Biomedical subjects
Publications and source records attributed to F Gobeil.
Congenital complete atrioventricular block is quite rare, with usually a benign clinical evolution. However, because the first manifestation can be sudden death, it is important to evaluate patients and to establish clear prognostic criteria. A case of complete congenital atrioventricular block in a 38-year-old woman is presented to illustrate these criteria.
A comparative study has been performed in isolated organs and in anesthetized animals, rabbits, and guinea pigs, to evaluated the myotropic responses (in the organs) and the blood pressure changes (in the animals) induced by bradykinin (BK) and related peptides. Antagonist affinities have also been estimated in vitro in terms of PA2 and in vivo in terms of ID50, to characterize the kinin B2 receptors in the two species. Differences have been found both in the order of potency of agonists and in the affinity of antagonists: in fact, in the rabbit, [Hyp3]BK > [Aib7]BK, is the opposite order of what is found in the guinea pig, namely, [Aib7]BK < [Hyp3]BK, both in vitro and in vivo. Results obtained with antagonists also show important differences between the two species, since DArg[Hyp3, DPhe7, Leu8]BK is more active in the rabbit than in the guinea pig, while WIN-64338 is fairly active in the guinea pig and almost inactive in the rabbit. HOE-140, the long-acting antagonist of the B2 receptor, shows similar affinities in vitro in the two species. In another series of experiments, peptide degradation by angiotensin converting enzyme (ACE) has been investigated to see whether the differences of potency observed between certain peptides interacting with the B2 receptor were due to metabolic degradation. When incubated in the presence of pure ACE from rabbit lung, BK,[Hyp3]BK, and des Arg9BK are readily degraded, while [Aib7]BK, HOE-140, and DArg[Hyp3, DPhe7, Leu8]BK are not. When applied intravenously (i.v.), to obtain degradation by the lung, and intraarterially (i.a.), to avoid such degradation, the effect of BK (i.v.) is markedly reduced (compared with the effect i.a.), while no difference is observed for [Aib7]BK. Thus, despite its resistance to degradation by ACE, [Aib7]BK shows very little activity in the rabbit, suggesting that the major cause in the variation of affinities observed between kinin analogs is related to their pharmacodynamic properties. Taken together, the results speak strongly in favor of the existence of B2 receptor subtypes in the peripheral circulation of the rabbit and the guinea pig. Results obtained in vivo, both in pharmacological and biochemical experiments, are in accord with the findings obtained in isolated organs and with purified ACE enzyme.
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.
A systematic study has been performed in various segments of the intestine and in the urinary bladder of the mouse to identify tissues that respond to kinins and possess B1 and (or) B2 receptors. The stomach was found to contain B1 and B2 functional sites that show pharmacological profiles compatible with B1 and B2 receptors, whereas the urinary bladder possesses only B2 sites. Myotropic responses mediated by B1 receptors show slow onset and reversibility compared with responses evoked by the activation of B2 receptors. The order of potency of agonists is bradykinin (BK) > or = [Hyp3]BK > [Aib7]BK on the B2 of both the stomach and urinary bladder, while desArg9-BK is inactive. The order of potency of agonists on the B1 receptor is [Lys]desArg9BK < or = desArg9BK, while BK and the other B2 agonists are inactive. B2 antagonists of the first generation, such as DArg[Hyp3,DPhe7]BK, act as partial agonists and show residual agonistic activities higher than 0.5, while HOE-140 shows high affinity and very little residual agonistic activity; WIN 64338 is almost inactive. On the B1 receptor, classical antagonists, such as [Leu8]desArg9BK and Lys[Leu8]desArg9BK, act as partial agonists. A modification of their structures has led to a new compound (R-715) that shows fairly high affinity (pA2 7.0) and little residual agonistic effect. This compound has been used for B1 receptor characterization in the stomach. Residual agonistic activities of both B2 and B1 antagonists appear to be mediated by B2 and B1 receptors, respectively. Data presented in this paper provide the pharmacological basis for sensitive and selective preparations to be used for studying B1 and B2 receptors in the mouse.
Bradykinin, desArg9BK, some agonist analogues and several antagonists have been tested in isolated organs in order to identify bradykinin B2 receptor subtypes. The initial pharmacological characterization was made in the rabbit jugular vein and the guinea pig ileum, two widely used B2 preparations which have shown marked differences in their sensitivities to both agonists and antagonists. The study has then been extended to peripheral tissues (stomach, colon, urinary bladder) of four species (the rat, guinea pig, rabbit and man) and to isolated vessels (rabbit jugular vein, rabbit vena cava, guinea pig pulmonary artery, rat portal vein) in order to determine if pharmacologic receptor subtypes may be related to species. It has been shown that B2 receptors in rat and guinea pig tissues belong to a similar pharmacological entity, a receptor which is different from that mediating the responses of rabbit and human tissues. Agonists order of potency ([Hyp3]BK > BK > [Aib7]BK) obtained in the rabbit jugular vein is different from that found in the guinea pig ileum (BK < or = [Aib7]BK > [Hyp3]BK). Affinities of competitive antagonists (for instance DArg[Hyp3,DPhe7,Leu8]BK) in rabbit tissues are higher than in guinea pig and rat tissues by at least 2 log units, while the non peptidic compound WIN 64338 is more active (also by two log units) in guinea pig than in human and rabbit tissues. The non competitive long-acting antagonist HOE 140 is very potent and equally active in the four species. Some antagonists (peptides without unnatural residues, peptides with unnatural residues, non peptides) have been shown to be specific for kinin receptors and selective for the B2. Altogether, the present results a) confirm the existence of two B2 receptor subtypes, b) suggest that receptor subtypes may be species dependent and c) indicate that the B2 receptor subtype found in the rabbit is similar to that found in man.
The existence of two neurokinin NK-3 receptor subtypes has been suggested on the basis of results obtained in binding assays. In the present study, we have confirmed the two NK-3 receptor subtypes by using data obtained in both biological and binding assays. Experiments have been performed in the rat portal vein and in the guinea-pig ileum treated with NK-1 and NK-2 selective antagonists, namely CP 96345 and SR 48968. Orders of potency of agonists on the rat portal vein are as follows: for neurokinins, NKB > NKA > SP; for tachykinins, KAS > ELE > PHY; and for selective agonist: [MePhe7]NKB >> senktide. On the guinea-pig ileum, the agonist rank orders of potency are: NKB > SP > NKA, ELE > KAS > PHY; and for selective agonist: [MePhe7]NKB = senktide. The apparent affinity of antagonists shows differences in both biological and binding assays. In fact, on the rat portal vein, SR 48968 is almost inactive (pA2 or IC50 approximately 4.8), while R-486 [Trp7, beta Ala8]NKA(4-10) shows a pA2 value of 7.45 and an IC50 of 5.6. An opposite pattern of activity is observed in the guinea-pig ileum, where SR 48968 shows a pA2 of 6.05 and an IC50 of 6.7, while R-486 has a pA2 of 6.1 and an IC50 of < 5.0. These results confirm the existence of two NK-3 sites differing pharmacologically. It is proposed to name NK-3A the receptor of the guinea-pig ileum and NK-3B the receptor of the rat portal vein.
1. Using the classical pharmacological criteria recommended by Schild, namely the order of potency of selective agonists (e.g., bradykinin, desArg9-bradykinin, [Hyp3]BK and [Aib7]BK) and the apparent affinity of competitive antagonists (e.g., DArg[Hyp3,DPhe7,Leu8]BK and WIN 64338), we have attempted to characterize B2 receptor subtypes. It has been shown that vascular tissues (e.g., dog carotid and renal arteries, rabbit jugular vein and rabbit aorta) are very sensitive to kinin agonists and antagonists (pD2 and pA2 values for BK and HOE 140 on B2 receptors are 8.5-10.1 and 9.2-9.4, respectively, and for desArg9BK and desArg9[Leu8]BK on B1 receptors they are 7.3-8.6 and 7.3-7.8, respectively). Mechanisms of action of kinins differ between pharmacological preparations. Kinin may act directly on the smooth muscle (e.g., rabbit jugular vein and rabbit aorta) as well as indirectly through other endogenous mediators such as nitric oxide (EDRF) (e.g., dog carotid and renal arteries) and prostaglandins (e.g., dog renal artery). 2. Pharmacological analysis of rabbit jugular vein (RJV) and guinea pig ileum (GPI) has revealed different sensitivities to certain synthetic analogs of BK and to competitive B2 receptor antagonists between the two tissues. 3. Agonist order of potency ([Hyp3]BK > BK > [Aib7]BK) obtained for RJV differed from that obtained for GPI (BK > or = [Aib7]BK > [Hyp3]BK). Competitive antagonists such as DArg[Hyp3, DPhe7, Leu8]BK and WIN 64338 discriminate in favor of B2A (RJV) and B2B (GPI) receptor subtypes, respectively. These data demonstrate the existence of B2 receptor subtypes. Correlation between data obtained in the present study and those reported for binding to the human B2 receptor support the view that the human receptor is similar to that of the rabbit.
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Kinins exert a variety of biological actions and have been implicated in the pathogenesis of inflammation, pain, asthma, and other diseases. Kinins act through specific receptors that are widespread and belong to two major categories, B1 and B2. B2 has been cloned and shown to be of the rhodopsin type, consisting of seven hydrophobic membrane domains connected by extracellular and intracellular loops. Recent pharmacological findings from various laboratories suggest the existence of new receptor types, which have been named B3, B4, and B5. These findings are analysed critically, especially with respect to the criteria that have been used for affirming the existence of new receptor entities. The analysis is restricted to data obtained in isolated organs, almost exclusively smooth muscle preparations. Criteria for receptor characterization and classification are the order of potency of agonists and the apparent affinities of antagonists. The analysis reveals that receptors for bradykinin and related kinins are of two types, B1 and B2. B1 mediates the rapid acute response (smooth muscle contraction or relaxation) as well as some effects occurring more slowly (e.g., collagen synthesis). B1 receptor functions have been shown to be modulated by interleukins. B2 receptors are responsible for most of the kinins' biological effects, including arterial vasodilatation, plasma extravasation, venoconstriction, activation of sensory fibers (e.g., fibers for pain), and stimulation of the release of prostaglandins, endothelium-dependent relaxing factor (from endothelia), noradrenaline (from nerve terminals and adrenals), and other endogenous agents. The pharmacological characteristics of the receptor sites (B2) mediating this array of biological effects show differences between species, and two B2 receptor subtypes are proposed, namely B2A (rabbit, dog, and possibly man) and B2B (guinea pig, hamster, rat). B2A and B2B receptor subtypes have been characterized by using fairly selective agonists and competitive antagonists (e.g., D-Arg[Hyp3, D-Phe7,Leu8]BK). Noncompetitive antagonists (non-equilibrium), such as HOE 140, do not discriminate between B2A and B2B subtypes. Species differences cannot account for the multiplicity of receptors that have been proposed for rat vas deferens, pre- and post-junctional sites, and rat uterus, guinea pig ileum, and rat blood pressure. The existence of hypothetical new receptor sites was based on data obtained with partial agonists and have not been substantiated by data obtained with potent pure antagonists. The B3 receptor, proposed to explain the unusual behaviour of the guinea pig tracheal response to kinins, has to be carefully reconsidered after the finding that HOE 140 acts as a pure antagonist on this tissue and shows a fairly high affinity for the tracheal site.(ABSTRACT TRUNCATED AT 400 WORDS)
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Two new B1 receptor antagonists, [Hyp3,Thi5,DTic7,Oic8]desArg9-BK and DArg[Hyp3,Thi5,DTic7,Oic8]desArg9-BK were tested in vitro on the rabbit jugular vein and the guinea pig ileum (preparations containing B2 receptors) and on the rabbit aorta (preparation containing B1 receptors) for pharmacological characterization. The results indicate that both compounds are antagonists on both B1 and B2 receptors, are competitive and discriminate between B2A and B2B receptor subtypes.
Physiological and pathological effects of kinins result from the activation of specific receptors which are present in various organs. Kinin receptors have been characterized through studies on isolated organs in vitro and have been classified as B1 and B2. A careful analysis of B2 receptors led to the identification of two subtypes, namely B2rb (in the rabbit) and B2gp (in the guinea-pig). The distinction between B2rb and B2gp receptors is primarily based on differences in the activities of selective agonists and particularly on differences in affinities of competitive antagonists, namely DArg[Hyp3,DPhe7,Leu8]BK and the non-peptide compound, WIN 64338. The non-competitive antagonist, HOE 140, has shown the same affinity on B2rb and B2gp. The potential role of B1 and B2 receptors in physiopathology is analysed on data obtained with specific and selective antagonists of the B1 (desArg9[Leu8]BK) and B2 (HOE140) receptors. The therapeutic potential of endogenous kinins as mediators of the therapeutic beneficial effects of the angiotensin-converting enzyme inhibitors or the potential of the use of exogenous kinins in the vascular permeability are discussed together with the therapeutic potential of B1 and B2 receptor antagonists.