scholarly journals β3-adrenoceptor-mediated increased circulating transaminase levels in mice treated with its agonist BRL 37344

2010 ◽  
Vol 35 (5) ◽  
pp. 779-784 ◽  
Author(s):  
Hiroko Kasahara ◽  
Shin-ichi Muto ◽  
Yoshiyuki Motokawa ◽  
Nobuhiko Arisaka ◽  
Sayaka Kobayashi ◽  
...  
Keyword(s):  
Brl 37344

scholarly journals Role of β1- and β3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes

1997 ◽  
Vol 273 (4) ◽  
pp. C1136-C1142 ◽  
Author(s):  
Claude Atgié ◽  
François D’Allaire ◽  
Ludwik J. Bukowiecki
Keyword(s):  
Competitive Inhibition ◽  
Synaptic Cleft ◽  
Minor Role ◽  
Brown Adipocytes ◽  
Respiratory Effects ◽  
High Affinity ◽  
Brown Adipose ◽  
A Minor ◽  
Brl 37344

To evaluate the physiological functions of β1-, β2-, and β3-adrenoceptors (ARs) in brown adipose tissue, the lipolytic and respiratory effects of various adrenergic agonists and antagonists were studied in rat brown adipocytes. The β-agonists stimulated both lipolysis and respiration (8–10 times above basal levels), with the following order of potency (concentration eliciting 50% of maximum response): CL-316243 (β3) > BRL-37344 (β3) > isoproterenol (mainly β1/β2) > norepinephrine (NE; mainly β1/β2) > epinephrine (mainly β1/β2) ≫ dobutamine (β1) ≫ procaterol (β2). Schild plot coefficients of competitive inhibition experiments using ICI-89406 (β1 antagonist) revealed that more than one type of receptor mediates NE action. It is concluded from our results that 1) NE, at low plasma levels (1–25 nM), stimulates lipolysis and respiration mainly through β1-ARs, 2) NE, at higher levels, stimulates lipolysis and respiration via both β1- and β3-ARs, 3) β2-ARs play only a minor role, and 4) β3-ARs may represent the physiological receptors for the high NE concentrations in the synaptic cleft, where the high-affinity β1-ARs are presumably desensitized. It is also suggested that lipolysis represents the flux-generating step regulating mitochondrial respiration.

scholarly journals sGCα1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling

2011 ◽  
Vol 301 (1) ◽  
pp. H157-H163 ◽  
Author(s):  
Sharon M. Cawley ◽  
Starsha Kolodziej ◽  
Fumito Ichinose ◽  
Peter Brouckaert ◽  
Emmanuel S. Buys ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Soluble Guanylate Cyclase ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Spermine Nonoate ◽  
Brl 37344

In the heart, nitric oxide (NO) modulates contractile function; however, the mechanisms responsible for this effect are incompletely understood. NO can elicit effects via a variety of mechanisms including S-nitrosylation and stimulation of cGMP synthesis by soluble guanylate cyclase (sGC). sGC is a heterodimer comprised of a β1- and an α1- or α2-subunit. sGCα1β1 is the predominant isoform in the heart. To characterize the role of sGC in the regulation of cardiac contractile function by NO, we compared left ventricular cardiac myocytes (CM) isolated from adult mice deficient in the sGC α1-subunit (sGCα1−/−) and from wild-type (WT) mice. Sarcomere shortening under basal conditions was less in sGCα1−/− CM than in WT CM. To activate endogenous NO synthesis from NO synthase 3, CM were incubated with the β3-adrenergic receptor (β3-AR) agonist BRL 37344. BRL 37344 decreased cardiac contractility in WT CM but not in sGCα1−/− myocytes. Administration of spermine NONOate, an NO donor compound, did not affect sarcomeric shortening in CM of either genotype; however, in the presence of isoproterenol, addition of spermine NONOate reduced sarcomere shortening in WT but not in sGCα1−/− CM. Neither BRL 37344 nor spermine NONOate altered calcium handling in CM of either genotype. These findings suggest that sGCα1 exerts a positive inotropic effect under basal conditions, as well as mediates the negative inotropic effect of β3-AR signaling. Additionally, our work demonstrates that sGCα1β1 is required for NO to depress β1/β2-AR-stimulated cardiac contractility and that this modulation is independent of changes in calcium handling.

scholarly journals Stimulation of β3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels

2008 ◽  
Vol 295 (5) ◽  
pp. C1344-C1353 ◽  
Author(s):  
Kiril L. Hristov ◽  
Xiangli Cui ◽  
Sean M. Brown ◽  
Lei Liu ◽  
Whitney F. Kellett ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bk Channels ◽  
Bk Channel ◽  
Bladder Smooth Muscle ◽  
Rat Urinary Bladder ◽  
Urinary Bladder Smooth Muscle ◽  
Brl 37344 ◽  
Stimulation Of

We investigated the role of large-conductance Ca2+-activated K+ (BK) channels in β3-adrenoceptor (β3-AR)-induced relaxation in rat urinary bladder smooth muscle (UBSM). BRL 37344, a specific β3-AR agonist, inhibits spontaneous contractions of isolated UBSM strips. SR59230A, a specific β3-AR antagonist, and H89, a PKA inhibitor, reduced the inhibitory effect of BRL 37344. Iberiotoxin, a specific BK channel inhibitor, shifts the BRL 37344 concentration response curves for contraction amplitude, net muscle force, and tone to the right. Freshly dispersed UBSM cells and the perforated mode of the patch-clamp technique were used to determine further the role of β3-AR stimulation by BRL 37344 on BK channel activity. BRL 37344 increased spontaneous, transient, outward BK current (STOC) frequency by 46.0 ± 20.1%. In whole cell mode at a holding potential of Vh = 0 mV, the single BK channel amplitude was 5.17 ± 0.28 pA, whereas in the presence of BRL 37344, it was 5.55 ± 0.41 pA. The BK channel open probability was also unchanged. In the presence of ryanodine and nifedipine, the current-voltage relationship in response to depolarization steps in the presence and absence of BRL 37344 was identical. In current-clamp mode, BRL 37344 caused membrane potential hyperpolarization from −26.1 ± 2.1 mV (control) to −29.0 ± 2.2 mV. The BRL 37344-induced hyperpolarization was eliminated by application of iberiotoxin, tetraethylammonium or ryanodine. The data indicate that stimulation of β3-AR relaxes rat UBSM by increasing the BK channel STOC frequency, which causes membrane hyperpolarization and thus relaxation.

Physiological desensitization of beta 3-adrenergic responses in brown fat cells: involvement of a postreceptor process

1993 ◽  
Vol 265 (5) ◽  
pp. C1340-C1348 ◽  
Author(s):  
L. Unelius ◽  
G. Bronnikov ◽  
N. Mohell ◽  
J. Nedergaard
Keyword(s):  
Oxygen Consumption ◽  
Brown Fat ◽  
Fat Cells ◽  
Cyclic Monophosphate ◽  
Adrenergic Response ◽  
Rate Of Oxygen Consumption ◽  
Cgp 12177 ◽  
Beta Adrenergic Agonist ◽  
Increased Activity ◽  
Brl 37344

To investigate a possible physiological desensitization process for beta 3-adrenergic responses, the effect of cold acclimation of hamsters on adrenergically stimulated oxygen consumption of isolated brown fat cells was investigated. Cells were prepared from control and from cold-acclimated hamsters. In agreement with earlier findings, cells isolated from cold-acclimated hamsters responded to norepinephrine addition with a decreased sensitivity (approximately 10 times higher 50% effective concentration) and a decreased maximal rate of oxygen consumption compared with cells from control hamsters. When cells were stimulated with the general beta-adrenergic agonist isoprenaline or with the beta 3-selective agonists BRL-37344 or CGP-12177, a similarly desensitized response was observed, demonstrating that it was indeed a beta 3-adrenergic response that was functionally desensitized. However, when the mitochondria within the cells were directly stimulated with exogenous free fatty acids (palmitate or octanoate), no difference between cells from control and cold-acclimated animals was seen, indicating that a mediatory step must be desensitized. When the cells were stimulated with forskolin (to activate adenylyl cyclase) or with 8-bromoadenosine 3',5'-cyclic monophosphate, the desensitized response was still observed. At post-adenosine 3',5'-cyclic monophosphate levels, a desensitization was not evident. Cyclic nucleotide phosphodiesterase activity was increased in cells from cold-acclimated animals. It is therefore suggested that this increased activity of phosphodiesterase could be (at least partly) responsible for the physiologically induced desensitized responses observed here.(ABSTRACT TRUNCATED AT 250 WORDS)

Predominance of beta 3-adrenergic component in catecholamine activation of lipolysis in garden dormouse adipocytes

1994 ◽  
Vol 266 (3) ◽  
pp. R896-R904 ◽  
Author(s):  
C. Carpene ◽  
L. Ambid ◽  
M. Lafontan
Keyword(s):  
Lipolytic Activity ◽  
Beta Agonist ◽  
Intrinsic Activity ◽  
White Adipocytes ◽  
Garden Dormouse ◽  
Half Maximal Effective Concentration ◽  
Eliomys Quercinus ◽  
Cgp 12177 ◽  
20 Nm ◽  
Brl 37344

The beta 3-adrenoceptor (AR) agonists are potent activators of lipolysis in white adipose tissue. beta-AR agonists were tested here on the lipolytic activity of a hibernator, the garden dormouse (Eliomys quercinus L.). All the agonists exhibited full intrinsic activity; the most potent was the beta 3-AR agonist BRL-37344 [half-maximal effective concentration (EC50) = 0.8 nM]. The beta-antagonist idocyanopindolol (ICYP) also stimulated lipolysis of white adipocytes with the same potency and intrinsic activity as BRL-37344. The blockade of lipolytic effects of epinephrine or norepinephrine was similar to that of BRL-37344: the beta 1- and the beta 2-antagonists were quite ineffective. Total blockade occurred only with 100 microM bupranolol whatever the beta-agonist tested. This argues for the presence of a beta 3-component in the adrenergic-induced lipolysis. (-)-[125I]ICYP and (-)-[3H]CGP-12177 both labeled two populations of binding sites. On adipocyte membranes, binding of 0.6 nM (-)-[3H]CGP-12177 was inhibited with the following order of potency: isoproterenol > BRL-37344 > epinephrine. This order was modified at 20 nM, arguing for the beta-atypical nature of the low-affinity sites. Thus garden dormouse adipocytes possess beta 3-ARs, which are involved to an important degree in the adrenergic activation of lipolysis.

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