Variable receptor affinity hypothesis

Bevan, John A.; Bevan, Rosemary D.; Shreeve, S. Martin

doi:10.1096/fasebj.3.6.2564831

Cited by 56 publications

(17 citation statements)

References 32 publications

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“…Although the potency of prazosin varied significantly between the species, the values nonetheless fall within the range reported for ai-adrenoceptor block ade [12,13]. Norepinephrine potency also varied among aortae, and this has been shown to correlate with varia tion in receptor affinity and receptor reserve [ 14,21 ].…”

Section: Discussionsupporting

confidence: 64%

“…It is not apparent why the maximum responses to norepinephrine were not depressed by chlor ethylclonidine. as would be characteristic of an irrevers ible antagonist [11], However, this unusual pattern of antagonism by chlorethylclonidine in vascular tissues has been observed by others [ 19,21 ]. We know that the antag onism of norepinephrine by chlorethylclonidine was, in deed.…”

Section: Resultsmentioning

confidence: 81%

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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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Section: Discussionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 81%

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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“…could, for example, be related to alterations in agonist affinity for the a,-adrenoceptsr. Investigations in diverse isolated vasculature from several species support such a hypothesis and have shown that variations in the sensitivity of tissue responsiveness to a,-adrenoceptor activation are strongly positively correlated with equivalent alterations in agonist affinity (Bevan et al 1986(Bevan et al , 1988(Bevan et al , 1989Oriowo et al 19887). Moreover, little, if any.…”

Section: Introductionmentioning

confidence: 99%

Age-dependent alterations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men

Christ

Stone

Melman³

1991

Can. J. Physiol. Pharmacol.

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Steady-state contractile responses elicited by phenylephrine activation of the alpha 1-adrenergic receptor subtype were studied in vascular smooth muscle strips isolated from the corpus cavernosum of impotent men. The dissociation constant of phenylephrine was determined by the method of partial irreversible receptor inactivation over a wide range of alpha 1-adrenergic receptor alkylation levels. Statistical analysis of mean population values revealed a significantly greater mean efficacy for phenylephrine-induced contractions in older patients (60-73 years old) than in younger patients (40-59 years old), in the absence of similar alterations in the mean phenylephrine dissociation constant (affinity). In addition, there was no significant effect of the diabetic state on the mean phenylephrine affinity or efficacy estimates. However, despite the absence of age- or pathology-dependent variations in agonist affinity, as assessed by group mean calculations, a detailed examination of all isolated tissues on an individual basis revealed that the phenylephrine affinity estimates varied over a range of almost two orders of magnitude. Furthermore, a linear regression analysis revealed a highly significant positive correlation between agonist affinity and the location of the phenylephrine concentration-response curve, which was characterized by a slope significantly less than unity. In conclusion, an increased efficacy of phenylephrine-induced contractions in vitro is consistent with the hypothesis that augmented corporal vascular smooth muscle contractility in vivo may contribute to the pathophysiology of impotence in older patients.

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“…Finally it must be said that the influence of the membraneous environment on the efficacy of hormones and agonists has been neglected. But as long as the molecular mechanisms of receptor activation are unknown, it will remain difficult to explain functional heterogeneity of receptors as a result of environmental effects, as exemplified by the case of vasoconstrictive a,-adrenoceptors which vary in different tissues and in different animal species in ligand affinity and biological activity (Bevan et al, 1989). What applies to p-adrenoceptor activation also applies to desensitization (Hausdorff et al, 1990a; see Fig.…”

Section: )mentioning

confidence: 99%

Structural heterogeneity of membrane receptors and GTP‐binding proteins and its functional consequences for signal transduction

Boege

Neumann

Helmreich

1991

European Journal of Biochemistry

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Recent information obtained, mainly by recombinant cDNA technology, on structural heterogeneity of hormone and transmitter receptors, of GTP-binding proteins (G-proteins) and, especially, of G-protein-linked receptors is reviewed and the implications of structural heterogeneity for diversity of hormone and transmitter actions is discussed. For the future, three-dimensional structural analysis of membrane proteins participating in signal transmission and transduction pathways is needed in order to understand the molecular basis of allosteric regulatory mechanisms governing the interactions between these proteins including hysteretic properties and cellcybernetic aspects.Thanks to recombinant DNA technology, there has been a recent flood of structural information on membrane receptors, G-proteins and target enzymes [for reviews see Gilman

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Variable receptor affinity hypothesis

Cited by 56 publications

References 32 publications

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

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

Age-dependent alterations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men

Structural heterogeneity of membrane receptors and GTP‐binding proteins and its functional consequences for signal transduction

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