Metabolism of a Thiazole Benzenesulfonamide Derivative, a Potent and Selective Agonist of the Human β3-Adrenergic Receptor, in Rats: Identification of a Novel Isethionic Acid Conjugate

Stimulation of the cAMP-signaling pathway modulates apoptosis in several cell types and inhibits Jo2-mediated apoptosis in cultured rat hepatocytes. No information is yet available as to whether the hepatic β2-adrenergic receptor (AR) expression level, including β2-AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by β2-AR ligands. We have examined this using C57BL/6 mice, in which hepatic β2-AR densities are low, and transgenic F28 mice, which overexpress β2-ARs and have elevated basal liver adenylyl cyclase activity. The F28 mice were resistant to Jo2-induced liver apoptosis and death. The β-AR antagonist propranolol sensitized the F28 livers to Jo2. In normal mice clenbuterol, a β2-AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another β2-AR-selective agonist, also reduced Jo2-induced apoptosis and retarded death but with less efficacy than clenbuterol; and propranolol blocked the protective effect of clenbuterol. This indicates that the expression level of functional β2-ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving β2-AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis.

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GW25-e3177 β 2 adrenergic receptor selective agonist clenbuterol protects cardiac arrhythmia after reperfusion

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2014.06.238 ◽

2014 ◽

Vol 64 (16) ◽

pp. C49

Author(s):

Fu Qin

Keyword(s):

Cardiac Arrhythmia ◽

Adrenergic Receptor ◽

Selective Agonist

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α1-Adrenergic-receptor responsiveness in skeletal muscle during dynamic exercise

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.6.2277 ◽

1998 ◽

Vol 85 (6) ◽

pp. 2277-2283 ◽

Cited By ~ 27

Author(s):

John B. Buckwalter ◽

Patrick J. Mueller ◽

Philip S. Clifford

Keyword(s):

Femoral Artery ◽

Adrenergic Receptor ◽

Skeletal Muscles ◽

Systemic Blood Pressure ◽

Dynamic Exercise ◽

Systemic Blood ◽

Iliac Arteries ◽

Selective Agonist ◽

Sympathetic Vasoconstriction ◽

Adrenergic Receptor Agonist

Attenuation of sympathetic vasoconstriction (sympatholysis) in working muscles during dynamic exercise is controversial. One potential mechanism is a reduction in α1-adrenergic-receptor responsiveness. The purpose of this study was to examine α1-adrenergic-receptor-mediated vasoconstriction in resting and working skeletal muscles by using intra-arterial infusions of a selective agonist. Seven mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. A selective α1-adrenergic-receptor agonist (phenylephrine) was infused as a bolus into the femoral artery catheter at rest and during exercise. All dogs ran on a motorized treadmill at two exercise intensities (3 and 6 miles/h). Intra-arterial infusions of the same effective concentration of phenylephrine elicited reductions in vascular conductance of 76 ± 4, 76 ± 6, and 67 ± 5% ( P > 0.05) at rest, 3 miles/h, and 6 miles/h, respectively. Systemic blood pressure and blood flow in the contralateral iliac artery were unaffected by phenylephrine. These results do not demonstrate an attenuation of vasoconstriction to a selective α1-agonist during exercise and do not support the concept of sympatholysis.

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Orexin Neurons Are Directly and Indirectly Regulated by Catecholamines in a Complex Manner

Journal of Neurophysiology ◽

10.1152/jn.01361.2005 ◽

2006 ◽

Vol 96 (1) ◽

pp. 284-298 ◽

Cited By ~ 77

Author(s):

Akihiro Yamanaka ◽

Yo Muraki ◽

Kanako Ichiki ◽

Natsuko Tsujino ◽

Thomas S. Kilduff ◽

...

Keyword(s):

Calcium Imaging ◽

Adrenergic Receptor ◽

Inward Rectifier ◽

High Concentration ◽

Synaptic Currents ◽

Inward Rectifier Potassium Channels ◽

Selective Agonist ◽

Circadian Time ◽

G Protein Coupled ◽

Complex Manner

We reported elsewhere that orexin neurons are directly hyperpolarized by noradrenaline (NA) and dopamine. In the present study, we show that NA, dopamine, and adrenaline all directly hyperpolarized orexin neurons. This response was inhibited by the α2 adrenergic receptor (α2-AR) antagonist, idazoxan or BRL44408 , and was mimicked by the α2-AR-selective agonist, UK14304. A low concentration of Ba2+ inhibited NA-induced hyperpolarization, which suggests that activation of G protein coupled inward rectifier potassium channels is involved in the response. In the presence of a high concentration of idazoxan, NA induced depolarization or inward current. This response was inhibited by α1-AR antagonist, prazosin, which suggests the existence of α1-ARs on the orexin neurons along with α2-AR. We also examined the effects of NA on glutamatergic and GABAergic synaptic transmission. NA application dramatically increased the frequency and amplitude of spontaneous inhibitory synaptic currents (sIPSCs) and inhibited excitatory synaptic currents (sEPSCs) in orexin neurons; however, NA decreased the frequency of miniature EPSCs (mEPSCs) and IPSCs and the amplitude of evoked EPSCs and IPSCs through the α2-AR, because the NA response on mPSCs was inhibited by idazoxan. These results suggest that the NA-induced increase in sIPSC frequency and amplitude is mediated via α1-ARs on the somata of GABAergic neurons that innervate the orexin neurons. Calcium imaging using orexin/YC2.1 transgenic mouse brain revealed that NA-induced inhibition of orexin neurons is not altered by sleep deprivation or circadian time in mice. The evidence presented here revealed that orexin neurons are regulated by catecholamines in a complex manner.

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DPI, a supposed selective agonist of inhibitory dopamine receptors, strongly increases rat diuresis through a-adrenergic receptor activitation

Life Sciences ◽

10.1016/0024-3205(81)90376-3 ◽

1981 ◽

Vol 28 (13) ◽

pp. 1449-1456 ◽

Cited By ~ 11

Author(s):

G. Baggio ◽

F. Ferrari

Keyword(s):

Dopamine Receptors ◽

Adrenergic Receptor ◽

Selective Agonist

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Mirabegron, alone and in combination, in the treatment of overactive bladder: real-world evidence and experience

Therapeutic Advances in Urology ◽

10.1177/1756287218801282 ◽

2018 ◽

Vol 10 (12) ◽

pp. 411-419 ◽

Cited By ~ 2

Author(s):

Sara J. Allison ◽

William Gibson

Keyword(s):

General Population ◽

Overactive Bladder ◽

Real World ◽

Adrenergic Receptor ◽

Current Evidence ◽

Urgency Incontinence ◽

Antimuscarinic Agents ◽

Selective Agonist ◽

Real World Evidence ◽

High Prevalence

Overactive bladder (OAB), the syndrome characterized by urgency, with or without urgency incontinence, usually with frequency and nocturia, in the absence of infection or other pathology, is a common, distressing and often debilitating condition with a high prevalence in the general population. For many years, the only available pharmacological treatment for OAB were the antimuscarinic agents. More recently, mirabegron, a selective agonist of the β3 adrenergic receptor, has become available. In this article we review the current evidence and experience of its use.

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