Central Hypotensive Effects of the α
            <sub>2a</sub>
            -Adrenergic Receptor Subtype

MacMillan, Leigh B.; Hein, Lutz; Smith, Marta S.; Piascik, Michael T.; Limbird, Lee E.

doi:10.1126/science.273.5276.801

Cited by 455 publications

(337 citation statements)

References 13 publications

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“…Our results support the data of Tolentino-Silva et al (2000) showing that moxonidine, another imidazoline-like drug, induces hypotension in D79N mice lacking functional a 2A ARs. This however does not corroborate the data of MacMillan et al (1996) obtained in the same strain of mice.…”

Section: Discussioncontrasting

confidence: 99%

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Bruban¹,

Feldman²,

Greney³

et al. 2001

British J Pharmacology

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1 The hypotensive e ect of imidazoline-like drugs, such as clonidine, was ®rst attributed to the exclusive stimulation of central a 2 -adrenoceptors (a 2 ARs). 2 However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. 3 This work aims (i) to check whether imidazoline-like drugs with no a 2 -adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an a 2 ARs agonist a-methylnoradrenaline (a-MNA). 4 We selected S23515 and S23757, two imidazoline-like drugs with negligible a nities and activities at a 2 ARs but with high a nities for non-adrenergic imidazoline binding sites (IBS). 5 S23515 decreased BP dose-dependently (727+5% maximal e ect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 mg kg 71 i.c.) was prevented by S23757 (1 mg kg 71 i.c.) and efaroxan (10 mg kg 71 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive e ect of a-MNA (3 and 30 mg kg 71 i.c.). Moreover, the a 2 ARs antagonist rauwolscine (3 mg kg 71 i.c.) did not prevent the e ect of S23515. 6 Finally, whilst 3 mg kg 71 of S23515 or 0.5 mg kg 71 of a-MNA had weak hypotensive e ects, the sequential i.c. administration of these two drugs induced a marked hypotension (723+2%). 7 These results indicate that an imidazoline-like drug with no a 2 -adrenergic properties lowers BP and interacts synergistically with an a 2 ARs agonist.

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Section: Discussioncontrasting

confidence: 99%

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Bruban¹,

Feldman²,

Greney³

et al. 2001

British J Pharmacology

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“…The D79N mouse line was created using a hit and run gene targeting strategy (18), as described (8). Male chimeras were mated with C57BL͞6 mice to generate heterozygous mice for intercrosses.…”

Section: Methodsmentioning

confidence: 99%

“…We used the ''hit and run'' targeting variant of homologous recombination (6,7) to substitute a subtle mutation of the ␣ 2a AR, D79N into the mouse genome as a tool to explore the role of the ␣ 2a AR in vivo (8). The aspartate residue at position 79 (D79) is highly conserved in a topologically identical position in the second transmembrane span in a large subset of G protein-coupled receptors (9).…”

mentioning

confidence: 99%

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

Lakhlani

MacMillan

Guo

et al. 1997

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

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315

234

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Norepinephrine contributes to antinociceptive, sedative, and sympatholytic responses in vivo, and ␣ 2 adrenergic receptor (␣ 2 AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each ␣ 2 AR subtype (␣ 2A , ␣ 2B , and ␣ 2C ) plays in these central effects. ␣ 2 -adrenergic receptors (␣ 2 ARs) present in the central nervous system (CNS) respond to norepinephrine (NE) and epinephrine and mediate sympatholytic, sedative-hypnotic, analgesic, anesthetic-sparing, hypotensive, and anxiolytic responses (1). Many of these responses are therapeutically useful and are exploited clinically, for example, during anesthesia and to attenuate the symptoms of opioid withdrawal (2). Three ␣ 2 AR subtypes have been revealed by pharmacological (␣ 2A AR, ␣ 2B AR, and ␣ 2C AR) and molecular cloning (␣ 2a AR, ␣ 2b AR, and ␣ 2c AR) strategies (3), and all couple, via pertussis toxin-sensitive G i ͞G o proteins, to attenuation of adenylyl cyclase, suppression of voltage-gated Ca 2ϩ channels, and activation of inwardly rectifying K ϩ channels (4).Multiple experimental limitations have precluded clarifying the involvement of each ␣ 2 AR subtype in catecholaminemediated physiological responses in the CNS. Subtype-specific ␣ 2 AR agonists and antagonists are not available (5); even when subtype selectivity has been noted in vitro, varying and unknown in vivo bioavailability precludes confident correlation of the administered dose with the amount of drug at the receptor site. Previous studies to explore ␣ 2 AR involvement in various responses have used prazosin to block catecholamine responses mediated by ␣ 1 adrenergic receptors (␣ 1 AR); however, it is now known that the ␣ 2B AR and ␣ 2C AR subtypes also are blocked by prazosin (5), thus confounding the interpretations of these earlier studies. In addition, because ␣ 1 AR can functionally antagonize ␣ 2 AR-mediated responses in some settings, ␣ 2 AR responses in the presence of prazosin (added to block ␣ 1 AR, ␣ 2B AR, and ␣ 2C AR) may reflect the disturbance of the balance between the functionally antagonistic ␣ 2 AR and ␣ 1 AR systems rather than provide insights concerning the role of the ␣ 2A AR subtype. Consequently, we manipulated the mouse genome to provide definitive evidence regarding the role of the ␣ 2A AR subtype in CNS responses.We used the ''hit and run'' targeting variant of homologous recombination (6, 7) to substitute a subtle mutation of the ␣ 2a AR, D79N into the mouse genome as a tool to explore the role of the ␣ 2a AR in vivo (8). The aspartate residue at position 79 (D79) is highly conserved in a topologically identical position in the second transmembrane span in a large subset of G protein-coupled receptors (9). Mutation of this residue has been shown to eliminate allosteric regulation of receptor binding by monovalent cations (10-13) and to perturb receptor-G protein-effector coupling (14-17) in heterologous expression systems. Thus, the animals expressing the D79N ␣ 2a AR provi...

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“…Conversely, a vasopressor response may be elicited by the central action of an a 2 -adrenoceptor antagonist (Goldberg et al, 1983). In mice with a point mutation of a 2A -adrenoceptors, the sustained decrease in blood pressure was absent (MacMillan et al, 1996), suggesting that centrallyinduced hypotension is induced via stimulation of a 2A -adrenoceptors. Because of the very low a nity of OPC-28326 for a 2A -adrenoceptors, the central antagonistic actioninduced pressor response may be weak.…”

Section: Discussionmentioning

confidence: 99%

“…In mice lacking a 2B -adrenoceptors, the pressor response induced by an a 2 -adrenoceptor agonist was absent (Link et al, 1996). The central hypotensive action of the a 2 -adrenoceptor agonist was absent in mice lacking the a 2A -adrenoceptors (MacMillan et al, 1996). It has also been reported that presynaptic a 2 -adrenoceptors are similar to a 2A -adrenoceptors (Smith & Docherty, 1992;Daniel et al, 1995).…”

Section: Opc-28326mentioning

confidence: 98%

α₂‐adrenoceptor antagonist properties of OPC‐28326, a novel selective peripheral vasodilator

Orito

Kishi

Imaizumi

et al. 2001

British J Pharmacology

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1 Antagonistic properties of OPC-28326 ([4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to a 2 -adrenoceptor subtypes. 2 Using a human recombinant receptor and rat kidney cortex, we found that OPC-28326 displays a nities to a 2A -, a 2B -and a 2C -adrenoceptors with K i values of 2040, 285, and 55 nM, respectively. The K i values of yohimbine for a 2A -, a 2B -, and a 2C -adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. 3 B-HT 920, an a 2 -adrenoceptor agonist, produced a pressor response via peripheral postsynaptic a 2 -adrenoceptor stimulation (thought to be an a 2B -subtype) in a reserpine-pretreated pithed rat preparation. OPC-28326 (3 ± 30 mg kg 71 , i.v.) and yohimbine (0.3 ± 3 mg kg 71 , i.v.) caused dosedependent rightward shift in the pressor dose-response curve induced by B-HT 920. The apparent pA 2 values were 1.55 (0.87 ± 2.75, 95% con®dence interval) and 0.11 (0.06 ± 0.21) mg kg 71 , respectively. The potency of OPC-28326 was about 14 times less than that of yohimbine. 4 Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic a 2A/D -adrenoceptor action. OPC-28326 (1 ± 100 mM) and yohimbine (10 ± 1000 nM) caused a rightward shift in the concentration-response curve of clonidine. The pA 2 values were 5.73 (5.54 ± 5.91) and 7.92 (7.84 ± 8.01), respectively, providing evidence for a potency of OPC-28326 of about 155 times less than that of yohimbine. 5 Mydriasis was induced by brimonidine via stimulation of central a 2A/D -adrenoceptors in anaesthetized rats. Intravenous OPC-28326 had no e ect on this action, even at a very high dose of 10 mg kg 71 i.v., while yohimbine (0.1 ± 0.3 mg kg 71 i.v.) inhibited mydriasis in a dose-dependent manner, indicating that OPC-28326 was at least 100 times less potent than yohimbine in regard to the anti-mydriatic e ect. 6 These data suggest that OPC-28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the a 2B -and a 2C -adrenoceptor subtypes.

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Central Hypotensive Effects of the α _2a -Adrenergic Receptor Subtype

Cited by 455 publications

References 13 publications

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

α₂‐adrenoceptor antagonist properties of OPC‐28326, a novel selective peripheral vasodilator

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Central Hypotensive Effects of the α 2a -Adrenergic Receptor Subtype

Cited by 455 publications

References 13 publications

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Respective contributions of α‐adrenergic and non‐adrenergic mechanisms in the hypotensive effect of imidazoline‐like drugs

Substitution of a mutant α 2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

α2‐adrenoceptor antagonist properties of OPC‐28326, a novel selective peripheral vasodilator

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Product

Resources

About

Central Hypotensive Effects of the α _2a -Adrenergic Receptor Subtype

Substitution of a mutant α _2a -adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo

α₂‐adrenoceptor antagonist properties of OPC‐28326, a novel selective peripheral vasodilator