Investigation of postjunctional α1‐ and α2‐adrenoceptor subtypes in vas deferens from wild‐type and α2A/D‐adrenoceptor knockout mice

Cleary, Linda; Vandeputte, Catherine; Docherty, James R.

doi:10.1038/sj.bjp.0705137

Cited by 22 publications

(25 citation statements)

References 29 publications

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“…f Pertovaara et al (2005). g Cleary et al (2003). similar to unity if the calculated experimental values correspond to published constants for a specific receptor.…”

Section: Tablesupporting

confidence: 55%

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

Jurgens¹,

Hammad²,

Lichter³

et al. 2007

Mol Pharmacol

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Norepinephrine has potent antiepileptic properties, the pharmacology of which is unclear. Under conditions in which GABAergic inhibition is blocked, norepinephrine reduces hippocampal cornu ammonis 3 (CA3) epileptiform activity through ␣ 2 adrenergic receptor (AR) activation on pyramidal cells. In this study, we investigated which ␣ 2 AR subtype(s) mediates this effect. First, ␣ 2 AR genomic expression patterns of 25 rat CA3 pyramidal cells were determined using real-time single-cell reverse transcription-polymerase chain reaction, demonstrating that 12 cells expressed ␣ 2A AR transcript; 3 of the 12 cells additionally expressed mRNA for ␣ 2C AR subtype and no cells possessing ␣ 2B AR mRNA. Hippocampal CA3 epileptiform activity was then examined using field potential recordings in brain slices. The selective ␣AR agonist 6-fluoronorepinephrine caused a reduction of CA3 epileptiform activity, as measured by decreased frequency of spontaneous epileptiform bursts. In the presence of ␤AR blockade, concentration-response curves for AR agonists suggest that an ␣ 2 AR mediates this response, as the rank order of potency was 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14304) Ն epinephrine Ͼ6-fluoronorepinephrine Ͼ norepinephrine phenylephrine. Finally, equilibrium dissociation constants (K b ) of selective ␣AR antagonists were functionally determined to confirm the specific ␣ 2 AR subtype inhibiting CA3 epileptiform activity. Apparent K b values calculated for atipamezole (1.7 nM), MK-912 (4.8 nM), BRL-44408 (15 nM), yohimbine (63 nM), ARC-239 (540 nM), prazosin (4900 nM), and terazosin (5000 nM) correlated best with affinities previously determined for the ␣ 2A AR subtype (r ϭ 0.99, slope ϭ 1.0). These results suggest that, under conditions of impaired GABAergic inhibition, activation of ␣ 2A ARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region.The noradrenergic system is a key modulator of numerous physiological and pathological processes. Within the central nervous system (CNS), noradrenergic neurons innervate copious neural networks and regulate a number of essential neurological functions, including attention and arousal, sleep, and learning and memory (Pupo and Minneman, 2001).

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“…f Pertovaara et al (2005). g Cleary et al (2003). similar to unity if the calculated experimental values correspond to published constants for a specific receptor.…”

Section: Tablesupporting

confidence: 55%

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

Jurgens¹,

Hammad²,

Lichter³

et al. 2007

Mol Pharmacol

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“…In many previous studies the contractility in the vas deferens was analysed in rats using conventional antagonists, such as chlorethylclonidine, a relatively selective α 1B ‐adrenoceptor antagonist, and RS 100329, an α 1A ‐adrenoceptor antagonist (Han et al , 1987a, 1987b; Cleary et al , 2004). It has been shown that a different subtype of adrenoceptor, as well as other receptors, is involved in the contraction between the proximal and distal segments of the vas deferens and that this regulation by different receptors is also observed between tonic and phasic contractions (Westfall and Westfall, 2001; Cleary et al , 2003; Cuprian et al , 2005). Moreover, while the α 1A ‐adrenoceptor can contribute to the contraction in the vas deferens via the sympathetic nerve in all species, including rats and mice, there may be considerable species differences with regard to the involvement of an additional subtype of adrenoceptor (Westfall and Westfall, 2001).…”

Section: Discussionmentioning

confidence: 99%

α₁‐Adrenoceptors are required for normal male sexual function

Sanbe

Tanaka

Fujiwara

et al. 2007

British J Pharmacology

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Background and purpose: a 1 -Adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for a 1A -adrenoceptors compared with other drugs of this class. This suggests that a 1A -adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level. Experimental approach: The physiological contribution of each a 1 -adrenoceptor subtype was characterized using a 1 -adrenoceptor subtype-selective knockout (KO) mice (a 1A -, a 1B -and a 1D -AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of a 1 -adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in a 1 -adrenoceptor subtype-selective KO mice and in mice with all their a 1 -adrenoceptor subtypes deleted (a 1 -AR triple-KO mice). Key results: The pregnancy rate was reduced by 50% in a 1A -adrenoceptor KO mice, and this reduction was dramatically enhanced in a 1 -adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in a 1A -adrenoceptor KO mice, and this contraction was completely abolished in a 1 -adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens. Conclusions and implications:These results demonstrate that a 1 -adrenoceptors, particularly a 1A -adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility.

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“…It was and still is widely used in various experimental studies in vitro [10, 19, 34] and in vivo in conscious animals [3, 5, 7] and as an antagonist of general anesthesia [11, 22, 24, 48]. …”

Section: Introductionmentioning

confidence: 99%

Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1mg/kg.

Zaretsky

Zaretskaia

DiMicco

et al. 2015

Neuroscience Letters

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Yohimbine is a prototypical alpha2-adrenergic receptor antagonist. Due to its relatively high selectivity, yohimbine is often used in experiments whose purpose is to examine the role of these receptors. For example, yohimbine has been employed at doses of 1–5 mg/kg to reinstate drug-seeking behavior after extinction or to antagonize general anesthesia, an effects presumably being a consequence of blocking alpha2-adrenergic receptors. In this report we characterized dose-dependent autonomic and behavioral effects of yohimbine and its interaction with an antagonist of 5-HT1A receptors, WAY 100635. In low doses (0.5 – 2 mg/kg i.p.) yohimbine induced locomotor activation which was accompanied by a tachycardia and mild hypertension. Increasing the dose to 3–4.5 mg/kg reversed the hypertension and locomotor activation and induced profound hypothermia. The hypothermia as well as the suppression of the locomotion and the hypertension could be reversed by the blockade of 5-HT1A receptors with WAY 100635. Our data confirm that yohimbine possesses 5-HT1A properties, and demonstrated that in doses above 1 mg/kg significantly activate these receptors.

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Investigation of postjunctional α₁‐ and α₂‐adrenoceptor subtypes in vas deferens from wild‐type and α_2A/D‐adrenoceptor knockout mice

Cited by 22 publications

References 29 publications

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

α₁‐Adrenoceptors are required for normal male sexual function

Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1mg/kg.

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Investigation of postjunctional α1‐ and α2‐adrenoceptor subtypes in vas deferens from wild‐type and α2A/D‐adrenoceptor knockout mice

Cited by 22 publications

References 29 publications

α2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

α2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

α1‐Adrenoceptors are required for normal male sexual function

Yohimbine is a 5-HT1A agonist in rats in doses exceeding 1mg/kg.

Contact Info

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Investigation of postjunctional α₁‐ and α₂‐adrenoceptor subtypes in vas deferens from wild‐type and α_2A/D‐adrenoceptor knockout mice

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

α₁‐Adrenoceptors are required for normal male sexual function