International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences.

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

Therapeutic prospects for bradykinin receptor agonists in the treatment of cardiovascular diseases.

Kinins are located in the vascular smooth muscle and the heart, and are the most potent biologically active polypeptides. Pharmacological studies of cardiovascular disorders, including hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy, indicate that reduced activity of the local kallikrein-kinin system (KKS) may be instrumental in the induction of these disorders. The ability of kallikrein gene delivery and bradykinin (BK) B2 receptor agonists to produce a wide spectrum of beneficial effects make them excellent candidate therapies for the treatment of hypertension, and cardiovascular and renal diseases. In addition, strategies that activate kinin receptors may be applicable to the treatment of cardiovascular and renal disorders. However, one major challenge of this approach is the unanswered question of whether there is a sufficiently safe therapeutic index between the potential cardioprotective and pro-inflammatory effects following administration of BK B2 receptor agonists.

B1 receptors as a new inflammatory target. Could this B the 1?

The kinins, particularly bradykinin (BK), are important mediators involved in both the initiation and progression of an inflammatory response. The pro-inflammatory effects of kinins are mediated by at least two receptors: the B2 subtype is expressed constitutively and the B1 receptor is induced following tissue inflammation and damage. The endogenous ligand for the B1 receptor is des-arg9BK, a cleavage product of the activity of carboxypeptidase on BK. Activation of B1 receptors produces a range of pro-inflammatory effects including oedema, pain and promotion of blood-borne leukocyte trafficking. In this article Amrita Ahluwalia and Mauro Perretti briefly describe the biology of BK and its receptors, and discuss the possible development of B1 receptor antagonists as novel anti-inflammatory agents.

B1 receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of FGF-2 effects.

1. Bradykinin (BK) contributes to the inflammatory response inducing vasodilation of postcapillary venules and has been demonstrated to induce neovascular growth in subcutaneous rat sponges. 2. In this study the ability of BK to stimulate cell growth and migration in cultured endothelium from coronary postcapillary venules (CVEC) has been investigated. 3. [3H]-thymidine incorporation in subconfluent and synchronised CVEC was used to monitor DNA synthesis over 24 h. BK promoted a concentration-dependent increase of DNA synthesis with maximal activity at 100 nM. At this concentration BK also induced 18 fold accumulation of c-Fos protein immunoreactivity in the nucleus within 1 h from peptide exposure. 4. The total number of cells recovered after 48 h exposure to BK was increased in a concentration-dependent manner. Maximal effect was produced by 100 nM concentration of the peptide which produced 50% increase in cell number. The selective B1 receptor agonist Des-Arg9-BK mimicked the proliferative effect of BK, while the B2 receptor agonist kallidin was devoid of any activity. The proliferation induced by BK was abolished in a concentration-dependent manner by the addition of the B1 selective antagonist Des-Arg9-Leu8-BK, while the selective B2 receptor antagonist HOE140 did not modify BK-induced growth. 5. DNA synthesis and growth promoted by a threshold concentration of fibroblast growth factor-2 (FGF-2) (0.25 nM) were potentiated by increasing concentrations of BK and Des-Arg9-BK. 6. Endothelial cell migration assessed by the Boyden Chamber procedure was not promoted by BK or the selective B1 and B2 receptor agonists. 7. These data are the first demonstration that BK promotes growth of endothelial cells from postcapillary venules. The mitogenic activity of BK involves c-Fos expression and potentiates the growth promoting effect of FGF-2. Only the B1 receptor appears to be responsible for the proliferation induced by BK and suggests that this type of receptor might be implicated in favouring angiogenesis of coronary venules.

Kinin B1 and B2 receptors in pig vessels: characterization of two monoreceptor systems.

The coronary artery and renal vein of the adult pig are sensitive and reliable monoreceptor systems for studying kinin receptors. The pig coronary artery with intact endothelium is highly sensitive to bradykinin (BK, pEC50 8.6), while being insensitive to the B1 receptor agonist, LysdesArg9BK. The tissue responds to BK with concentration-dependent relaxation, which is prevented by B2 receptor antagonists, particularly DArg[Hyp3, Thi5, DTic7, Oic8]BK (HOE 140, pKB 9.3), (E)-3-(6-acetoamido-3-pyridyl)-N-(N-{2, 4-dichloro-3-[(2-methyl-8-quinolinyl)oxy-methyl]phenyl}-N- methylaminocarbonyl-methyl)acrylamide (FR 173657), a new non peptide compound (pKB 9.3), while B1 receptor antagonists (e.g. Lys[Leu8]desArg9BK) are inactive. The order of potency of kinin-related peptides in this vessel is: LysBK > or = BK > [Hyp3]BK > [Aib7]BK, a sequence typical of a B2 receptor system. Antagonists such as HOE 140 and FR 173657, at high concentrations reduce the maximum effect of BK and thus behave as noncompetitive antagonists. The kinin B1 receptor was studied in the pig renal vein without endothelium and incubated for several hours in order to allow for the de novo formation of this functional site. After 7-8 h in vitro incubation, the vessel shows high sensitivity to LysdesArg9BK (pEC50 8.3) and is insensitive to BK. The pig renal vein responds to B1 receptor agonists with concentration-dependent contraction which maintains a stable plateau and is prevented by selective B1 receptor antagonists such as Lys[Leu8]desArg9BK (pKB 6.7). The most active antagonist has been found to be desArg9HOE 140 (pA2 7.6) which acts as competitive antagonist in this preparation. Some B2 antagonists (e.g. HOE 140) show weak (pKB 6.1) anti-B1 receptor activity while the non-peptide compound FR 173657 is inactive on the B1 receptor and therefore acts as a potent and selective kinin B2 receptor antagonist in the pig. The data obtained in this study allow us to compare the porcine B2 and B1 receptors with those of other species including man, and underline some interesting features that are unique to the porcine functional sites.

Antagonists for kinin B1 and B2 receptors in the mouse.

Contractile responses to B1 and B2 receptor agonists have been demonstrated in the mouse stomach; the mouse urinary bladder responds only to B2 receptor agonists. These tissues were used in this study to investigate the antagonistic effect of four B2 receptor antagonists, namely, DArg[Hyp3,DPhe7,Leu8]BK (BK, bradykinin), HOE-140, WIN 64338, and FR-173657 (B2 receptor antagonists), as well as three B1 kinin receptor antagonists; [Leu8]desArg9BK, Lys[Leu8]desArg9BK, and AcLys[D beta Nal7,Ile8]desArg9BK, were investigated. Results shown indicate that DArg[Hyp3,DPhe7,Leu8]BK is a partial agonist, while HOE-140 and FR-173657 are pure antagonists, devoid of direct myotropic effects, and quite selective for the B2 receptor. WIN 64338 was essentially inactive on both B1 and B2 receptors. The myotropic effect of DArg[Hyp3,DPhe7,Leu8]BK is blocked by HOE-140. Similarly, Lys[Leu8]desArg9BK and [Leu8]desArg9BK are B1 receptor partial agonists whose activities are blocked by AcLys[D beta Nal7,Ile8]desArg9BK (code name R 715), a fairly pure B1 receptor antagonist. Both HOE-140 and FR-173657 are long-acting, slowly reversible compounds that exert a noncompetitive type of antagonism, while R 715 is rapidly reversible and, thus, possibly competitive. Data presented in this paper provide a pharmacological characterization of B1 and B2 receptor antagonists in the mouse and underline the positive features of FR-173657 as a potent and selective B2 receptor antagonist, as well as the potency and purity of R 715 as a B1 receptor antagonist in the mouse.

The kinin B1 receptor: an inducible G protein coupled receptor.

The B1 receptor, selectively stimulated by des-Arg9 fragments of native kinins, has a place in the vast family of G protein coupled receptors. We discuss a series of six criteria useful for comparing the B1 receptor with the more prominent and studied bradykinin B2 receptor. The B1 receptor has attracted interest because it is rapidly upregulated in biological systems following some types of tissue injury, notably the injection of bacterial materials to rabbits, rats, or pigs. A fast and specific genetic program recruits the expression of what we know now to be a G protein coupled receptor in smooth muscle cells, endothelial cells, fibroblasts, and a few other cell types. The cytokine network has been linked to B1 receptor expression in functional experiments, and this may be related to the recent finding of potential cytokine response elements in the proposed gene promoter of the human B1 receptor gene. The experimental approach of B1 receptor mRNA transcriptional regulation, protein synthesis, and maturation is illustrated, based on the biochemical (Northern blot) and functional analysis of isolated organs from rabbits injected with bacterial lipopolysaccharide or incubated in vitro with or without interleukin-1.

Is there a role for bradykinin in the therapeutic and side effects of angiotensin-converting enzyme inhibitors?

OBJECTIVE: To review critically the persistent suggestion that at least a part of the beneficial and side effects of angiotensin I converting enzyme inhibitors (ACEIs) is derived from the potentiation of endogenous bradykinin (BK). DATA SOURCES: Selected clinical studies of the pharmacology and analytical biochemistry of the kallikrein-kinin system, current literature on novel drugs binding to receptors for BK and angiotensin II, and a few animal studies when clinical data were not available. DATA EXTRACTION: Current concepts of the kallikrein-kinin system and related analytical/pharmacological tools are briefly reviewed and applied to the analysis of the role of endogenous kinins in the therapeutic and side effects of ACEIs. DATA SYNTHESIS: The development of effective BK antagonists is recent and provides novel opportunities to assess the role of BK in physiology and pathology. The role of BK as an inflammatory mediator is relatively well understood, and current drug development programs for kinin receptor agonists and antagonists are focused on the inflammatory pharmacological profile of kinins. The kallikrein-kinin system may not be active to a significant degree in normal individuals, but rather recruited during tissue injury or by specific physiological conditions (such as high sodium intake). The role of BK in some inflammatory/anaphylactoid side effects of ACEIs is not firmly established, but possible. The role of BK in the therapeutic effects of ACEIs depends on the model in animal studies and is likely to be modest in essential hypertension. CONCLUSION: Several methodological problems have delayed the progress of clinical research of the kallikrein-kinin system. While ACEIs clearly potentiate the tissue effects of exogenous BK, the role of endogenous BK in the normal and pathological circulation is still uncertain.

Selective labelling of bradykinin receptor subtypes in WI38 human lung fibroblasts.

1. Binding of the B1 bradykinin receptor radioligand, [3H]-des-Arg10-kallidin (-KD) and the B2 receptor radioligand [3H]-bradykinin (-BK) was investigated in membranes prepared from WI38 human foetal lung fibroblasts. 2. One-site analysis of the saturation data for [3H]-des-Arg10-KD gave an equilibrium dissociation constant (KD) value of 0.51 +/- 0.12 nM and a maximum receptor density (Bmax) of 260 +/- 49 fmol mg-1 of protein. [3H]-des-Arg10-KD binding was displaced by ligands in the order: des-Arg10-KD > KD > > des-Arg9[Leu8]-BK > des-Arg9-BK > Hoe 140 > > BK, implying that it was binding selectively to B1 receptors. 3. One-site analysis of the binding of [3H]-BK to W138 membranes indicated that it had a KD value of 0.25 +/- 0.06 nM and a Bmax of 753 +/- 98 fmol mg-1 of protein. The potencies for displacement of [3H]-BK binding were: Hoe 140 > > BK = KD > > > des-Arg10-KD = des-Arg9[Leu8]-BK = des-Arg9-BK, which was consistent with binding to B2 receptors. 4. This is the first characterization of [3H]-des-Arg10-KD binding to include both kinetic and equilibrium data, and demonstrates that [3H]-des-Arg10-KD has a high affinity for human B1 bradykinin receptors and is sufficiently selective to be used as a radioligand for B1 receptors in human cells or tissues expressing an excess of B2 BK receptors.

Renal bradykinin and vasopressin receptors: ligand selectivity and classification.

We studied the specific binding of radiolabeled bradykinin ([3H]BK) and vasopressin ([3H]AVP) to membrane preparations of bovine and porcine kidney medulla. [3H]BK reversibly labeled a single site (Kd = 1.06 nM) in bovine kidney medulla independently of [Mg2+]. The number of BK receptors in bovine kidney medulla, Bmax = 122 fmol/mg protein, is markedly (2- to 3-fold) higher than that reported in other tissues. Further characterization by ligand binding indicated that the bovine bradykinin receptor was the B2a subtype, pharmacologically related to B2a receptors expressed by human and rabbit tissues. In contrast, the specific binding of [3H]BK, but not [3H]AVP, to porcine kidney medulla (Kd = 0.32 nM, Bmax = 45 fmol/mg) was dependent upon the presence of enzyme inhibitors to prevent the rapid and selective degradation of bradykinin. Interspecies differences were revealed for renal medulla V2 vasopressin receptors with respect to their abundance and their affinity for several V2-selective ligands. In summary, (i) bovine kidney medulla is a convenient source of tissue for studying the B2a bradykinin receptor subtype; (ii) there are significant species-dependent differences in both the abundance of renal medulla B2a and V2 receptors and the ligand selectivity of V2 receptors; and (iii) these findings are significant in relation to the physiological and pathological roles of renal kinins and their interaction with the neurohypophysial peptide hormone system.

A pharmacological analysis of receptor subtypes and the mechanisms mediating the biphasic response induced by kinins in the rat stomach fundus in vitro.

Bradykinin (BK), des-Arg9-BK (DABK) and related kinins caused biphasic response (BR) in rat stomach fundus (RSF) precontracted with BaCl2. The B2 receptor antagonist HOE 140 (3-30 nM) produced parallel rightward shifts of the contractile concentration-response curve (CRC) for BK, yielding a pA(2) value of 9.07 +/- 0.27 and slope of 0.99, but caused only discrete rightward shift of the relaxant CRC for BK, leaving the BR CRC to DABK unaffected. The B1 receptor antagonist des-Arg9-NPC 17761 (10 nM to 1 microM) caused graded rightward shifts of the relaxant (but not the contractile) CRC to DABK, yielding a pA2 value of 8.35 +/- 0.05 and slope of 0.59, but had no effect on BK-induced BR. BK- and DABK- (100 nM) induced relaxation were almost suppressed by apamin (1 microM) or by nifedipine (1 nM), but were unaffected by nitric oxide synthase inhibitors, methylene blue, lipo and cyclooxygenase inhibitors, selective receptor antagonist for histamine (H1 and H2), nicotine, platelet activating factor, tachykinins (both NK1 and NK2, calcitonin gene-related peptide, vasoactive intestinal peptide and ganglion blocking agent. BK- and DABK-mediated relaxations were reduced in Ca2+ -free medium plus EGTA, although BK-mediated contraction was more resistant. Escherichia coli endotoxin treatment (10 microgram /rat), 24 hr before, potentiated DABK-induced relaxation, but not contraction, and reduced BK-mediated relaxation (P < .05). It is concluded that RSF express both B1 and B2 receptors. BK-induced contraction involves activation of B2 receptors, although DABK-induced relaxation is mediated by B1 receptors. Both B1 and B2 receptors in RSF are constitutive, but LPS treatment caused induction of B1 and down-regulation of B2 receptors. Finally, kinin-mediated relaxation in RSF are coupled to activation of Ca2+ activated K+ channels, and rely on Ca2+ influx via L-type voltage-sensitive channels.

Inhibition of RNA synthesis by bradykinin involves both the B1 and B2 receptor subtypes.

The efficacy of angiotensin converting enzyme inhibitors in the treatment of heart disease is due in part to the accumulation of bradykinin (BK). Since BK can exert its effect by influencing cell proliferation, we chose to study the effect of BK on the growth of A10 vascular smooth muscle cells. Ligand binding studies to determine which BK receptor subtypes are present on A10 cells showed that both B1 and B2 receptors were present in approximately equal numbers. Examination of RNA synthesis demonstrated that BK inhibits uridine incorporation in a dose-dependent manner. This decrease in RNA synthesis was blocked by both B1 and B2 receptor antagonists, as well as by addition of indomethacin, a cyclooxygenase inhibitor. The latter result suggested that prostaglandins mediate the biological actions of BK. Consequently, we examined the direct effect of two prostaglandins, PGE2 and PGI2 (prostacyclin), on A10 cells. PGE2 caused a decrease in RNA synthesis, thus mimicking the effect of BK, while PGI2 did not. Therefore, the inhibition of RNA synthesis in A10 vascular smooth muscle cells by BK requires both B1 and B2 receptor subtypes and this action of BK is apparently mediated by de novo synthesis of prostaglandins.

Effects of captopril and Icatibant on bradykinin (BK) and des [Arg9] BK in carrageenan-induced edema.

The effects of captopril, an angiotensin-converting enzyme inhibitor (ACEI), and a selective B2 kinin receptor antagonist (Icatibant) were examined on the paw edema and tissue contents of bradykinin (BK) and des[Arg9]BK following the intraplantar injection of carrageenan in rats. To this end, BK-like immunoreactivity (BK-LI) and des[Arg9]BK-LI were measured with highly sensitive and specific chemiluminescent enzyme immunoassays. Because pentobarbital significantly reduced the carrageenan-induced edema between 3 and 8 h, experiments were conducted in conscious rats. Icatibant (32.5 nmol/paw; intraplantar) significantly reduced carrageenan-induced paw edema between 3 and 8 h in captopril-untreated rats and at 1 and 3 h in captopril-treated rats (0.2 mg/kg x 5 days, per os). The paw content of BK-LI was increased 10-fold in captopril-untreated and 29-fold in captopril-treated rats 1 h after carrageenan injection. In parallel, des[Arg9]BK-LI was increased 8-fold in captopril-untreated and 24-fold in captopril-treated rats. Icatibant prevented the maximal increases in BK-LI and des[Arg9]BK-LI induced by carrageenan. It is concluded that inhibition of ACE by captopril enhanced the early production of endogenous BK and the edema formation induced by carrageenan through a B2 receptor-mediated mechanism. However, the B2 receptor does not appear to be involved in the late phase of the inflammatory response (from 5 to 24 h) to carrageenan in rats pretreated with ACEI. Although the concentrations of des[Arg9]BK were greater than those of BK, it is unlikely that B1 receptors play a significant role in this model of carrageenan-induced edema.

Identification of receptor ligands and receptor subtypes using antagonists in a capillary electrophoresis single-cell biosensor separation system.

A capillary electrophoresis system with single-cell biosensors as a detector has been used to separate and identify ligands in complex biological samples. The power of this procedure was significantly increased by introducing antagonists that inhibited the cellular response from selected ligand-receptor interactions. The single-cell biosensor was based on the ligand-receptor binding and G-protein-mediated signal transduction pathways in PC12 and NG108-15 cell lines. Receptor activation was measured as increases in cytosolic free calcium ion concentration by using fluorescence microscopy with the intracellular calcium ion indicator fluo-3-acetoxymethyl ester. Specifically, a mixture of bradykinin (BK) and acetylcholine (ACh) was fractionated and the components were identified by inhibiting the cellular response with icatibant (HOE 140), a selective antagonist to the BK B2 receptor subtype (B2BK), and atropine, an antagonist to muscarinic ACh receptor subtypes. Structurally related forms of BK were also identified based on inhibiting B2BK receptors. Applications of this technique include identification of endogenous BK in a lysate of human hepatocellular carcinoma cells (Hep G2) and screening for bioactivity of BK degradation products in human blood plasma. The data demonstrate that the use of antagonists with a single-cell biosensor separation system aids identification of separated components and receptor subtypes.

Pharmacology of kinin receptors: recent developments.

Fifteen years after the classification of kinin receptors into B1 and B2, both receptors have been shown to differ between species. New receptor types have been proposed and named B3, B4, and B5. However, it is not established whether different pharmacologic profiles describing B2 receptors in various species are indicative of different receptor types or of different subtypes (species dependent) subserving the same biological functions. To answer these questions, a systematic search of new pharmacologic tools was undertaken to find monoreceptor systems (isolated organs whose responses are contributed by a single receptor) as well as new selective agonists and competitive or noncompetitive antagonists. Classical pharmacologic experiments were performed in isolated organs for quantifying agonist activities in terms of pD2 and antagonist affinities in terms of pA2. Competitivity of antagonists was established from Schild plots. Results obtained in tissues from rabbits or guinea pigs indicate the existence of two different pharmacological entities, well characterized by selective agonists and competitive antagonists. In vivo experiments performed on anesthetized rabbits and guinea pigs have confirmed the B2 receptor heterogeneity between the two species. Correlations have been established between data obtained in rabbit and guinea pig tissues (biological assays) and in human receptors raised by genic transfection in Chinese hamster ovary (CHO) cells. A good correlation has been found between the IC50 values of kinins and derivatives to displace [3H]bradykinin from the membranes of CHO cells containing the human receptor and the pD2 or pA4 values of the same compounds in the rabbit jugular vein.

Bradykinin receptor subtypes in rat lung: effect of interleukin-1 beta.

We have characterized bradykinin (BK) receptors in the rat lung and studied the effect of recombinant human interleukin-1 beta (IL-1 beta) on BK receptors in vitro and in vivo. In lung membranes, saturation studies with [3]BK revealed a single class of specific and saturable binding sites. The BK B1 antagonist des-Arg9[Leu8]-BK was less effective in displacing [3H]BK binding sites from lung membranes. In contrast, the selective BK B2 antagonists, Hoe 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK) and NPC 567 (D-Arg-[Hyp3,D-Phe7]-BK) fully inhibited the binding of [3H]BK to lung membranes with Ki values of 96.7 +/- 17.8 pM and 9.0 +/- 2.5 nM, respectively. Intratracheal administration of 500 U of IL-1 beta induced airway hyper-responsiveness to inhaled BK and neutrophilia in bronchoalveolar lavage fluid 18 to 24 hr later. Compared to naive or saline-treated animals, IL-1 beta had no effect on [3H]BK binding characteristics at 4, 12 or 24 hr after IL-1 beta administration. Twenty-four hours after IL-1 beta instillation, there was no change in the affinity of the selective BK B1 or B2 antagonists when compared to control animals. In vivo, the selective BK B2 receptor antagonists, NPC 567 (3 mumol kg-1 i.v.) and Hoe 140 (100 nmol kg-1 i.v.), inhibited BK-induced increase in lung resistance, whereas the selective BK B1 antagonist, des-Arg9[Leu8]-BK (10 mumol kg-1 i.v.), was without effect. These data suggest that the action of BK in the rat lung is dependent mainly on the activation of the BK B2 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of a binding assay for the B1 receptors for kinins.

A novel binding assay to kinin B1 receptors was developed, based on the design of a high-affinity agonist ligand, [125I]Tyr-Gly-Lys-Aca-Lys-des-Arg9-BK. Binding to rabbit aortic smooth muscle cells is highly temperature-dependent (optimal at 37 degrees C); apparent binding equilibrium is reached within 30 min, and competition by kinin analogs reveals the expected correlation with the B1 receptor pharmacology. The dissociation constant (Kd) of the labeled ligand is approx. 0.2 nM and this value does not change significantly as a function of cytokine pretreatment. However, the receptor abundance (Bmax) is significantly increased (1.5-fold) by pretreating the cells with interleukin-1 (IL-1), while oncostatin M (OSM) produces a marginal increase of the Bmax. This assay may be useful in documenting the regulation of B1 receptors in pathology.

Early blockade of bradykinin B2-receptors alters the adult cardiovascular phenotype in rats.

We evaluated whether long-term inhibition of bradykinin B2-receptors by the long-acting antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140-treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet. Controls were given vehicle instead of Hoe 140. At 9 weeks of age, rats given Hoe 140 during prenatal and postnatal phases of life showed greater systolic pressures, heart rates, and body weights than controls (122 +/- 1 versus 113 +/- 1 mm Hg, 444 +/- 6 versus 395 +/- 8 beats per minute, 258 +/- 7 versus 213 +/- 3 g, respectively, P < .01), whereas urinary creatinine excretion was reduced (1.13 +/- 0.05 versus 1.36 +/- 0.04 mumol/100 g body wt in controls, P < .05). The difference in blood pressure (confirmed by direct intra-arterial measurement) persisted after 20 days of dietary sodium loading, whereas it was nullified by sodium restriction. In additional experiments, the offspring of untreated rats received Hoe 140 or vehicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140-treated rats compared with controls, and heart rate was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinins and kinin receptors in the nervous system.

Kinins, including bradykinin and kallidin, are peptides that are produced and act at the site of tissue injury or inflammation. They induce a variety of effects via the activation of specific B1 or B2 receptors that are coupled to a number of biochemical transduction mechanisms. In the periphery the actions of kinins include vasodilatation, increased vascular permeability and the stimulation of immune cells and peptide-containing sensory neurones to induce pain and a number of neuropeptide-induced reflexes. Mechanisms for kinin synthesis are also present in the CNS where kinins are likely to initiate a similar cascade of events, including an increase in blood flow and plasma leakage. Kinins are potent stimulators of neural and neuroglial tissues to induce the synthesis and release of other pro-inflammatory mediators such as prostanoids and cytotoxins (cytokines, free radicals, nitric oxide). These events lead to neural tissue damage as well as long lasting disturbances in blood-brain barrier function. Animal models for CNS trauma and ischaemia show that increases in kinin activity can be reversed either by kinin receptor antagonists or by the inhibition of kinin production. A number of other central actions have been attributed to kinins including an effect on pain signalling, both within the brain (which may be related to vascular headache) and within the spinal dorsal horn where primary afferent nociceptors can be stimulated. Kinins also appear to play a role in cardiovascular regulation especially during chronic spontaneous hypertension. Presently, however, direct evidence is lacking for the release of kinins in pathophysiological conditions of the CNS and it is not known whether spinal or central neurones, other than afferent nerve terminals, are sensitive to kinins. A more detailed examination of the effects of kinins and their central pharmacology is necessary. It is also important to determine whether the inhibition of kinin activity will alleviate CNS inflammation and whether kinin receptor antagonists are useful in pathological conditions of the CNS.