla velutina crude extract by silica gel chromatography fractionization were analysed for their inhibitory effects on uterine contractions induced by bradykinin (BK), lysylbradykinin (L-BK), acetylcholine (ACh) and oxytocin, in vitro. None of the compounds tested affected uterine tone. Pre-incubation for 20 min with fraction 12 (20 to 80 micrograms ml-1), isolated from M. velutina produced a parallel and concentration-dependent displacement to the right of the concentration-response curves for BK and L-BK (1 to 1000 nM). Schild plots of these data were linear (correlation close to unity) and yielded a nominal pA2 value (as g ml-1) of 5.1 and 4.9, respectively, and the values of the slopes were not significantly different from unity. Fraction 11 (10 to 40 micrograms ml-1) also produced a parallel and concentration-dependent displacement to the right of the BK concentration-response curve. The Schild plot gave a mean pA2 value (g ml-1) of 5.4 and a slope not significantly different from unity. Fraction 12 did not influence the uterine contractile responses induced by ACh (0.1 to 100 microM) and oxytocin (0.01 to 30 miu ml-1) at concentrations less than 80 micrograms ml-1. Fraction 16 (20 to 80 micrograms ml-1) antagonized the action of BK only at concentrations greater than 40 micrograms ml-1, whereas fraction 5 (20 to 80 micrograms ml-1) was completely inactive against BK-induced responses. 5 As observed previously with the crude extract, the onset of the BK antagonistic action of these compounds was rapid and completely reversible following intermittent washing of the preparation for 30-60 min. 6 These results indicate the existence of at least two compounds in the crude extract of Mandevilla velutina that act as competitive and selective kinin antagonists on the isolated uterus of the rat.

Angiotensin I converting enzyme and kinin–hydrolyzing enzymes along the rabbit nephron

Angiotensin I converting enzyme (ACE) and kininase activities were measured in various segments of the rabbit nephron. ACE was determined with tritiated hippuryl-glycylglycine as substrate. Lysyl-bradykinin (LBK) hydrolysis (kininase activity) was measured by radioimmunoassay. ACE was only found in the glomerulus and in the two parts of proximal tubule: the convoluted proximal tubule and the pars recta (PR). It was distributed along a concentration gradient which increased from the glomerulus to PR. Kininase activity was found in both proximal and distal parts of the nephron. Besides intense LBK-hydrolyzing activity in the proximal tubule, a kininase activity was also found in the medullary collecting tubule (MCT). Kininase activity in the glomerulus and the proximal tubule was completely inhibited by chelating agents. Captopril inhibited this activity only in the PR and at high concentrations (above 10(-7) M). These results indicate that several types of enzymes other than ACE hydrolyze kinins in the glomerulus and in the proximal tubule. The contribution of ACE to kinin hydrolysis appears only minimal. The kininase activity found in MCT was different from ACE and other proximal tubule kininases because it was not inhibited by chelating agents. This kininase may play a physiological role in inactivating the kinins formed by kallikrein at or beyond the connecting tubule.

Renal vasoconstrictive effect of kinins mediated by B 1-kinin receptors

The nature of the renal vascular actions of kinins, their dependence on prostaglandins and B 1-kinin receptor responses were studied in functioning isolated perfused rat kidneys (IK). Lysylbradykinin (LBK), 0.28 and 0.7 μM, transiently decreased and then markedly increased the renal vascular resitance (RVR) in a sustained manner. Bradykinin (BK) at the same doses also had a transient vasorelaxant but not a sustained vasoconstrictive effect. The inactivation of LBK and BK by the IK did not account for the transient nature of their vasorelaxant effect. Indomethacin (5 μM) markedly blunted LBK-induced decrease but not increase in RVR. The B 1-kinin receptor agonist desArg 9-BK (0.4–1.0 μM) did not decrease RVR but, as LBK, markedly increased RVR in a dose-related manner. The B 1-kinin receptor antagonist [Leu 8]desArg 9-BK had no effect on its own but inhibited the desArg 9-BK-induced vasoconstriction in a stoichiometric manner. This antagonist at 4.0 μM also completely abolished the vasoconstrictive effect of 0.7 μM LBK, whereas it potentiated and prolonged its vasorelaxant effect. The results demonstrate that kinins, particularly LBK, have bimodal effects on the renal vascular resistance of the isolated perfused rat kidney. The vasorelaxant effect is at least partly mediated by prostaglandins whereas the vasoconstrictive effect of LBK and/or its renal metabolites has the typical character of a B 1-kinin receptor response. It is postulated that B 1-kinin receptor responses may be of importance in the generation and/or maintenance of renal vasoconstriction in disease states which lead to renal failure.

Electrogenic anion secretion in cultured rat epididymal epithelium.

Primary monolayer cultures enriched with principal cells from rat cauda epididymis were grown on pervious supports until confluence was reached. The epithelia so formed were used for short-circuit current recording. Epididymal monolayers had a transepithelial potential of 0.2 mV (apical side negative), a basal short-circuit current of 2 microA/cm2 and a transepithelial resistance of 60-90 omega cm2 when bathed on both sides with Krebs-Henseleit solution at 37 degrees C and gassed with 95% O2-5% CO2. 8-bromo-adenosine 3',5'-phosphate (1 mM) and forskolin (10 microM) caused an inward-flowing current in short-circuited monolayers. The current was partially sensitive to acetazolamide and to frusemide, suggesting that anion secretion was responsible for the responses. In the absence of chloride in the bathing fluid the response to forskolin was sensitive to acetazolamide but not to frusemide. The peptide lysylbradykinin (LBK) and prostaglandin E2 (PGE2) also produced inward-flowing currents which again appeared to be due to anion secretion. The actions of PGE2 were seen only when this agent was added to the basolateral side of the tissue, while LBK had effects from both sides. The responses to kinin, but not to PGE2, were inhibited by cyclo-oxygenase inhibitors such as piroxicam and indomethacin. It seems the kinin effects are dependent, at least in part, upon eicosanoid formation. Responses to kinin and PGE2 were severely attenuated in chloride-free bathing solution. Readdition of chloride-containing solution restored the responses to both agents. Assuming electrogenic ion secretion in the epididymis is accompanied by osmotic fluid flow it is evident that the transit time of sperm in the cauda epididymis will be reduced. Possible consequences for the maturation of spermatozoa are discussed.

Studies of the digestion of bradykin, lys-bradykinin, and des-Arg 9-bradykinin by angiotensin converting enzyme

We have studied the degradation of bradykinin, lysyl bradykinin and des-Arg 9-bradykinin by the angiotensin converting enzyme. Beadykinin was cleaved at two sites to produce the pentapeptide Arg-Pro-Pro-Gly-Phe plus dipeptides Ser-Pro and Phe-Arg. Lysyl bradykinin was cleaved similarly to release the same dipeptides plus the hexapeptide Lys-Arg-Pro-Pro-Gly-Phe. The tripeptidase activity of ACE was observed when des-Arg 9-bradykinin was digested. A single cleavage yielded the above pentapeptide plus Ser-Pro-Phe. Although des-Arg 9-bradykinin was the most rapidly digested, when mixtures of des-Arg 9-bradykinin and bradykinin or lysyl bradykinin were tested, virtually all of the bradykinin and most of the lysyl bradykinin was digested prior to the onset of digestion of des-Arg 9-bradykinin. This was shown to be due to inhibition of des-Arg 9-bradykinin cleavage by kinins and kinin-degradation products. The order in terms of potency was bradykinin > lysyl bradykinin > Ser-Pro ⪢ Phe-Arg > Arg-Pro-Pro-Gly-Phe. The concentration of chloride ion was an important parameter which affected the rate of digestion of each substrate examined. des-Arg 9-bradykinin was not digested by ACE in the absence of sodium chloride and the rate of digestion increased as the chloride concentration was increased to 100–150 mM. On the other hand, increasing NaCl concentration was inhibitory for bradykinin digestion. The rate of Lys-bradykinin digestion was increased from 0 to 1 mM NaCl and decreased thereafter up to physiologic concentration. A half-maximal rate was seen at 100–150 mM NaCl compared to no salt. Of the divalen cations examined, cupric ion inhibited further digestion of des-Arg 9-bradykinin at physiologic concentrations. Our data indicate that the rate of degradation of kinins and the nature of the stable final cleavage rpoducts in plasma or serum (studied in vitro) are dependent upon the effects of chloride ion, metal ions, and the kinetic effects of multiple metabolites produced by at least two kininases.

Studies of the digestion of bradykinin, lysyl bradykinin, and kinin-degradation products by carboxypeptidases A, B, and N

We have compared the digestion of bradykinin, lysyl bradykinin, and kinin degradation products by carboxypeptidases N, B and A (CPN, CPB and CPA). Carboxypeptidase N removed the C-terminal arginine from bradykinin or lysyl bradykinin to leave the des-Arg derivative of each, and no further degradation occurred regardless of enzyme concentration or time of incubation. However, both CPB and CPA degraded the des-Arg derivatives to remove the C-terminal phenylalanine. The inhibitory effect of phosphate ions upon this activity of CPB (but not CPA) suggests that CPA may be responsible for the formation of free phenylalanine seen upon degradation of kinins in plasma or serum. However, angiotensin converting enzyme degraded des-Arg 9-bradykinin in plasma or serum prior to such Phe removal to yield the pentapeptide Arg-Pro-Pro-Gly-Phe and the tripeptide Ser-Pro-Phe. We demonstrated that CPB degraded Arg-Pro-Pro-Gly-Phe but not Ser-Pro-Phe; this reaction was also inhibited by phosphate ions. Carboxypeptidase A, on the other hand, liberated Phe from both peptides in phosphate-buffered saline and accounted, at least in part, for the free phenylalanine detected. Carboxypeptidase N did not digest the aforementioned pentapeptide or tripeptide. It is clear that carboxypeptidase B and carboxypeptidase A had overlapping activities, depending upon the substrate tested, and were distinguished by the effects of different ionic environments. We further suggest a role for carboxypeptidase other than CPN in the degradation of kinins in human plasma or serum.

Kinin-induced prostaglandin release in rat colon does not display serosal/mucosal 'sidedness' after epithelial removal.

Release of prostaglandin E2 (PGE2) from rat colon in response to 1 microM lysylbradykinin (LBk) displayed 'sidedness' in preparations with an intact epithelial cell layer (PGE2 release, sensitivity to LBk and inhibition by indomethacin all occurred on the serosal side only). Preparations with histologically-verified removal of the epithelial layer and which were impermeable to prostaglandins (i.e. intact) continued to demonstrate LBk-induced PGE2 generation, but this and indomethacin inhibition did not display sidedness. The results show that kinin-induced PGE2 derives principally from cells in the lamina propria and not from the epithelial cells as previously supposed, and that the apparent sidedness of LBk responsiveness, PGE2 generation and its inhibition by indomethacin results from the barrier property of the epithelial cells and is not indicative of an asymmetric response.

Urinary Kinin Excretion Following Alterations of Vasopressin Levels in Man and Rat

To investigate the interaction between arginine-vasopressin (AVP) and the renal kallikrein-kinin system (KKS), urinary excretion rates of bradykinin (BK) and lysyl-bradykinin (LBK) were monitored in humans following water-loading, and in conscious diabetes insipidus (DI) rats during the infusion of AVP. In humans, the excretion rate of both BK and LBK decreased markedly 90 min after the water load. There was a close positive correlation between plasma AVP levels and urinary BK excretion, while urine flow was correlated negatively with the excretion rates of both kinins. In DI rats infusion of AVP caused a significant, reversible increase (from 14 +/- 2.8 to 35 +/- 5.1 fmol/min) in BK excretion. These results further implicate AVP in the regulation of the activity of the renal KKS.

Transporting epithelia as targets for kinin effects.

One approach which can be used to discover the function(s) of the kallikrein-kinin system is to make the assumption that tissue kallikrein can generate lysyl bradykinin (LBK, kallidin) in tissues, where it then acts as local hormone. If this be true then it follows that novel effects of kinin may be discovered in tissues where kallikrein is especially localized. Consideration of these effects may then allow some conclusions to be drawn about the roles of the kallikrein-kinin system in either physiological or pathological states.

Synthesis of prostaglandin E2 in different segments of isolated collecting tubules from adult and neonatal rabbits.

Prostaglandin E2 (PGE2) inhibits the action of the antidiuretic hormone (ADH) in isolated collecting tubules. A negative feedback loop has been postulated whereby ADH stimulates PGE2 synthesis. Furthermore, lysyl-bradykinin (LBK) inhibits the antidiuretic effect of ADH, probably via PGE2. Enhanced PGE2 synthesis has also been implicated as contributing to the inability to maximally concentrate urine during the neonatal period. We investigated PGE2 synthesis in microdissected cortical (CCT), medullary (MCT), and branched cortical (BCT) collecting tubules from adult and in corticomedullary collecting tubules (CT) from newborn rabbits. Isolated BCT produced significantly less PGE2 (12 +/- 2 pg X mm-1 X 20 min-1) than CCT (65 +/- 9) or MCT (76 +/- 8) from kidneys of adult rabbits. CT from newborn rabbits produced only 19 +/- 3 pg/mm, significantly less than either CCT or MCT from adults. A large variability in basal PGE2 production and hormonal response was observed from tubule to tubule. Under either basal conditions or in the presence of 2 microM arachidonic acid, LBK enhanced PGE2 synthesis in CCT and MCT from adults. ADH enhanced PGE2 production in MCT under basal conditions and in CCT in the presence of arachidonic acid. Neither LBK nor ADH stimulated PGE2 synthesis in neonatal CT. A23187 consistently stimulated PGE2 synthesis in CCT and MCT from adults and, to a lesser extent, in CT from newborn rabbits. Our results support the hypothesis that ADH and LBK enhance PGE2 synthesis in the collecting tubule. This response is, however, subject to large variations from tubule to tubule and depends on the in vitro incubation conditions.

Response of the renal kallikrein-kinin system, intravascular volume, and renal hemodynamics to sodium restriction and diuretic treatment in essential hypertension.

The renal kallikrein-kinin system, distinct from the plasma system, is an enzyme sequence producing kinins, principally lysyl bradykinin. While the functions of the system have not been conclusively established, it has been implicated in renal vasodilation and natriuresis, although the evidence is often conflicting. Measurement of urinary kallikrein excretion is the most common way to assess the system, although kallikrein excretion and kinin excretion are often dissociated. Kallikrein excretion is influenced by several hormonal systems, as well as dietary alterations, disease states (including hypertension), and numerous drugs. Kallikrein excretion is diminished in hypertension (especially hypertension with reduced renal function), suggesting involvement in the pathogenesis of the disease. Dietary sodium restriction increases kallikrein excretion while lowering blood pressure, but the blood pressure reduction correlates with plasma volume contraction rather than the increase in kallikrein. Thiazide diuretics lower blood pressure and renal vascular resistance while increasing kallikrein excretion, and blood pressure "responders" to thiazides have a greater kallikrein increment than the "nonresponders," suggesting a role for renal kallikrein in the hypotensive response to thiazides.

Changes in rectal temperature of the rabbit by intracerebroventricular injection of bradykinin and related kinins.

The effects of intracerebrovascular injections of bradykinin (BK), lysyl-bradykinin (L-BK), methionyl-lysyl-bradykinin (ML-BK) and des-arginyl-bradykinin (Des-Arg9-BK) on the rectal temperature of rabbits were investigated. A linear dose-response curve could be obtained with bradykinin. Equimolar doses to BK of L-BK and ML-BK gave responses of the rectal temperature undistinguishable from those of BK. In contrast, the smaller polypeptide Des-Arg9-BK did not show any hyperthermic properties. Since prostaglandins (PG) are known to potentiate (facilitate) the peripheral effects of BK and display a hyperthermic action, their synthesis being inhibited by antipyretics, we studied the effect of indomethacin and paracetamol on the BK-induced rise in rectal temperature in rabbits. It could be shown that these drugs inhibited partially the response to BK. The possible participation of BK in thermoregulation will be discussed.

Comparative contractile actions of different kinins on human umbilical arteries and veins

The present experiments demonstrate that three naturally occurring kinin polypeptides, namely bradykinin (BK), lysyl-bradykinin (Lys-BK) and methionyl-lysyl-bradykinin (Met-Lys-BK), induce potent contractile responses on isolated longitudinally and helically cut human umbilical arteries and veins (HUAV). An extrapolation of these in vitro contractile concentrations to the in vivo situation suggests that threshold concentrations for BK and Lys-BK would be in the range of maternal plasma levels, while umbilical cord plasma concentrations found at birth could be within a range whereby all three kinins could induce potent (25–60% maximal responses) contractions. These findings support previous suggestions that kinins may play a physiologic role in control of umbilical cord blood flow and effecting closure of the umbilical vessels at birth. The addition of a lysine moiety (in e.g. Lys-BK) or methionine and lysine moieties (in e.g. Met-Lys-BK) to BK not only can decrease the affinity of the resultant peptides for the kinin receptor in HUAV but the instrinsic activity as well. Although specific kinin receptors appear to exist in HUAV, the data suggest that heterogeneity of the kinin receptors, which subserve contraction, exist within the circularly and longitudinally arranged vascular smooth muscle cells.

Isolation of a fragment (C3a) of the third component of human complement containing anaphylatoxin and chemotactic activity and description of an anaphylatoxin inactivator of human serum.

A small fragment of C3, called C3a, which has smooth muscle contracting activity, was isolated by three different methods. At pH 8.6, C3a behaved as cation, and using the Archibald method, its mol wt was determined to be 7000. A specific antiserum to C3a showed the fragment to be antigenically distinct from the rest of the C3 molecule, i.e., the C3b portion. The same antiserum and an anti-whole C3 were able to inhibit the biologic activity of C3a. In addition to anaphylatoxin activity, leukocyte chemotactic activity was shown to reside in C3a. Treatment with trypsin caused the cationic fragment to become anionic and abolished the anaphylatoxin but not the chemotactic activity. C3a fragments with identical biologic activity and comparable cationic properties, as determined by acid disc electrophoresis, were obtained by treatment of C3 with C3 convertase, C3 inactivator complex, trypsin, and plasmin. Thrombin produced a similar C3 fragment which was inactive. It was concluded that C3a corresponds to an unusually basic portion of C3 which may be liberated by attack of a variety of enzymes on a highly susceptible region of the native C3 molecule. C3b was cleaved by trypsin and less efficiently by thrombin or plasmin into two antigenically distinct pieces: the larger C3c fragment corresponding to beta(1A) and the smaller C3d fragment to alpha(2D) of aged serum. The c- and the d-fragments were separated and characterized. Isolated C3a rapidly lost its anaphylatoxin activity when treated with small amounts of a partially purified, thermolabile 10S alpha-pseudoglobulin of human serum. The conditions of inactivation suggested an enzymatic reaction. The anaphylatoxin inactivator also destroyed the activity of C5-derived anaphylatoxin and of lysyl bradykinin.

Follicular fluid kinin and its action on fallopian tube.

Human, rabbit and bovine follicular fluid was found to contain a substance which affected isolated smooth muscle preparations. By means of drug antagonists, chymotrypsin digestion and determination of solubility characteristics, the active principle was identified with a polypeptide. Increased formation was detected following contact with glass, incubation with saliva, trypsin or bovine tubal fluid, suggesting an association with kinin-like activity. Following column, thin layer and paper chromatography, pharmacological activity was identified with lysyl bradykinin and bradykinin. FoUicular kinins and bradykinin decreased the tone of isolated rabbit and bovine fallopian tubes. (Endocrinology 84: 931, 1969)

Abstracts of Papers Presented at the Third International Complement Workshop, Harvard Medical School, Boston, Massachusetts, June 3–5, 1968

Abstract Plasma from persons with hereditary angioneurotic edema develops permeability factor and kinin activity, both of which seem to be due to the action of a relatively small polypeptide molecule. Histamine plays no role in these activities, clearly distinguishing the permeability factor and kinin properties in this plasma from the anaphylatoxins which may be formed from purified components of complement. Partially purified preparations of this kinin-permeability factor activity contracted rat uterus but not guinea pig ileum; and when injected intravenously into anesthetized rats, their arterial blood pressure was raised slightly. The kinin and permeability factor activity of this preparation could be destroyed during incubation with trypsin, chymotrypsin and carboxypeptidase. The effect on rat arterial blood pressure and susceptibility to trypsin suggest that the polypeptide differs from bradykinin and lysyl bradykinin, both of which have vasodepressor effects in the rat, and neither of which loses its kinin or permeability factor activity during incubation with trypsin.

The Role of 5-Hydroxyindoles in the Carcinoid Syndrome

Publisher Summary This chapter assesses the role of 5-HT in carcinoidosis in the context of recent developments. The carcinoid syndrome is a model system to study the pharmacology of 5-HT in man; the symptoms and signs, apart from those of malignancy in general and tryptophan deficiency in particular, are all explicable in terms of one or other action of the amine. Bradykinin and lysyl bradykinin are of importance in carcinoid flush. Apart from direct evidence of their involvement, it is well recognized that there is no correlation between degree of flush and 5-hydroxyindole production; that patients may have a pronounced flush and yet put out a minimal excess of 5-HIAA. Carcinoid is most commonly derived from the gastrointestinal tract or related structures, including such unusual sites as thyroid, parotid, and biliary tract. Its origin from the female or male genital tract is well established. By far, the commonest location is the ovary. Histamine secretion and “geographical” flush in gastric carcinoid and the high intensity flush of bronchial carcinoid are discussed in the chapter. The chapter identifies those areas in this field of study where further experiment or observation is required.