Effects of complement fragments on pulmonary and vascular smooth muscle.
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Anaphylatoxins↗
Biomedical subjects
F Marceau
Publications and source records attributed to F Marceau.
C5a-induced hemodynamic and hematologic changes in the rabbit. Role of cyclooxygenase products and polymorphonuclear leukocytes.
Hemodynamic and hematologic changes occurring after intravascular complement activation have implicated the anaphylatoxins in this response. In this study, the hemodynamic and hematologic effects of purified C5a were investigated in rabbits; and involvement of prostanoids, histamine, and polymorphonuclear leukocytes (PMNs) were examined. The anaphylatoxin C5a induces a reversible systemic arterial hypotension which coincides with an increase in central venous pressure (CVP), decreased cardiac output (CO), increased plasma prostanoid levels, as well as neutropenia. Total peripheral resistance (TPR) remained unchanged. The cyclooxygenase inhibitor indomethacin abolished the C5a-induced hypotension and normalized plasma prostanoid levels without altering the C5a-induced neutropenia. The thromboxane (Tx) A2 synthetase inhibitor dazoxiben reduced TxB2 plasma levels and increased 6-keto-prostaglandin PGF1 alpha and PGE2 levels without altering the hypotensive response. However, with dazoxiben treatment both TPR and CVP decreased. The H2-receptor antagonist cimetidine reduced C5a-induced hypotension and diminished prostanoid release. Both the hypotensive response and elevated prostanoid release were observed after C5a challenge in animals rendered neutropenic prior to challenge. It is concluded that C5a-induced arterial hypotension in the rabbit is a PMN-independent reaction, mediated through cyclooxygenase products and, to some degree, by histamine. The mechanism producing systemic arterial hypotension does not seem to involve peripheral vasodilation but appears to be a secondary effect of pulmonary vasoconstriction, possibly mediated by TxA2.
6-Ketoprostaglandin F1 alpha↗
Mitogenic effect of bradykinin and of des-Arg9-bradykinin on cultured fibroblasts.
Bradykinin (BK) and its fragment des-Arg9-BK failed to stimulate thymidine incorporation in all but one observed fibroblast cultures derived from human amniotic fluid or rabbit dermis. The rabbit dermis fibroblast line designated R51 acquired the capacity to increase its DNA synthesis in response to kinins after several weeks in culture. It was more sensitive to des-Arg9-BK than to BK and the effect of both peptides was antagonized by the analog Leu8, des-Arg9-BK; these features are shared with certain smooth muscle preparations responsive to kinins such as the rabbit aorta. Recently isolated rabbit dermis or human amniotic fibroblasts could not be made responsive to kinins by pre-incubating them with bacterial lipopolysaccharide. The line R51 released more PGE2 than baseline when stimulated with BK or des-Arg9-BK at low concentrations; it was also doubling faster than recently isolated cells of similar origin.
Animals↗
Anaphylatoxin C5a fails to promote prostacyclin release in cultured endothelial cells from human umbilical veins.
Subcultured endothelial cells from human umbilical veins respond to histamine and melittin with increased prostacyclin production, measured as 6-keto-prostaglandin F1 alpha by radioimmunoassay. However, no response to leukotriene C4 was observed. Primary cultured cells, on the other hand, respond to leukotriene C4 and the histamine response was 7 times more potent for these cells than for subcultured cells. In contrast, neither primary cultures nor subcultures of endothelial cells released prostacyclin following application of either human anaphylatoxin C5a (100 nM) or C3a (1 microM). In addition, these endothelial cells appear to have no specific binding sites for 125I-C5a. However, endothelial cells released prostacyclin in the presence of human polymorphonuclear leukocytes that were activated with C5a. We conclude that involvement of endothelial cells in the haemodynamic response to anaphylatoxin is an indirect function, i.e. C5a activates circulating or tissue cells which in turn stimulate the endothelial cell to produce prostacyclin.
6-Ketoprostaglandin F1 alpha↗
Effects of the C5a anaphylatoxin and its relationship to cyclo-oxygenase metabolites in rabbit vascular strips.
Strips of rabbit blood vessels were suspended in vitro and responses to complement peptides C3a and C5a were recorded isotonically. Human C3a (up to 1.5 microM) was inactive on rabbit vascular strips. Human C5a (2.9-59 nM) decreased spontaneous activity of the rabbit portal vein under resting baseline tension. The C5a relaxed strips of portal vein and pulmonary artery that were precontracted with noradrenaline (NA, 200 nM). On the portal vein, C5a-induced relaxation was preceded by a transient contractile phase which decreased with repeated applications of C5a. The magnitude of C5a-induced relaxation of both vessels increased with repeated stimulation by C5a. Maximal levels of relaxation for the third application of C5a at 59 nM averaged 44% and 17% of the NA-induced contraction plateau in portal vein and pulmonary artery, respectively. Strips of rabbit aorta responded minimally to C5a. Indomethacin (5.6 microM) significantly inhibited C5a-induced relaxation of the portal vein and pulmonary artery but had no effect on the early contractile response of the portal vein. Mepyramine (10 microM) failed to modify the C5a response from either vessel, but it reduced the contractile phase of the C5a response on the portal vein when applied in conjunction with indomethacin. The drug SKF 88046, an end organ antagonist of thromboxane (TX) A2 and some contractile prostaglandins, reduced the contractile phase and increased relaxation of the portal vein to C5a but did not modify the response of the pulmonary artery. Radioimmunoassays for 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and TXB2 were performed on the fluid bathing rabbit isolated blood vessels. C5a promoted release of 6-keto-PGF1, over the basal release rate in rabbit tissues. Only trace quantities of TXB2 were produced by rabbit vessels exposed to C5a. 7 It is concluded that the mechanical response of blood vessels to C5a is mainly determined by the type of cyclo-oxygenase products released and by the sensitivity of each blood vessel to these active lipids. Tissue histamine release is also responsible for a component of the response of rabbit portal vein to C5a. The relaxant effect of C5a on rabbit blood vessels may be a phenomenon related to the previously reported hypotensive action of classical anaphylatoxins in vivo.
6-Ketoprostaglandin F1 alpha↗
Selective induction of cardiovascular responses to des-Arg9-bradykinin by bacterial endotoxin.
Bacterial lipopolysaccharide (LPS) induces in 5 h a hypotensive response mediated by the B1-receptor for kinins in the rabbit, an effect which is not observed in untreated animals. The present study is intended to evaluate the capacity of other acute toxic treatments to induce such a response and to analyze the mechanism of induction. Intravenous injections of inulin (20 mg), Naja venom (50 micrograms), compound 48/80 (1 mg), and etiocholanolone (6 mg) failed to induce hypotensive response to des-Arg9-bradykinin (the selective agonist of the B1-receptor) in 5 h. LPS from Salmonella (100 micrograms) and E. coli (10 micrograms) were highly effective, whereas trypsin (2 mg) gave doubtful responses. White blood cell counts revealed a profound and rapid neutropenic effect of the 2 LPS and a less marked one for trypsin. It is concluded that (1) LPS is a selective inducer of a new cardiovascular response to kinins mediated by the B1-receptor, and (2) that the mechanism of induction may include an intimate interaction between neutrophil leukocytes and blood vessel walls.
Adrenergic beta-Agonists↗
Effect of C3a and C5a anaphylatoxins on guinea-pig isolated blood vessels.
Four major guinea-pig blood vessels were isolated and studied in vitro for their contractile responses to anaphylatoxins C3a and C5a. Both peptides were assayed in the 10(-9) to 10(-7) M range and their effects were parallel, although C3a was less potent and more tachyphylactic than C5a. The most responsive blood vessel, relative to a histamine maximal response, was the portal vein, followed by the pulmonary artery and the thoracic aorta. The abdominal vena cava did not respond to either C3a or C5a. Participation of secondary mediators in the vasoconstrictor effect of C3a and C5a was assessed by exposing portal veins and pulmonary arteries to specific inhibitors. The four drugs were: indomethacin, a cyclooxygenase inhibitor; pyrilamine, an antagonist of H1 receptors for histamine; FPL55712, an antagonist of the leukotriene component of slow-reacting substance of anaphylaxis; and phentolamine, an alpha adrenergic blocker. This pharmacological analysis suggests that prostaglandin-like substances mediate most of the anaphylatoxin vasoconstrictor effects, with a biologically significant participation of leukotrienes in the case of C3a and histamine in the case of C5a. High variability between individual tissue responses to the anaphylatoxins was investigated in terms of previous exposure to activated complement. Cobra venom factor (200 micrograms) was injected i.v. in five guinea pigs 2 hr before sacrifice. This treatment reduced the serum concentration of C3 and C5 to 9 and 32%, respectively, as compared with saline-treated animals. The portal vein excised from the cobra venom factor-treated animals exhibited reduced sensitivities to C3a, but showed normal response to C5a. The selective desensitization to C3a after complement activation in vivo is presumably related to the highly tachyphylactic effect of C3a on blood vessels.
Anaphylatoxins↗
Rapid assay of human plasma carboxypeptidase N by high-performance liquid chromatographic separation of hippuryl-lysine and its product.
A rapid and sensitive method for measuring carboxypeptidase N (CPN) activity in human plasma is described. The procedure is based on the hydrolysis of a high-specificity/low-affinity substrate, hippuryl-L-lysine, to its products hippuric acid and lysine. The substrate and product are separated quantitatively by high-performance liquid chromatography in less than 10 min following a minimal sample preparation time. The advantages of this method over previous ones are discussed and data are presented demonstrating the reliability of this method for the routine clinical determination of CPN activity.
Carboxypeptidases↗
Pharmacology of kinins: their relevance to tissue injury and inflammation.
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Amino Acid Sequence↗
Kininases and vascular responses to kinins.
We have utilized several inhibitors to assess the effects of kininases on the contractile activity of bradykinin (BK), kallidin (KD), des-Arg9-BK and des-Arg10-KD on two isolated blood vessels, the rabbit aorta and mesenteric vein. The response of the two vessels to kinins are mediated by B1-receptors, implying that fragments of kinins without the C-terminal arginine are much more active on these tissues than the whole kinin sequences. Blockers of carboxypeptidase B-like enzymes, such as SQ24798 and pivalyl-L-arginine decrease the apparent affinity of BK and KD on the two vessels, while not changing those of des-Arg9-BK and des-Arg10-KD; this suggests that a major part of the contractile activities of BK and KD are mediated by des-Arg metabolites formed in situ at the tissue level by a kininase I. The block of kininase II by captopril or desacetylated MK-421 bring about a complex pattern of activity changes that include the potentiation of BK and KD and the depression of des-Arg10-KD. These results, in conjunction with those obtained with the non-specific inhibitors of metallopeptidases, thioglycolic acid and EDTA, suggest that the relative contribution of kininase I and kininase II to the degradation of kinins in arterial and venous vessels may be different. The implications of these findings on the pharmacology of B1-receptors are discussed.
Angiotensin-Converting Enzyme Inhibitors↗
Induction of beta 1-receptors for kinins in the rabbit by a bacterial lipopolysaccharide.
The intravenous injection of 10 microgram of a lipopolysaccharide extracted from E. Coli to rabbits leads to the appearance of a hypotensive effect for des-Arg9-BK and increases significantly the vasodilator effect of this peptide in isolated hearts and its contractile effects in strips of large arteries and veins. LPS elicits these responses when administered 5 or 20 h before anesthesia; the hypotensive response of animals receiving LPS just before anaesthesia is similar to that of untreated rabbits. All actions of des-Arg9-BK in vivo, in isolated hearts and in isolated tissues are blocked by des-Arg10,[Leu9]-kallidin (KD), a specific inhibitor of kinins B1-receptor. These data are taken as evidence of the appearance of B1-response to kinins in the few hours following LPS injection. The response of the animals, perfused organs and isolated tissues to other agonists, such as substance P or [Tyr(Me)8]-BK (an activator of B2-receptors for kinins) are not affected by the treatment with LPS nor are they modified by the antagonist des-Arg10,[Leu9]-KD. The present data, together with previous studies on the sensitization mechanism of B1-receptor containing preparations, suggest that LPS induces the formation of B1-receptors in the rabbit, within a few hours. The activation of B1-receptors by des-Arg9-BK produces hypotension, coronary vasodilation and stimulation of large arteries and veins isolated and suspended in vitro. Some large arteries and veins (e.g. the aorta and the anterior mesenteric vein) as well as some peripheral vascular beds (e.g. the coronary vessels) have the ability of generating B1-receptors, while other organs (e.g. the external jugular vein) have not or very little. The reason for this phenomenon as well as the intimate mechanism by which LPS induces the formation of B1-receptors remain to be elucidated.
Animals↗
The degradation of bradykinin (BK) and of des-Arg9-BK in plasma.
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Animals↗
Pharmacological characterization of the vascular permeability enhancing effects of kinins in the rabbit skin.
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Animals↗
Kinin receptors in experimental inflammation.
The contractile response of the rat isolated urinary bladder to kinins is meated by receptors of the B1 and of the B2 types, as this preparation responds to des-Arg9-bradykinin (des-Arg9-BK), a fairly selective stimulant of receptor B1 and to [Tyr(Me)8]-BK, a potent agonist on receptor B2. Des-Arg10-[Leu9]-kallidin, a specific and competitive antagonist of the action of kinins on receptor B1, has been found to block the effect of des-Arg9-BK in concentrations similar to those required in the rabbit aorta; therefore, the B1 receptor of the rat urinary bladder is analogous to that of the rabbit vascular tissue. The response of the rat urinary bladder to des-Arg9-BK increases progressively from near null level during the incubation in vitro and can be abolished by cycloheximide; this suggests that receptor B1 of the rat urinary bladder is formed de novo. The inflammation of the bladder induced by intravesical injection of the detergent Triton X-100 enhances the initial response to des-Arg9-BK without modifying the response to other agents. The B1 receptor is formed in vivo in the rat urinary bladder submitted to the Triton X-100 treatment but not in the control untreated organ. The local de novo synthesis of B1 receptors for kinins that follows a noxious stimulus is proposed as a possible mechanism implicated in the chemical mediation of the inflammatory process.
Animals↗
[Vasoactive polypeptide receptors].
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Angiotensins↗
Cardiovascular actions of kinins in the rabbit.
The hypotensive action of bradykinin (BK) and congeners was measured in anesthetized rabbits by administering the peptides intravenously and intraarterially in order to evaluate their pulmonary inactivation. A systematic study of the distribution of receptors for BK in the cardiovascular system of the rabbit was approached: (a) by measuring the myotropic effects of several peptides related to BK in strips of large arteries and veins; (b) by recording the changes of tension and rate of isolated atria; and (c) by evaluating the changes of perfusion pressure in isolated hearts, kidneys, and ears. This investigation was extended to strips of aortae of various mammals and to isolated atria of guinea pigs, for comparison. Receptors for BK were classified into two main types, B1 and B2, using the order of potency of these agonists [Tyr(Me)8]-BK, BK, and [des-Arg9]-BK, and an antagonist, specific and competitive for the B1 receptors, the octapeptide [Leu-OMe8,des-Arg9]-BK. The results obtained in this study indicate that the complex cardiovascular effect of BK in vivo may result from direct actions on vascular smooth muscles, presumably mediated by at least two types of receptors, as well as from the release of endogenous prostaglandins. BK and congeners exert a direct action on vascular smooth muscle by stimulating specific receptors both of the B1 type (in the aorta, the large arteries, and the mesenteric vein) and of the B2 type (in the jugular vein); and these vascular tissues provide useful preparations for pharmacological studies of bradykinins. Isolated organs perfused through their main arteries with physiological medium respond to BK by an increase of perfusion pressure (vasoconstriction in isolated ears and kidneys) or by a decrease (vasodilation in the rabbit heart). The vascular effects of BK in the heart and the kidney depend in part on the release of endogenous prostaglandins and on the activation of receptors that appear to be of the B2 type. Like other endogenous hypotensive agents, BK appears to reduce the tonus of the peripheral vessels, while contracting large arteries and veins. The results obtained in vitro are discussed with respect to the hypotensive effect in vivo and to the role of kinins in inflammation and oedema.
Animals↗
The rabbit mesenteric vein: a specific bioassay for substance P.
The anterior mesenteric vein of the rabbit responds to substance P with dose-dependent contractions and is among the vascular smooth muscles most sensitive to this peptide. In spite of its high sensitivity to numerous other agents, including angiotensin and bradykinin, the rabbit mesenteric vein can be made selective for substance P by the use of specific inhibitors that will prevent the myotropic effects of acetylcholine, catecholamines, histamine, 5-hydroxytryptamine, and of the two above-mentioned peptides, without modifying the contractions elicited by substance P. It appears that this peptide acts directly on specific receptors and not through the release of neurotransmitters. Interference by intramural prostaglandins is excluded because substance P is equally active on tissues pretreated with indomethacin or untreated. Dose-response curves obtained with substance P are close to the theoretical curves predicted by the mass action law. The rabbit mesenteric vein contains a new type of receptor for bradykinin, recently identified (REGOLI, D., MARCEAU, F., and BARABE, J. 1978. De novo formation of vascular receptors for bradykinin. Can, J. Physiol. Pharmacol. 56, in press.). The action of bradykinin on this receptor can be prevented with the use of specific and competitive inhibitors and, therefore, the mesenteric vein will distinguish between peptides of the kinins or of the substance P types.
Animals↗
De novo formation of vascular receptors for bradykinin.
Two different types of receptors for bradykinin have been found in isolated veins of the rabbit. The first receptor is a stable component of the smooth muscle membrane and it is found in the jugular vein, while the second is generated de novo during incubation in vitro and it is present in the mesenteric vein. Actinomycin D and cycloheximide block the generation of receptors in the mesenteric vein, without exerting any action either on receptors for other agonists (e.g. substance P) in the same tissue, or on the other receptor for bradykinin in the jugular vein.
Animals↗