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CARDIOVASCULAR
Departments of Pharmacology (Y.H.), Anesthesiology and Critical Care Medicine (N.M., Y.T., S.G.), Cardiovascular Medicine (S.J., I.S.) and Cardiovascular Surgery (E.H.), Hokkaido University School of Medicine, Sapporo, Japan; Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan (M.K.); Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Tokushima, Japan (K.M., N.K., H.F.); and Department of Pharmacology, Weill Medical College of Cornell University, New York, New York (R.L.)
Received November 17, 2003; accepted January 29, 2004.
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Abstract |
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). The primary and direct actions of histamine in the heart are characterized by an increase in sinus rate and ventricular automaticity, a decrease in AV conduction velocity, and an increase in force of contraction (Levi et al., 1991; Hattori, 1999). Because histamine is present in high concentrations in cardiac tissues in most animal species, including humans (Bristow et al., 1982; Wolff and Levi, 1986), its release from cardiac stores and its subsequent actions on the heart may be of importance in pathological conditions associated with histamine release (Levi, 1988). In this context, we recently reported that superinduction of histamine receptor gene products and histamine overproduction contribute to the hemodynamic derangement characteristic of septic shock (Matsuda et al., 2002).
The negative dromotropic and positive chronotropic effects of histamine invariably result from the activation of H1 and H2 receptors, respectively (Levi et al., 1991; Hattori, 1999). In contrast, there is a marked species difference in the sub-type of histamine receptors mediating the positive inotropic effect. Moreover, different receptor subtypes mediate the inotropic effect in different parts of the heart within the same species. In the guinea pig heart, only H1 receptors are responsible for the positive inotropic effect of histamine in left atrium, whereas H2 receptors predominantly mediate its positive inotropic effect in ventricle (Steinberg and Holland, 1975; Verma and McNeill, 1977; Hattori et al., 1994). In contrast, in the rabbit heart, H2 receptors mediate the positive inotropic effect of histamine in left atrium, whereas H1 receptors are predominantly involved in the ventricle (Hattori et al., 1988, 1990, 1994). On the other hand, the positive inotropic effect of histamine in the human heart, whether in the atria or in the ventricle, is invariably blocked by cimetidine, and not by pyrilamine, indicating an exclusive H2 receptor involvement (Eckel et al., 1982; Du et al., 1993). In yet another mode, a positive inotropic response in the rat occurs only with very high concentrations of histamine and is blocked by propranolol or reserpine pretreatment, suggesting the involvement of adrenergic mechanisms (Laher and Mc-Neill, 1980).
Whether such species differences result from a different distribution of H1 and H2 receptors remains an open question. To date, the distribution of histamine receptors in different mammalian tissues has been studied with selective radioligands for each receptor subtype. Yet, these studies have been hampered by high nonspecific binding and/or significant binding to secondary nonhistamine-receptor sites (Chang et al., 1979; Hill and Young, 1980; Foreman et al., 1985; Rising and Norris, 1985; Liu et al., 1992). Thus, many of the radioligands used to label H1 and H2 receptors seem to be of limited value for an accurate estimate of the distribution and molecular characteristics of cardiac histamine receptors (Hattori et al., 1991, 1994).
In recent years, the genes encoding each of the H1 and H2 receptor subclasses have been cloned (Gantz et al., 1991b; Yamashita et al., 1991a; Fujimoto et al., 1993; Horio et al., 1993; Traiffort et al., 1995), and the amino acid sequence and structure of their proteins have been elucidated. Thus, the application of molecular biology techniques to the study of histamine receptor subtypes has enabled us to assess by Northern and Western blotting the expression of their mRNAs and proteins in the heart. In the present study, we analyzed the gene and protein expression levels of H1 and H2 receptors in atria and ventricles from guinea pig, rabbit, rat, and human hearts. Furthermore, we used immunocytochemical techniques to examine the regional expression of H1 and H2 receptor proteins in the sinus node, AV conduction system, and surrounding myocardium of the guinea pig heart.
We report evidence from Northern and Western blot studies that cardiac histamine H1 and H2 receptors are variably distributed not only among different mammalian species but also in different regions of the heart and that H2 receptors are abundantly expressed in human atrial and ventricular myocardium.
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Materials and Methods |
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Right atrial tissue was obtained from patients undergoing aorta-coronary bypass surgery; these patients had no heart failure, or only a moderate form of it, as measured by echocardiography. Also, portions of left ventricle were excised from patients with moderate heart failure during surgical resection of left ventricular aneurysms. The apex of the left temporal lobe of the brain was taken from patients undergoing internal decompression after subarachnoid hemorrhage with severe cerebral edema. Written informed consent was obtained for use of organs in research from patients undergoing cardiac surgery, or in the case of neurosurgery, from their relatives.
Northern Blot Analysis. Total RNA was extracted from tissues by the guanidinium thiocyanate-phenol-chloroform method with Isogen (Nippon Gene, Toyama, Japan) used routinely in our laboratory (Matsuda et al., 1999). RNA purity was determined by the ratio of optical density measured at 260 and 280 nm (OD260/OD280), and RNA quantity was estimated at OD260.
RNA (30 µg/lane) was subjected to electrophoresis on agarose/formaldehyde gels and then transferred to a Hybond-N+ nylon membrane (Amersham Biosciences UK, Ltd., Little Chalfont, Buckinghamshire, UK). The membrane was prehybridized in prewarmed rate-enhanced hybridization buffer (Rapid-hyb buffer; Amersham Biosciences UK, Ltd.) at 65°C for 60 min. The amino acid sequence of the human histamine H1 receptor displays an 81 and 75% homology with the rat and guinea pig receptors, respectively. The comparison of the amino acid sequence of the human histamine H2 receptor with that of the rat and guinea pig H2 receptors revealed an overall identity of 85 and 86%, respectively. The molecular cloning of the rabbit H1 and H2 receptors has not been yet reported, but their amino sequences would be predicted to show high homology with those of other rodents. We thus used guinea pig H1 receptor cDNA (Horio et al., 1993) and the rat H1 receptor cDNA (Fujimoto et al., 1993), both of which were kindly provided by Prof. E. Senba (Department of Anatomy, Wakayama Medical College, Wakayama, Japan). The human H2 receptor cDNA (accession no. NM_022304
[GenBank]
) was isolated from gel after electrophoretic separation of the products that were amplified by the PCR using two oligodeoxynucleotide primers (sense, 5'-CTCTACCGCATGCAAGATCA-3'; and antisense, 5'-CCCCAGGTGGATAGACAGAA-3') (Matsuda et al., 2002). The cDNA probes were radiolabeled using a random primer labeling system (Rediprime; Amersham Biosciences UK, Ltd.) in the presence of [32P]dCTP (6000 Ci/mmol; Amersham Biosciences). The blot was washed in 2x standard saline citrate/0.1% SDS at room temperature for 10 min and in 1x standard saline citrate/0.1% SDS twice at 65°C for 5 min. The histamine H1 or H2 receptor mRNA was quantified by counting the radioactivity using a bioimaging analyzer (Fujix BAS 2000; Fuji Photo Film, Tokyo, Japan), as described previously (Matsuda et al., 1999). Ethidium bromide staining was used as a control to verify gel loading, and the expression of H1 or H2 receptor mRNA was normalized as the ratio of the H1 or H2 receptor mRNA over 28 S ribosomal RNA.
Antibody Specificity to Histamine Receptors. The coding regions of the human H1 receptor gene and of the human H2 receptor gene were subcloned into a pBluescript SK(+) vector (Stratagene, La Jolla, CA). Then, nucleotide sequences that encoded 10-amino acid peptides (EQKLISEEDL) of the human c-myc epitope were inserted between the amino-terminal initiator methionine and the second amino acid of the human H1 or H2 receptor by PCR. PCR was carried out with the following primers using pBluescript vectors containing the human H1 or H2 receptor gene as template. Primary pairs (forward, 5'-GCGGCCGCATGGAGCAAAAGCTCATCAGTGAGGAAGACCTAAGCCTCCCCAATTCCTGCCTC-3'; and reverse, 5'-GCGGCGGCTAACCTCGCTTATACGTCTTAAGA-3') were used for the H1 receptor. Primary pairs (forward, 5'-GCGGCCGCATGGAGCAAAAGCTCATCAGTGAGGAAGACCTAGCACCCAATGGAACAGCCTCT-3'; and reverse, 5'-GCGGCGGCTAATGGACAGACACCGAGGGACCC-3') were used for the H2 receptor. The resulting PCR products were digested and ligated into the pBluescript vectors. The entire coding region, including the epitope tag, was sequenced and transferred into a mammalian expression vector, pdKCR-dhfrs. CHO cells deficient in dihydrofolate reductase were transfected with the plasmid constructs using the calcium phosphate precipitation method (Fujimoto et al., 1993). Cells were cultured in a-minimum essential medium without ribonucleosides and deoxyribonucleosides (Invitrogen, Carlsbad, CA) supplemented with 10% fetal calf serum. After 2 weeks of incubation, individual colonies were transferred to new plates.
Viewed by immunostaining, CHO cells were confirmed as being successfully transfected with the plasmid-containing the H1 or H2 receptor by the expression of c-myc. Transfected CHO cells expressing the H1 and H2 receptor proteins were stained with anti-human H1 and H2 receptor rabbit polyclonal antibody (Chemicon International, Temecula, CA) used in this study. However, control cells that were subjected to the transfection procedure with no plasmid present showed no reactivity with these antibodies. The specificity of the histamine receptor antibodies was also certified in transfected cells by Western blot (Fig. 1). Therefore, these data confirmed that anti-human H1 and H2 receptor antibodies were specific to the H1 and H2 receptor proteins, respectively.
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Western Blot Analysis. Samples of tissue homogenate (20 µg) were run on SDS-polyacrylamide gel electrophoresis (14% polyacrylamide gel), and electrotransferred to a polyvinylidene difluoride filter membrane. To reduce nonspecific binding, the membrane was preincubated for 60 min at room temperature in PBS (137 mM NaCl, 2.7 mM KCl, 8.1 mM Na2HPO4, and 1.5 mM KH2PO4) containing 1% bovine serum albumin. The membranes were then incubated overnight 4°C with anti-histamine receptor antibody at 1:500 dilution in PBS (10 µg/ml). After extensive washing with in PBS containing 0.05% Tween 20, the membrane was incubated with horseradish peroxidase-conjugated anti-rabbit antibody (1:6000 dilution; Bio-Rad Laboratories, Hercules, CA) for 60 min at room temperature. The blots were washed twice in PBS-Tween buffer and subsequently visualized with an enhanced chemiluminescence detection system (Amersham Biosciences), exposed to X-ray film, and analyzed by NIH Image Software produced by Wayne Rasband (National Institutes of Health, Bethesda, MD). To check for protein loading/transfer variations, all blots were stained with Ponceau red (washable, before incubation with antibodies) and with Coomassie Brilliant Blue (permanent, after the enhanced chemiluminescence detection system). Intensity of total protein bands per lane was evaluated by densitometry. Loading/transfer variation between samples was negligible.
Immunohistochemistry. For immunohistochemical determination of histamine receptors, tissue specimens were fixed in 10% buffered-formalin solution, dehydrated, and then embedded in paraffin. The preparations were cut in 5-µm sections, deparaffinized, and treated for 10 min with citrate buffer (10 mM citric acid; pH 6.0) in a microwave oven (750 W) before immunostaining. Endogenous peroxidase activity was quenched by incubation in 3% hydrogen peroxide for 7 min. After incubation with primary antibodies overnight at 4°C, the sections were washed with PBS and exposed to DAKO EnVision, Peroxidase, Rabbit (DAKO, Carpinteria, CA) for 30 min at room temperature. Slides were rinsed in PBS, incubated with DAKO Liquid DAB Large Volume Substrate-Chromogen System (DAKO), rinsed gently with distilled water, and counterstained. Coverslips were mounted with malinol (Muto Pure Chemicals, Tokyo, Japan). The specificity of immunoreactivity was confirmed by negative controls in which nonimmune IgG was used instead of the primary antibodies.
Immunofluorescent Staining. After overnight incubation with each primary antibody as mentioned above, the sections were exposed to the fluorescent secondary antibody, Cy3-conjugated AffiniPure anti-rabbit IgG or fluorescein-conjugated AffiniPure goat anti-rabbit IgG (Jackson ImmunoResearch Laboratories Inc., Westgrove, PA), for 2 h according to the manufacturer's instructions. Samples processed without primary antibodies served as negative controls. Coverslips were mounted with Immunon (Thermo Shandon, Pittsburgh, PA). Immunofluorescent images were observed under a laser scanning confocal imaging system (MRC-1024; Bio-Rad, Hemel Hempstead, UK).
Data Analysis. All values are expressed as mean ± S.E.M. of n observations, where n represents the number of animals or patients. The results were examined by Student's t test or one-way analysis of variance with repeated measurements followed by Bonferroni's multiple comparison test when appropriate.
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Northern blot analysis using the H2 receptor probe revealed a major mRNA species of 3.2 kb in guinea pig and rabbit tissues (Fig. 4, A and B). In rat and human tissues, however, 7 kb H2 receptor mRNA was also detected (Fig. 4, C and D). In the guinea pig, H2 receptor mRNA expression was much higher in ventricle than in atrium (Figs. 4A and 5A). Its expression level was 26% in atrium and 64% of the cerebral level in ventricle. In contrast, in the rabbit, H2 receptor mRNA expression was higher in the atrium than in the ventricle (Figs. 4B and 5B). The levels of the H2 receptor mRNA were 66 and 30% of the cerebral level in atrium and ventricle, respectively. In the rat, the H2 receptor transcripts were less abundantly expressed in both atrial and ventricular tissues (Figs. 4C and 5C). Compared with the H2 receptor transcript level in cerebral tissue, the levels in atrial and ventricular tissues were 17 and 23%, respectively. In the human, a considerable expression level of the H2 receptor transcripts was detected in myocardial tissues (Figs. 4D and 5D). Thus, atrial and ventricular tissues showed 68 to 94% and 43 to 71% of the H2 receptor transcript levels in cerebral tissue, respectively.
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Histamine Receptor Protein Expression. Immunological detection of the histamine H1 receptor was performed using a anti-human H1 receptor polyclonal antibody, which recognized a 57-kDa band in mammalian cerebral and myocardial tissues (Fig. 6). In the guinea pig, the band was evidently lighter in ventricle than in atrium and cerebrum (Fig. 6A). Densitometric quantification of the signal showed that the H1 receptor protein level was 86% in atrium and 65% in ventricle compared with the cerebral level (Fig. 7A). In the rabbit, the atrial band was very faint, and the ventricular band was modest but clearly evident (Fig. 6B). Quantitative analysis revealed that the atrial and ventricular levels of the H1 receptor protein were 10 and 38% of the cerebral level, respectively (Fig. 7B). In the rat, the protein bands were intensely labeled in both atrial and ventricular tissues (Fig. 6C). Thus, the relative amount of immunodetectable H1 receptor, as determined by densitometric scanning, was more than 70% of the cerebral level in these tissues (Fig. 7C). In the human, the H1 receptor protein was much less abundant in myocardial tissues compared with cerebral tissue (Fig. 6D). Quantitative analysis of immunoblots showed that the amounts of atrial and ventricular H1 receptor protein were only 4 and 15% of the cerebral level, respectively (Fig. 7D).
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Immunoblot analysis using anti-human H2 receptor polyclonal antibody showed a single protein band with a molecular mass of 69 kDa in mammalian cerebral and myocardial tissues (Fig. 8). In the guinea pig, the band was markedly less in atrium than in ventricle and cerebrum (Fig. 8A). Quantification of the H2 receptor protein indicated that the protein levels in atrial and ventricular tissues were 21 and 64% of the cerebral level, respectively (Fig. 9A). In the rabbit, the atrial band was apparently darker than the ventricular band, although it was not so marked in comparison with the cerebral band (Fig. 8B). On scanning these bands, the atrial and ventricular levels were 67 and 30% of the cerebral level, respectively (Fig. 9B). In the rat, the H2 receptor protein signal was marginally visible in myocardial tissues (Fig. 8C). Densitometric analysis revealed that the H2 receptor protein levels in atrial and ventricular tissues were 13 and 15% of the cerebral level, respectively (Fig. 9C). In the human, immunodetectable H2 receptor was found at high levels in both atrial and ventricular tissues (Fig. 8D). Compared with the cerebrum, the atrial and ventricular expression levels of the H2 receptor protein were 79 and 70%, respectively (Fig. 9D).
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As can be seen in Fig. 10, immunofluorescence studies confirmed the results obtained from Western blotting. Thus, immunofluorescence staining for H1 receptor protein in the guinea pig heart showed that its expression was high in the atrial tissue and low in the ventricular tissue. About 83% of cells in the atrium and 50% of cells in the ventricle showed positive immunoreactivity for the H1 receptor. In contrast, positive staining for H2 receptor protein was strong in the ventricle, but weak in the atrium: 90% of ventricular cells and only 45% of atrial cells showed positive staining for H2 receptors.
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Identification of Histamine Receptors on the Specialized Conductive Tissue of the Heart. Immunohistochemical studies showed abundant expression of both H1 and H2 receptor proteins in the SA node in the guinea pig heart (Fig. 11). Furthermore, the AV node seemed to equally express H1 and H2 receptor proteins (Fig. 12).
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Discussion |
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57 and 69 kDa, respectively.
Photoaffinity binding studies using [125I]iodoazidophenpyramine and subsequent SDS-polyacrylamide gel electrophoresis analysis had previously indicated that the H1 receptor protein has a molecular mass of 56 kDa under reducing conditions in rat, guinea pig, and mouse brain (Ruat and Schwartz, 1989). Similarly, studies in bovine adrenal medulla membranes with the photoaffinity ligand [3H]azidobenzamide had found labeled peptides in the size range of 53 to 58 kDa (Yamashita et al., 1991b). Moreover, when the bovine adrenal medulla H1 receptor had been expression-cloned in Xenopus oocytes, it was deduced to correspond to a 491-amino acid protein with a calculated molecular mass of 56 kDa (Yamashita et al., 1991a). Thus, the molecular mass for the H1 receptor estimated in this study is comparable with those noted in the previous reports.
On the other hand, the molecular mass of 69 kDa obtained for the H2 receptor is considerably larger than the previously calculated molecular masses (40.2-40.5 kDa) for the cloned H2 receptors (Gantz et al., 1991a; Ruat et al., 1991; Traiffort et al., 1995; Kobayashi et al., 1996). This difference could be explained by glycosylation of the native H2 receptor. Indeed, cloned H2 receptor protein carries N-glycosylation sites in the N terminus region (Gantz et al., 1991a,b; Ruat et al., 1991; Traiffort et al., 1995).
We found that the expression levels of H1 and H2 receptor proteins in cardiac tissues from each mammalian species correlated with their mRNA expression levels, as determined by Northern blot analysis. This correlation implies that the expression of H1 and H2 receptors in the mammalian heart is regulated in a transcriptional manner. Northern blot analysis of cardiac and cerebral tissues from the four mammals, including human, revealed two hybridizing forms of mRNA for the H1 receptor, 3.3- and 3.9-kb transcripts. These transcripts may correspond to the use of distinct start sites in the 5' region of the gene or distinct polyadenylation sites or, alternatively, to products of distinct genes (Traiffort et al., 1994). Northern blot analysis of H2 receptor mRNA identified a single transcript of 3.2 kb in guinea pig and rabbit cardiac and cerebral tissues, whereas the second higher molecular mass species of 7 kb was clearly evidenced in rat and human tissues. Although hybridization in most previous studies indicated the presence of a single H2 receptor transcript of 4.6 to 6 kb (Ruat et al., 1991; Traiffort et al., 1995; Karlstedt et al., 2001), it is interesting to note that, although not addressed by the authors, an earlier study had shown the presence of several H2 receptor transcripts on Northern blots from various canine tissues (Gantz et al., 1991b).
In guinea pigs, we found H1 receptors to be expressed in the heart at a relatively high level, mainly in the atrium and less in the ventricle, compared with their abundant expression in the brain. In contrast, H2 receptors were abundant in the ventricle and slightly expressed in the atria. Conversely, in rabbits, H2 receptors seemed to be the predominant histamine-receptor subtype in the atrium, with much less H1 receptor expression; whereas the ventricle expressed an abundance of H1 receptors and much less H2 receptors.
Indeed, previous pharmacological studies had indicated a marked difference between guinea pig and rabbit hearts in terms of which receptor subtypes mediate the positive inotropic effect of histamine in left atrium and ventricle. Although the positive inotropic effect of histamine in the left atrium of the rabbit is exclusively mediated by H2 receptors (Hattori et al., 1988), in the guinea pig, the positive inotropic effect in the left atrium is mediated entirely by H1 receptors (Steinberg and Holland, 1975; Verma and McNeill, 1977). On the other hand, in guinea pig ventricular muscle, the positive inotropic effect of histamine is mediated predominantly by H2 receptors (Hattori et al., 1994), whereas H1 receptors almost exclusively mediate the inotropic effect in the rabbit ventricle (Hattori et al., 1990, 1994). Thus, the particular distribution of H1 and H2 receptors in guinea pig and rabbit myocardial tissues that we report here, well explains previous pharmacological findings.
In the rat heart, H2 receptors were present at a rather low level both in the atrium and ventricle; in contrast, the expression of H1 receptors was significant in both tissues. Yet, in the rat heart, histamine is known to cause a weak positive inotropic effect and only at very high concentrations. Notably, this inotropic effect is attenuated by 
-blockers rather than by H1 receptor antagonists (Laher and McNeill, 1980; Levi et al., 1991). Although this suggest that the weak positive inotropic response in the rat heart may result from catecholamine release, it is also conceivable that in the rat heart H1 receptors are weakly coupled to their transduction pathways.
In human atrial and ventricular tissue, H1 receptor expression was less abundant, whereas H2 receptors were richly expressed. This is the first study showing that H2 receptors are present as the predominant histamine receptor subtype in the human heart at both mRNA and protein levels, using Northern and Western blot analysis. The present data are also in good agreement with the previous functional reports that histamine produces a positive inotropic effect in human atrial and ventricular muscles, likely due to the exclusive activation of H2 receptors (Eckel et al., 1982; Levi et al., 1991; Du et al., 1993).
Our immunohistochemical studies clearly show the presence of both H1 and H2 receptors in the SA and AV nodes of the guinea pig heart. Indeed, pharmacological evidence for the presence of H2 receptors in the SA node was already strong. In fact, a sinus rate increase in response to histamine had been demonstrated in isolated hearts from guinea pigs, rabbits, and cats, and in isolated right atria from guinea pigs, rabbits, and monkeys (Levi et al., 1991; Hattori, 1999). In these preparations, the histamine-induced increase in sinus rate was selectively and competitively antagonized by H2 receptor antagonists such as cimetidine, indicating that H2 receptors that are present in the SA node primarily mediate the positive chronotropic effect of histamine. On the other hand, it is not clear at this time what role, if any, is played by the H1 receptors present in the SA node.
In the guinea pig heart, histamine is known to impair AV conduction (Levi, 1972; Levi and Kuye, 1974). This negative dromotropic effect is effectively abolished by H1 receptor antagonists and is mimicked by selective H1 receptor agonists (Levi et al., 1975), suggesting that H1 receptors mediate the histamine-induced slowing of AV conduction. However, histamine may also enhance automaticity in the AV node. Electrophysiological experiments using AV node preparations from the rabbit and guinea pig have indicated that H2 receptors promoting an increase in automaticity are likely to exist in the AV node (Borchard and Hafner, 1986; Sanchez-Chapula and Elizalde, 1987). Therefore, our immunohistochemical data demonstrating the presence of both H1 and H2 receptors in the AV conduction system are in good agreement with the results of previous pharmacological studies.
In conclusion, we provide here for the first time evidence from Northern and Western blot studies that histamine H1 and H2 receptors are variably distributed not only among different mammalian species but also in different regions of the heart. Notably, these novel molecular findings agree with previous pharmacological results obtained in whole animal and isolated tissue experiments. With the exception of the rat heart, where pharmacological responses are apparently dissociated from the abundant expression of H1 receptors, and where adrenergic mechanism may also play a role, we find that in guinea pig, rabbit, and human heart the expression level of H1 and H2 receptors clearly determines the functional response to histamine. The fact that a highly abundant expression of H2 receptors was found in human atrial and ventricular myocardium, substantiates our previous evidence of histamine arrhythmogenicity in the human heart in various disease states (Levi et al., 1981; Wolff and Levi, 1986; Levi, 1988). Moreover, we recently reported that endotoxin-induced sepsis results in a dramatic increase in the expression of H1 and H2 receptor and histidine decarboxylase genes in the cardiovascular system, causing a marked increase not only in the production of histamine but also in its effects (Matsuda et al., 2002). These changes may well contribute to the cardiovascular deterioration associated with sepsis in humans. The new knowledge of a differential distribution of histamine receptor subtypes in the human heart will foster a better understanding of histamine roles in cardiovascular pathophysiology and possibly contribute to new therapeutic approaches to histamine-induced cardiac dysfunctions.
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ABBREVIATIONS: AV, atrioventricular; PCR, polymerase chain reaction; CHO, Chinese hamster ovary; PBS, phosphate-buffered saline; SA, sinoatrial.
Address correspondence to: Dr. Yuichi Hattori, Department of Pharmacology, Hokkaido University, School of Medicine, Sapporo 060-8638, Japan. E-mail: yhattori{at}med.hokudai.ac.jp
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References |
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Borchard U and Hafner D (1986) Electrophysiological characterization of histamine receptor subtypes in mammalian heart preparations. Naunyn-Schmiedeberg's Arch Pharmacol 334: 294-302.[CrossRef][Medline]
Bristow MR, Ginsburg R, and Harrison DC (1982) Histamine and the human heart: the other receptor system. Am J Cardiol 49: 249-251.[CrossRef][Medline]
Chang RSL, Tran VT, and Snyder SH (1979) Characteristics of histamine H1-receptors in peripheral tissues labeled with [3H]mepyramine. J Pharmacol Exp Ther 209: 437-442.
Dale HH and Laidlaw PP (1910) The physiological action of beta-imidazolylethylamine. J Physiol (Lond) 41: 318-344.
Du XY, Schoemaker RG, Bax WA, Bos E, and Saxena PR (1993) Effects of histamine on porcine isolated myocardium: differentiation from effects on human tissue. J Cardiovasc Pharmacol 22: 468-473.[Medline]
Eckel L, Gristwood RW, Nawrath H, Owen DAA, and Satter P (1982) Inotropic and electrophysiological effects of histamine on human ventricular heart muscle. J Physiol (Lond) 330: 111-123.
Foreman JC, Norris DB, Rising TJ, and Webber SE (1985) The binding of [3H]tiotidine to homogenates of guinea-pig lung parenchyma. Br J Pharmacol 86: 475-482.[Medline]
Fujimoto K, Horio Y, Sugama K, Ito S, Liu YQ, and Fukui H (1993) Genomic cloning of the rat histamine H1 receptor. Biochem Biophys Res Commun 190: 294-301.[CrossRef][Medline]
Gantz I, Munzert G, Tashiro T, Schäffer M, Wang L, and Yamada T (1991a) Molecular cloning of the human histamine H2 receptors. Biochem Biophys Res Commun 178: 1386-1392.[CrossRef][Medline]
Gantz I, Schäffer M, DelValle J, Logsdon C, Campbell V, Uhler M, and Yamada T (1991b) Molecular cloning of a gene encoding the histamine H2 receptor. Proc Natl Acad Sci USA 88: 429-433.
Hattori Y (1999) Cardiac histamine receptors: their pharmacological consequences and signal transduction pathways. Methods Find Exp Clin Pharmacol 21: 123-131.[CrossRef][Medline]
Hattori Y, Endou M, Gando S, and Kanno M (1991) Identification and characterization of histamine H1- and H2-receptors in guinea-pig left atrial membranes by [3H]-mepyramine and [3H]-tiotidine binding. Br J Pharmacol 103: 1573-1579.[Medline]
Hattori Y, Gando S, Nagashima N, and Kanno M (1994) Histamine receptors mediating a positive inotropic effect in guinea pig and rabbit ventricular myocardium: distribution of the receptors and their possible intracellular coupling processes. Jpn J Pharmacol 65: 327-336.[Medline]
Hattori Y, Nakaya H, Endou M, and Kanno M (1990) Inotropic, electrophysiological and biochemical responses to histamine in rabbit papillary muscles: evidence for coexistence of H1- and H2-receptors. J Pharmacol Exp Ther 253: 250-256.
Hattori Y, Sakuma I, and Kanno M (1988) Differential effects of histamine mediated by histamine H1- and H2-receptors on contractility, spontaneous rate and cyclic nucleotides in the rabbit heart. Eur J Pharmacol 153: 221-230.[CrossRef][Medline]
Hill SJ and Young JM (1980) Histamine H1-receptors in the brain of the guinea-pig and the rat: differences in ligand binding properties and regional distribution. Br J Pharmacol 68: 687-696.[Medline]
Horio Y, Mori Y, Higuchi I, Fujimoto K, Ito S, and Fukui H (1993) Molecular cloning of the guinea-pig histamine H1 receptor gene. J Biochem 114: 408-414.
Karlstedt K, Senkas A, Åhman M, and Panula P (2001) Regional expression of the histamine H2 receptor in adult and developing rat brain. Neuroscience 102: 201-208.[CrossRef][Medline]
Kobayashi T, Inove I, Jenkins NA, Gilbert DJ, Copeland NG, and Watanabe T (1996) Cloning RNA expression and chromosomal location of a mouse histamine H2-receptor gene. Genomics 37: 390-394.[CrossRef][Medline]
Laher IE and McNeill JH (1980) Effects of histamine on rat isolated atria. Can J Physiol Pharmacol 58: 1256-1261.[Medline]
Levi R (1972) Effects of exogenous and immunologically released histamine on the isolated heart: a quantitative comparison. J Pharmacol Exp Ther 182: 227-238.
Levi R (1988) Cardiac anaphylaxis: models, mediators, mechanisms and clinical considerations, in Human Inflammatory Disease, Clinical Immunology (Marone G, Lichtenstein LM, Condorelli M, and Fauci AS eds) pp 93-105, BC Decker Inc., Toronto, ON, Canada.
Levi R, Capurro N, and Lee C-H (1975) Pharmacological characterization of cardiac histamine receptors: sensitivity to H1- and H2-receptor agonists and antagonists. Eur J Pharmacol 30: 328-335.[CrossRef][Medline]
Levi R and Kuye JO (1974) Pharmacological characterization of cardiac histamine receptors: sensitivity to H1-receptor antagonists. Eur J Pharmacol 27: 330-338.[CrossRef][Medline]
Levi R, Malm JR, Bowman FO, and Rosen MR (1981) The arrhythmogenic actions of histamine on human atrial fibers. Circ Res 49: 545-550.
Levi R, Rubin LE, and Gross SS (1991) Histamine in cardiovascular function and dysfunction: recent developments, in Handbook of Experimental Pharmacology, Vol. 97 Histamine and Histamine Antagonists (Uvnäs B ed) pp 347-383, Springer, Berlin.
Liu YQ, Horio Y, Mizuguchi H, Fujimoto K, Imamura I, Abe Y, and Fukui H (1992) Re-examination of 3H-mepyramine binding assay for histamine H1-receptor using quinine. Biochem Biophys Res Commun 189: 378-384.[CrossRef][Medline]
Matsuda N, Hattori Y, Gando S, Akaishi Y, Kemmotsu O, and Kanno M (1999) Diabetes-induced down-regulation of 1-adrenoceptor mRNA expression in rat heart. Biochem Pharmacol 58: 881-885.[CrossRef][Medline]
Matsuda N, Hattori Y, Sakuraya F, Kobayashi M, Zhang X-H, Kemmotsu O, and Gando S (2002) Hemodynamic significance of histamine synthesis and histamine H1- and H2-receptor gene expression during endotoxemia. Naunyn-Schmiedeberg's Arch Pharmacol 366: 513-521.[CrossRef][Medline]
Rising TJ and Norris DB (1985) Histamine H2-receptor radioligand binding studies, In Frontiers in Histamine Research, Advances in the Biosciences (Ganellin CR and Schwartz JC ed) pp 61-67, Pergamon, New York.
Ruat M and Schwartz JC (1989) Photoaffinity labeling and electrophoretic identification of the H1-receptor: comparison of several brain regions and animal species. J Neurochem 53: 335-339.[CrossRef][Medline]
Ruat M, Traiffort E, Arrang JM, Leurs R, and Schwartz JC (1991) Cloning and tissue expression of a rat histamine H2-receptor gene. Biochem Biophys Res Commun 179: 1470-1478.[CrossRef][Medline]
Sanchez-Chapula J and Elizalde A (1987) Characterization of the effects of histamine on the transmembrane electrical activity of guinea-pig and rabbit SA- and AV-node cells. Naunyn-Schmiedeberg's Arch Pharmacol 336: 218-223.[CrossRef][Medline]
Steinberg MI and Holland DR (1975) Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atria. Eur J Pharmacol 34: 95-104.[CrossRef][Medline]
Traiffort E, Leurs R, Arrang JM, Tardivel-Lacombe J, Diaz J, Schwartz J-C, and Ruat M (1994) Guinea pig histamine H1 receptor. I. Gene cloning, characterization and tissue expression revealed by in situ hybridization. J Neurochem 62: 507-518.[Medline]
Traiffort E, Vizuete ML, Tadivellacombe J, Souile E, Schwartz JC, and Ruat M (1995) The guinea-pig histamine H2 receptor-gene cloning, tissue expression and chromosomal localization of its human counterpart. Biochem Biophys Res Commun 211: 570-577.[CrossRef][Medline]
Verma SC and McNeill JH (1977) Cardiac histamine receptors: differences between left and right atria and ventricle. J Pharmacol Exp Ther 200: 352-362.
Wolff AA and Levi R (1986) Histamine and cardiac arrhythmias. Circ Res 58: 1-16.
Yamashita M, Fukui H, Sugama K, Horio Y, Ito S, Mizoguchi H, and Wada H (1991a) Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc Natl Acad Sci USA 88: 11515-11519.
Yamashita M, Ito S, Sugama K, Fukui H, Smith B, Nakanishi K, and Wada H (1991b) Biochemical characterization of histamine H1-receptors in bovine adrenal medulla. Biochem Biophys Res Commun 177: 1233-1239.[CrossRef][Medline]
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