Dual Histamine Receptor Mechanism in Guinea-Pig Lung

Chand, N.; DeRoth, L

doi:10.1159/000137308

Cited by 21 publications

(5 citation statements)

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“…Dissociation constant (pA2) values of 8.0-9.3 for mepyramine and 6.1-7.0 for cimetidine have been reported in different test preparations (Ottosson et al, 1988). Thus, the pA2 values found in the present study, 9.57 and 8.75 for mepyramine In some species, bronchodilatation is mediated via H2-receptors (Okpako et al, 1978;Chand & De Roth, 1979). In contrast, and Vincec et al (1984) have described a histamine-induced tracheal relaxation not affected by H2-antagonists and have suggested the existence of HIreceptor subtypes or a third histamine receptor in the trachea.…”

Section: Discussionsupporting

confidence: 64%

Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H₃ receptors in the trachea

Cardell

Edvinsson

1994

British J Pharmacology

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1 The histamine receptors were characterized on isolated circular segments of trachea and pulmonary arteries from the guinea-pig. The motor responses to histamine HI-, H2-and H3-receptor agonists and antagonists were tested and the responses obtained were analysed in relation to the respiratory epithelium and the vascular endothelium. 2 Histamine induced a biphasic response in trachea and in pulmonary arteries. In low concentrations, histamine acted as a potent relaxant agent of precontracted segments and in moderate concentrations it constricted both precontracted and resting segments. When arterial segments from different parts of the pulmonary vascular tree were compared, only small interregional differences in the vasomotor response were seen. 3 Mepyramine caused a parallel shift to the right of the histamine-induced concentration-response curves for both the trachea and the pulmonary artery, indicating a contractile HI-receptor. Cimetidine did not affect the histamine-induced contraction of the trachea, but a shift to the left was evident for low concentrations of histamine in the pulmonary artery. This is consistent with a dilator H2-receptor in the pulmonary artery. The pA2-value for mepyramine in the pulmonary artery, 8.75, was not affected by the presence of cimetidine. Thioperamide, a selective H3 antagonist, shifted the concentration-response for the trachea to the left. Schild analysis for histamine and mepyramine yielded a line with a slope of 0.61, whereas the same analysis in the presence of thioperamide yielded a line with a slope of 1.05 and an approximated pA2-value of 9.57. These results indicate the presence of a relaxant H3 receptor in the trachea. In precontracted tracheal segments, application of mepyramine and cimetidine did not affect the low dose histamine relaxation. Thioperamide caused a parallel shift of the histamine concentrationresponse curve to the right, supporting the suggestion of a dilator H3-receptor in the trachea. The pA2-value for thioperamide, in the presence of mepyramine, was 7.79. In precontracted pulmonary arteries the histamine-induced dilatation was small. In the presence of mepyramine a rather strong histamine-induced dilatation became evident and this concentration-response curve could be shifted to the right by cimetidine, with a pA2-value of 6.49. This is compatible with a dilator H2-receptor. 4 The H1-receptor agonists, thiazolylethylamine, 2-methylhistamine and pyridylethylamine and the rather unselective H2-agonist, 4-methylhistamine, induced contraction of resting tracheal and pulmonary arterial segments. In precontracted segments of trachea, all H1 and H2 agonists studied induced a dilator response. The two rather unselective histamine receptor agonists 2-methylhistamine and 4-methylhistamine were about 100 times more potent than other H1 and H2 agonists tested. In the pulmonary artery, the H2 agonists, impromidine, dimaprit and 4-methylhistamine induced a concentration-dependent relaxation. The relaxation of the pulmonary artery, elicited by the H1 a...

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Section: Discussionsupporting

confidence: 64%

Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H₃ receptors in the trachea

Cardell

Edvinsson

1994

British J Pharmacology

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“…Inasmuch as the guinea pig is highly sensitive to histamine (24,25) and easily subjected to anaphylaxis (26,27), we next used individual bronchial rings microdissected from sensitized guinea pigs and determined whether renin could be released in active form by anaphylactic mast cell degranulation, leading to ANG II formation and, thus, BC. Antigen challenge of bronchial rings excised from sensitized guinea pigs resulted in a smooth muscle contraction comparable in amplitude to that elicited by maximal depolarization with K ϩ (80 mM) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mast cell renin and a local renin–angiotensin system in the airway: Role in bronchoconstriction

Veerappan¹,

Reid²,

Estephan³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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We previously reported that mast cells express renin, the ratelimiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT 1R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT 1R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and ␤-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.angiotensin II ͉ angiotensin II type 1 receptors ͉ asthma ͉ hypersensitivity ͉ lung T he renin-angiotensin system (RAS) has been traditionally viewed as a circulating axis, whereby renin is released into the circulation from the kidneys in response to decreased renal perfusion pressure, decreased delivery of NaCl at the macula densa, and/or increased renal sympathetic nerve activity (1). The proteolytic cleavage of angiotensinogen (aogen) by renin constitutes the rate-limiting step of the RAS cascade.In addition to this classical view, it is believed that many tissues, including the lung, may possess the capacity to generate angiotensin (ANG II) locally (2, 3). This is supported by experiments demonstrating that ANG II persists in lung of nephrectomized rats (4) and findings showing that ANG II can be elevated in the lungs in the absence of an elevated systemic RAS (5). Components of RAS have been identified in lung tissue, including aogen mRNA (6, 7), and angiotensin-converting enzyme (ACE), the pulmonary endothelium being the primary source for ACE in the body (8). ANG II receptors are also expressed in lung tissue, with the ANG II type 1 receptor (AT 1 R) subtype found on bronchial smooth muscle cells (9) and ANG II type 2 receptor (AT 2 R) observed on the bronchial epithelial cell brush border (10). An intrapulmonary source of renin protein has not yet been identified.We previously reported that mast cells synthesize, st...

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“…It is generally accepted that activa tion of the H| receptors results in contraction of the guinea pig respiratory smooth muscles, while H2 re ceptor activation is accompanied by smooth muscle relaxation [Okpako et al, 1978;Drazen et al, 1979;Chand and de Roth, 1978;Harrison et al, 1984], It was shown that stobadine, a potent antiarrhythmic and cardioprotective drug [Stoic et al, 1983], and its racemate carbidine had pronounced antihistaminic effects on the guinea pig ileum, cat peripheral and central nervous system [Lukovic and Machova, 1984] and respiratory smooth muscles in vivo [Bauer and Buran, 1987;Buran et al, 1987],…”

Section: Introductionmentioning

confidence: 99%

Effect of Stobadine and Histamine H<sub>1</sub> and H<sub>2</sub> Blockers on Histamine–Induced Contraction of Guinea Pig Airways in vitro

Matyas

Bauer³

1990

Respiration

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Histamine, a nonselective histamine receptor agonist, activates simultaneously both H₁ and H₂receptors in the guinea pig trachea and lung strip. The resulting contraction is due to the prevalence of H₁ receptors, because they are blocked by the selective H₁antagonist diphenhydramine. The H₂ receptor antagonists cimetidine and ranitidine increased the sensitivity of both tissues to histamine by affecting primarily the amplitude of contractions induced by high histamine concentrations. Since the lung strips were more sensitized by ranitidine and low concentrations of the other studied antagonists (diphenhydramine, dithiadene, stobadine) than the tracheal smooth muscle, it is inferred that the density of H₂ receptors is higher in peripheral than central airways. From all the studied histamine receptor antagonists only dithiadene was able to unmask the relaxation induced by H₂ receptor activation indicative of its highest H₁ selectivity. In the light of the concentration-dependent antihistaminic effect of stobadine, i.e. potentiation in low and inhibition in high concentrations, stobadine is suggested to belong to antihistaminics with no histamine receptor subtype selectivity

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Dual Histamine Receptor Mechanism in Guinea-Pig Lung

Cited by 21 publications

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Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H₃ receptors in the trachea

Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H₃ receptors in the trachea

Mast cell renin and a local renin–angiotensin system in the airway: Role in bronchoconstriction

Effect of Stobadine and Histamine H<sub>1</sub> and H<sub>2</sub> Blockers on Histamine–Induced Contraction of Guinea Pig Airways in vitro

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Dual Histamine Receptor Mechanism in Guinea-Pig Lung

Cited by 21 publications

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Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H3 receptors in the trachea

Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H3 receptors in the trachea

Mast cell renin and a local renin–angiotensin system in the airway: Role in bronchoconstriction

Effect of Stobadine and Histamine H<sub>1</sub> and H<sub>2</sub> Blockers on Histamine–Induced Contraction of Guinea Pig Airways in vitro

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Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H₃ receptors in the trachea

Characterization of the histamine receptors in the guinea‐pig lung: evidence for relaxant histamine H₃ receptors in the trachea