α1-Adrenergic receptor regulation: basic science and clinical implications

Michelotti, Gregory A.; Price, David T.; Schwinn, Debra A.

doi:10.1016/s0163-7258(00)00092-9

Cited by 212 publications

(191 citation statements)

References 193 publications

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“…␣1A͞C expression in gut and renal arteries was suspected from prior studies in other species (4). However, the LacZ reporter gene provided new insights.…”

Section: Discussionmentioning

confidence: 99%

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Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure

Rokosh

Simpson

2002

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

181

185

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␣1-adrenergic receptors (ARs) play a major role in blood pressure regulation. The three ␣1-AR subtypes (A͞C, B, and D) stimulate contraction of isolated arteries, but it is uncertain how different subtypes contribute to blood pressure regulation in the intact animal. We studied the role of the ␣1A͞C subtype by using gene knockout. ␣1A͞C knockout (KO) mice were viable and overtly normal. The LacZ reporter gene replaced ␣1A͞C coding sequence in the KO, and ␤-galactosidase staining was present in resistance arteries and arterioles, but not in the thoracic aorta or its main branches. By tail cuff manometer and arterial catheter in conscious mice, ␣1A͞C KO mice were hypotensive at rest, with an 8 -12% reduction of blood pressure dependent on ␣1A͞C gene copy number. A61603, an ␣1A͞C-selective agonist, caused a pressor response that was lost in the KO and reduced but significant in heterozygous mice with a single copy of the ␣1A͞C. A subtype-nonselective agonist [phenylephrine (PE)] caused a pressor response in KO mice, but the final arterial pressure was only 85% of wild type. The baroreflex was reset in the KO, and heart rate variability was decreased. After baroreflex blockade with atropine, PE increased blood pressure but did not change heart rate. Cardiac and vascular responses to the ␤-AR agonist isoproterenol were unchanged, and the arterial lumen area was not altered. We conclude that the ␣1A͞C-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation. ␣1A͞C-selective antagonists might be desirable antihypertensive agents.

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“…␣1A͞C expression in gut and renal arteries was suspected from prior studies in other species (4). However, the LacZ reporter gene provided new insights.…”

Section: Discussionmentioning

confidence: 99%

“…All three ␣1-AR subtypes can mediate constriction in many isolated arteries (4,5). This complexity and the lack of subtype antagonists with sufficient selectivity have so far made it impossible to define the role of any individual ␣1-AR subtype in blood pressure regulation in the intact animal.…”

mentioning

confidence: 99%

Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure

Rokosh

Simpson

2002

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

181

185

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“…α 1 -Adrenoceptors mediate their actions through stimulation of inositol phosphate release (Michelotti et al 2000), while β-adrenoceptors stimulate (Stiles et al 1984) and α 2 -adrenoceptors inhibit (Limbird 1988) adenylyl cyclase.…”

Section: Adrenoceptorsmentioning

confidence: 99%

“…α 1 -Adrenoceptors are G-protein-coupled receptors and mediate their responses via a G q/11 mechanism (Michelotti et al 2000). This involves activation of phospholipase Cdependent hydrolysis of phosphatidyl 4,5-biphosphate generating inositol 1,4,5 -trisphosphate (IP 3 ), which acts on the IP 3 receptor in the endoplasmic reticulum to release stored Ca 2+ and diacylglycerol that (together with Ca 2+ ) can activate protein kinase C. Production of these second messengers activates both voltage-dependent and voltage-independent Ca 2+ -channels, leading to smooth muscle contraction in both vascular and non-vascular tissues (e.g., prostate, vas deferens, and heart).…”

Section: Adrenoceptorsmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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“…The α 1 ARs can mediate proliferation and cell growth in the periphery (Hoffman and Hu 2000;Michelotti et al 2000). α 1 AR activation stimulates DNA synthesis in human vascular smooth muscle cells through a PI3 kinase and MAPK pathway (Hu et al 1996;Hoffman and Hu 2000).…”

Section: Introductionmentioning

confidence: 99%

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

Collette

Amoth

et al. 2014

AGE

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The α 1 -adrenergic receptor (α 1 AR) subtypes, α 1A AR and α 1B AR, have differential effects in the heart and central nervous system. Long-term stimulation of the α 1A AR subtype prolongs lifespan and provides cardio-and neuro-protective effects. We examined the lifespan of constitutively active mutant (CAM)-α 1B AR mice and the incidence of cancer in mice expressing the CAM form of either the α 1A AR (CAM-α 1A AR mice) or α 1B AR. CAM-α 1B AR mice have a significantly shortened lifespan when compared with wild-type (WT) animals; however, the effect was sex dependent. Female CAM-α 1B AR mice lived significantly shorter lives, while the median lifespan of male CAM-α 1B AR mice was not different when compared with that of WT animals. There was no difference in the incidence of cancer in either sex of CAM-α 1B AR mice. The incidence of cancer was significantly decreased in CAM-α 1A AR mice when compared with that in WT, and no sex-dependent effects were observed. Further study is warranted on cancer incidence after activation of each α 1 AR subtype and the effect of sex on lifespan following activation of the α 1B AR. The implications of a decrease in cancer incidence following long-term α 1A AR stimulation could lead to improved treatments for cancer.

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α1-Adrenergic receptor regulation: basic science and clinical implications

Cited by 212 publications

References 193 publications

Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure

Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure

Current and prospective pharmacological targets in relation to antimigraine action

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

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