Receptor Interactions of Imidazolines: Α‐adrenoceptors of Rat and Rabbit Aortae Differentiated by Relative Potencies, Affinities and Efficacies of Imidazoline Agonists

Ruffolo, Robert; Waddell, J E

doi:10.1111/j.1476-5381.1982.tb09283.x

Cited by 65 publications

(17 citation statements)

References 19 publications

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“…The rank order of potency of the antagonists, interpreted from pA2 values (Table 2) Although the values of the affinity constants are somewhat different from those of Ruffolo et al (1979) and Ruffolo & Waddell (1982), especially for phenylephrine which was significantly lower in our hands, a reasonable agreement exists with respect to rank order of affinity for the three agonists which in this study, was: clonidine > phenylephrine > noradrenaline.…”

Section: Discussionsupporting

confidence: 74%

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with α‐adrenoceptors in the rat aorta

Alosachie

Godfraind

1988

British J Pharmacology

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1 We have examined the effect of endothelium on the antagonistic action of prazosin, doxazosin, yohimbine and phentolamine against phenylephrine, clonidine and noradrenaline. 2 The action of prazosin against phenylephrine was similar to that earlier reported against noradrenaline, acting as a non-competitive antagonist in the presence of endothelium and as a competitive antagonist in the absence of endothelium. Prazosin also acted as a non-competitive antagonist against clonidine in the absence of endothelium. 3 Doxazosin behaved in a similar way to prazosin against noradrenaline, phenylephrine and clonidine acting as a non-competitive antagonist in the presence of endothelium and as competitive antagonist after removal of endothelium. In contrast, yohimbine and phentolamine acted as competitive antagonists both in the presence and in the absence of endothelium. 4 Analysis of the concentration-response curves for noradrenaline, phenylephrine and clonidine in the presence and in the absence of endothelium showed that the affinity for all three agonists was the same but not the efficacy and the receptor reserve, both of which were lower in the presence than in the absence of endothelium. 5The rank order of agonist potency in the absence of endothelium was noradrenaline > phenylephrine > clonidine. The rank order of antagonist potency was prazosin > doxazosin > phentolamine > yohimbine. 6 The results show that vascular endothelium modulates the contractile response to a-adrenoceptor agonists and also modifies the action of the antagonists prazosin and doxazosin but not that of yohimbine and phentolamine. This effect of endothelium was related to a change in agonist efficacy and receptor reserve. These results also suggest that the a-adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the a1-subtype.

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Section: Discussionsupporting

confidence: 74%

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with α‐adrenoceptors in the rat aorta

Alosachie

Godfraind

1988

British J Pharmacology

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“…Hence, the lack of 5-HT1D8 receptor message in human trigeminal ganglia was unexpected because of evolutionary considerations and because of results suggesting the existence of prejunctional 5-HT1B trigeminovascular receptors in the rat that mediate the effects of sumatriptan (4). However, the expression of different receptor isotypes mediating identical responses in cells from different species has been observed previously (30,31) and establishes precedent for the unanticipated results obtained in human trigeminal ganglia. The mechanisms of action of sumatriptan in rat may be clarified by studies of a newly described 5-HTlD-like receptor (32,33) which, on the basis of sequence homology, tissue distribution, and pharmacology, is likely to be the species homolog of the human 5-HT1Da receptor.…”

Section: Resultsmentioning

confidence: 78%

Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development.

Rebeck

Maynard

Hyman

et al. 1994

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

109

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Pharmacological data suggest that the actions of -antimiine drugs such as sumatriptn may be medated by 5-HT1D-lke serotonin recepors on trigemnhovascular nerve endings. We sought molecular evidence for the expreion of an mRNA species encoding the 5-HT1D receptor subtype in guinea pig and human trigeminal g i, using the polymerase chain reaction with oigon tides uniquely homologous to the coding sequences of the 5-HT1B/D family (human 5-HTmDa and 5-HT1DP; rat 5-HTo The 5-HT1D serotonin receptor subtype comprises a family of at least two closely related receptors encoded by distinct genes (1, 2) designated 5-HTDDa and 5-HT1DP (2) or 5-HT1D and 5-HT1I (3). Pharmacological evidence supports the existence of prejunctional serotonin (5-hydroxytryptamine, 5-HT) receptors resembling 5-HTj and 5-HT1B on trigeminovascular axons transmitting nociceptive information from guinea pig and rat meninges, respectively (4,5). Serotonin agonists and antimigraine compounds such as sumatriptan and ergot alkaloids bind to these receptor sites to block the development of meningeal neurogenic inflammation and to suppress nociceptive activity within trigeminovascular afferents (6-10).Receptors for the 5-HTlD-like subtype have also been pharmacologically characterized on postjunctional vascular smooth muscle, where they mediate vasoconstriction (11). Recently, Northern blot analyses provided evidence for the selective expression of the 5-HT1Dq receptor gene in pial blood vessels (12). Activation of contractile postjunctional receptors on human coronary and cerebral arteries has been linked to the development of coronary vasospasm (13, 14), myocardial infarction (15), and possibly stroke, complicating the treatment of migraine.Our own studies were undertaken to examine the possible expression of a selective receptor subtype which differentiates the pre-and postjunctional 5-HT1D receptor family. We Human trigeminal ganglia were removed from the skull base of eight individuals 5-18 hr after death. Ganglia were carefully dissected from the surrounding tissue and frozen at -800C.RNA Isolation. Tissue samples were sonicated in GTC buffer [4 M guanidinium thiocyanate/10 mM Tris, pH 7.5/1 mM EDTA/0.5% (wt/vol) N-lauroylsarcosine/1% (vol/vol) 2-mercaptoethanol], and total RNA was extracted as described (16). In brief, the cell lysate was extracted twice with phenol/chloroform and nucleic acids were precipitated in 2-propanol. RNA was resuspended in GTC buffer, precipi- (Fig. 1) (17) and highly homologous to the rat 5-HT1B and human 5-HT1D sequences, but not other 5-HT receptor gene subtypes, including the 5-HT1D pseudogene (18). Primer pairs specific for the human 5-HT1D0 and 5-HTD receptor . §To whom reprint requests should be addressed at: Massachusetts

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“…We have previously demonstrated that heterogeneity exists in postjunctional a|-adrenoceptors in mammalian aortae [1][2][3][4], where differences of over 200-fold were observed in the affinities of clonidine and yohimbine for a|-adrenoceptors in the rat aorta at one extreme, and the guinea-pig and rabbit aortae at the other. Aortae from the cat.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Postjunctional α<sub>1</sub>-Adrenoceptors in Mammalian Aortae: Subclassification Based on Chlorethylclonidine, WB 4101 and Nifedipine

Oriowo

Ruffolo²

1992

J Vasc Res

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The effects of chlorethylclonidine, WB 4101 and nifedipine on norepinephrine-induced contractions of rat, guinea-pig, rabbit and dog aortae were investigated in order to characterize the α₁-adrenoceptor subtype(s) present in the aortae of these different species. The putative α_1A-adrenoceptor antagonist, WB 4101, was significantly more potent in the rat aorta compared to the rabbit, guinea-pig and dog aortae which were not significantly different from each other. The calcium channel antagonist, nifedipine (1 µM), had little or no effect on norepinephrine-induced contractions in aortic segments from the rabbit, guinea pig and dog; whereas in the rat aorta, nifedipine significantly inhibited the response to norepinephrine. Based on the studies with WB 4101 and nifedipine, α₁-adrenoceptors in rat aorta would be tentatively classified as α_1A-adrenoceptors, whereas those in the guinea-pig, rabbit and dog aortae would be of the α_1B-adrenoceptor subtype. The putative irreversible α_1B-adrenoceptor antagonist, chlorethylclonidine, inhibited the response to norepinephrine in aortae from all species, but to dramatically different degrees. The response to norepinephrine was inhibited by 500-fold and 450-fold by chlorethylclonidine in the rat and dog aortae, respectively, whereas in the guinea-pig and rabbit aortae, the potency of norepinephrine was reduced by only 3- and 20-fold, respectively. Thus, based on studies with chlorethylclonidine, α₁-adreno-ceptors in the rat and dog aortae would be classified as α_1B-adrenoceptors (i.e., chlorethyl-clonidine-sensitive), whereas α_1A-adrenoceptors (chlorethylclonidine-insensitive) would predominate in the guinea-pig aorta, and possibly both α_1A- and α_1B-adrenoceptors would coexist in the rabbit aorta. It is apparent that the subclassification of α₁-adrenoceptors based on chlorethylclonidine does not agree with the subclassification based on WB 4101 and nifedipine in these tissues. Specifically, studies with WB 4101 and nifedipine indicate that the rat aorta contains primarily α_1A-adrenoceptors, whereas the high sensitivity to chlorethylclonidine in the rat aorta would indicate the existence of α_1B-adrenoceptors. Similar discrepancies exist in the aortae from the other species. The results indicate clearly that significant heterogeneity exists in α₁-adrenoceptors in mammalian aortae. Furthermore, our findings suggest that chlorethylclonidine and WB 4101 are not sufficiently reliable tools to use in subclassifying α₁-adrenoceptors in vascular smooth muscle, and the results obtained in the present study do not allow α₁-adrenoceptors in mammalian aortae to be subclassified reliably as either α_1A-or α_1B-adrenoceptors.

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Receptor Interactions of Imidazolines: Α‐adrenoceptors of Rat and Rabbit Aortae Differentiated by Relative Potencies, Affinities and Efficacies of Imidazoline Agonists

Cited by 65 publications

References 19 publications

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with α‐adrenoceptors in the rat aorta

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with α‐adrenoceptors in the rat aorta

Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development.

Heterogeneity of Postjunctional α<sub>1</sub>-Adrenoceptors in Mammalian Aortae: Subclassification Based on Chlorethylclonidine, WB 4101 and Nifedipine

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