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Thread: Nebivolol

  1. #61
    Senior Member The450Man's Avatar
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    by the way, would nebivolol potentiate the effects of pde5 inhibitors?

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    Senior Member Benson's Avatar
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    Quote Originally Posted by The450Man View Post
    by the way, would nebivolol potentiate the effects of pde5 inhibitors?
    Possibly. Erection is a parasympathetic-mediated action...so getting in the way of beta-adrenergic agonism might help with this...nebivolol, specifically, is also thought to work via increased nitric oxide levels so it might be more likely to improve erectile response than other beta blockers.
    Remember, believe none of what you hear and half of what you see...





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    Senior Member The450Man's Avatar
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    How long does nebivolol last in the body?

    I know the half life is like 10 hours.

    It seems to work well for 6 -10 hours after i take it but I seem to have anxiety symptoms in the evening.

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    Senior Member Benson's Avatar
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    Quote Originally Posted by The450Man View Post
    It seems to work well for 6 -10 hours after i take it but I seem to have anxiety symptoms in the evening.
    You've answered your own question. After one half-life, the circulating dose has dropped below what you require for anxiety control. So you can either dose it BID or take twice as much...
    Remember, believe none of what you hear and half of what you see...





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    I'm on atenolol @25mg/ed.What kind of benefits would i see by switching to nebivolol ?
    Which different kinds of receptors would be more/less stimulated by nebivolol and what would be a similar potency dosage ?

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    Senior Member The450Man's Avatar
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    Im still confused as hell as to how nebivolol increases testosterone.

    Is it because it increases ledig cell sensitivity?

    This is the only mode I can think of, unless it decreases aromatase activity...

    I cant find much literature at all.

  7. #67
    Senior Member Benson's Avatar
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    Quote Originally Posted by The450Man View Post
    Im still confused as hell as to how nebivolol increases testosterone.
    I don't think anyone knows the answer to this.
    Remember, believe none of what you hear and half of what you see...





  8. #68
    Senior Member The450Man's Avatar
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    Quote Originally Posted by Benson View Post
    I don't think anyone knows the answer to this.
    yea its driving me nuts.

    Im combining it with clomid so hopefully they both compliment each other.

  9. #69
    Senior Member The450Man's Avatar
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    helps burn body fat

    Abstract 1617: Nebivolol Induces Lipolysis and Uncoupling Protein 1 Expression in Ex-vivo Human Visceral Adipocytes -- Bordicchia et al. 120 (10018): S530 -- Circulation

    Introduction and Hypothesis. Selective β1 blockers havemetabolic side effects such as increasing adiposity, dyslipidemia,and dysglycemia. Nebivolol (a racemic mixture of D- and L-enantiomers)is a β1 blocker with vasodilatatory activity mediated throughβ3 adrenergic receptors (ADRB3) because of agonist activityof the L-enantiomer. Nebivolol appers to lack the adverse metabolicside effects of other β1 blockers. In this study we examinedwhether nebivolol was able to induce ADRB3-mediated lipolysisand UCP1 expression, key steps in the use of fatty acids forthermogenesis.
    Methods. Human visceral mature adipocytes were isolated fromomental adipose tissue obtained during elective abdominal surgery(n=20). Gene expression of ADRB1, ADRB2, ADRB3, and uncouplingprotein 1 (UCP1), and adipocyte markers were analysed. ADRB3were also investigated by western blotting. The effects of isoproterenol,ADRB3 agonists (CL316243 , BRL37344 ), ADBR1 blocker (metoprolol),ADRB3 antagonist (SR59230A), nebivolol (D and L mixture as wellas both pure enantiomers) on lipolysis (free glycerol production)and UCP1 expression (evaluated by Real Time PCR-TaqMan assay)were studied in vitro.
    Results. Ex-vivo tissue and adipocytes expressed all ADRB receptors,hormone sensitive lipase, and adipocyte markers (adiponectinand leptin). ADRB3 mRNA and protein were expressed in variableamounts. As expected, isoproterenol and ADRB3 agonists inducedfrank lipolysis whereas non-vasodilating β1 blockers didnot. ADBR3 antagonist did not induce lipolysis. Nebivolol inducedsignificant lipolysis (about 2.8-fold, p=0.026) that was mediatedby the L-enantiomer (about 50% of the isoproterenol-inducedlipolysis at same concentrations). Pre-incubation for 30’with SR59230A induced a blockade of the lipolytic effects ofL-nebivolol and nebivolol. Only nebivolol was able to induceUCP1 gene expression (about 3-fold, P=0.032).
    Conclusions. Nebivolol activates ADRB3-mediated lipolysis andinduces UCP1 gene expression in human visceral adipocytes, apathway known to lead to thermogenesis and weight loss. Treatmentof obese hypertensive patients with nebivolol reduce blood pressurebut also could induce positive metabolic effect acting on visceraladipose tissue.

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    Senior Member The450Man's Avatar
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    makes sense

    From wiki:

    Stimulation of β1 receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity.[26] Stimulation of β1 receptors on the kidney causes renin release.[27] Stimulation of β2 receptors induces smooth muscle relaxation,[28] induces tremor in skeletal muscle,[29] and increases glycogenolysis in the liver and skeletal muscle.[30] Stimulation of β3 receptors induces lipolysis.[31]
    one thing that intrigued me was that stimulation of B2 receptors induces tremor in skeletal muscle.

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    Senior Member The450Man's Avatar
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    Been doing lots of thinking lately.

    It appears chronic treatment with sildenafil increases testosterone through cAMP mediated effects.

    Nebivolol also seems to have an effect on cAMP. I wonder if this is how or part of the reason why nebivolol increases testosterone.

    Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway, Silvana A. Andric, AJP - Endo October 2010 vol. 299 no. 4 E544-E550

    Abstract

    Sildenafil citrate (Viagra), a cGMP-selective phosphodiesterase (PDE) inhibitor, is widely used to treat erectile dysfunction and pulmonary arterial hypertension. In contrast to its well established action on erectile dysfunction, little is known on the action of sildenafil on cGMP/cAMP signaling and testicular steroidogenesis. This study was designed to assess the effects of prolonged sildenafil treatment on NO synthase-dependent signaling and steroidogenic function of rat Leydig cells.

    Male adult rats were treated with Viagra (1.25 mg/kg body wt) daily for 30 days. In our studies, serum testosterone and ex vivo testosterone production significantly increased in sildenafil-treated animals. Human chorionic gonadotropin-stimulated testosterone production and cAMP accumulation were also significantly higher in Leydig cells obtained from sildenafil-treated rats. The expression of soluble guanylyl cyclase (GUCY1) subunits (Gucy1a1, Gucy1b1) significantly increased; cAMP-specific Pde4a, cGMP-specific Pde6c, and dual Pde1c and Nos2 were inhibited and expression of Nos3, protein kinase G1 (Pkg1), and Pde5 remained unchanged. Treatment of purified Leydig cells with NO donor caused a dose-dependent increase in both testosterone and cGMP production. Testosterone and cGMP production was significantly higher in Leydig cells obtained from sildenafil-treated animals. The stimulatory effect of NO donor was significantly enhanced by saturating concentrations of hCG in both Leydig cells obtained from control and sildenafil-treated animals. Occurrence of mature steroidogenic acute regulatory protein also increased in sildenafil treated animals in accord with increased cAMP and cGMP production. In summary, inhibition of PDE activity during prolonged sildenafil treatment increased serum testosterone level and Leydig cells' steroidogenic capacity by coordinated stimulatory action on cAMP and cGMP signaling pathway.

  14. #74
    Senior Member The450Man's Avatar
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    Would nebivolol increase activation of β2-adrenergic receptors? as an "indirect agonist"?

    Possible benefits:

    Expression profiling of skeletal muscle following acute and chronic β2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm.
    Michael A Pearen, James G Ryall, Gordon S Lynch and George EO Muscat

    Abstract

    BACKGROUND: Systemic administration of beta-adrenoceptor (beta-AR) agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of beta-AR signaling has been highlighted by the inability of beta(1-3)-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic (acute and chronic) administration of the beta(2)-AR agonist formoterol.


    RESULTS: Skeletal muscle gene expression (from murine tibialis anterior) was profiled at both 1 and 4 hours following systemic administration of the beta(2)-AR agonist formoterol, using Illumina 46K mouse BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. Differentially expressed genes relevant to the regulation of muscle mass and metabolism (in the context of the hypertrophic phenotype) were further validated by quantitative RT-PCR to examine gene expression in response to both acute (1-24 h) and chronic administration (1-28 days) of formoterol at multiple timepoints. In terms of skeletal muscle hypertrophy, attenuation of myostatin signaling (including differential expression of myostatin, activin receptor IIB, phospho-Smad3 etc) was observed following acute and chronic administration of formoterol. Acute (but not chronic) administration of formoterol also significantly induced the expression of genes involved in oxidative metabolism, including hexokinase 2, sorbin and SH3 domain containing 1, and uncoupling protein 3. Interestingly, formoterol administration also appeared to influence some genes associated with the peripheral regulation of circadian rhythm (including nuclear factor interleukin 3 regulated, D site albumin promoter binding protein, and cryptochrome 2).


    CONCLUSION: This is the first study to utilize gene expression profiling to examine global gene expression in response to acute beta(2)-AR agonist treatment of skeletal muscle. In summary, systemic administration of a beta(2)-AR agonist had a profound effect on global gene expression in skeletal muscle. In terms of hypertrophy, beta(2)-AR agonist treatment altered the expression of several genes associated with myostatin signaling, a previously unreported effect of beta-AR signaling in skeletal muscle. This study also demonstrates a beta(2)-AR agonist regulation of circadian rhythm genes, indicating crosstalk between beta-AR signaling and circadian cycling in skeletal muscle. Gene expression alterations discovered in this study provides insight into many of the underlying changes in gene expression that mediate beta-AR induced skeletal muscle hypertrophy and altered metabolism.

  15. #75
    Senior Member Benson's Avatar
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    Nevibolol is an antagonist.

    This article is talking about the anabolic effects of stuff like clenbuterol.
    Remember, believe none of what you hear and half of what you see...





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    Senior Member The450Man's Avatar
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    Quote Originally Posted by Benson View Post
    Nevibolol is an antagonist.

    This article is talking about the anabolic effects of stuff like clenbuterol.
    yes but isnt it a selective antagonist at beta 1 receptors? Wouldnt this indirectly act as an agonist at beta2, beta 3 etc. due to less adrenic hormones "attached" to the beta 1 receptor allowing a greater level of adrenic hormones to attach to the other adrenic receptors?

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    Quote Originally Posted by The450Man View Post
    yes but isnt it a selective antagonist at beta 1 receptors? Wouldnt this indirectly act as an agonist at beta2, beta 3 etc. due to less adrenic hormones "attached" to the beta 1 receptor allowing a greater level of adrenic hormones to attach to the other adrenic receptors?
    Doesn't work that way. "Attached" doesn't mean "trapped" and, more importantly, the key here is that the beta-1 receptor is not an autoreceptor.

    In contrast, a 5-HT1A antagonist does indirectly result in 5-HT2A, 5-HT2C, 5-HT3, etc. agonism, as reduced autoreceptor binding means more 5-HT release. But this only works because the 5-HT1A receptor is -- in some regions -- an autoreceptor, and has nothing to do with "attaching" or "trapping" 5-HT.

  18. #78
    Senior Member The450Man's Avatar
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    Quote Originally Posted by Ex Dubio View Post
    Doesn't work that way. "Attached" doesn't mean "trapped" and, more importantly, the key here is that the beta-1 receptor is not an autoreceptor.

    In contrast, a 5-HT1A antagonist does indirectly result in 5-HT2A, 5-HT2C, 5-HT3, etc. agonism, as reduced autoreceptor binding means more 5-HT release. But this only works because the 5-HT1A receptor is -- in some regions -- an autoreceptor, and has nothing to do with "attaching" or "trapping" 5-HT.
    icic

    antagonising an autoreceptor would increase production of the hormone/neurotransmitter.

    BUT

    Crudely it is, wouldnt there be the same levels of said hormone in circulation?

    A crude example. You have A receptor a B Receptop and a C Receptor. X has equal affinity for all receptors (A, B, and C)

    You block off receptor a with an antagonist. This leaves what would of attached to receptor A to attach to receptor B and C.

    The one explanation is that one of the beta adrenic receptors not effected by nebivolol is an auto receptor, possibly decreasing adrinic hormone levels.

    Sorry, Im in a complete mind fuck right now.

  19. #79
    Senior Member Ex Dubio's Avatar
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    Quote Originally Posted by The450Man View Post
    icic

    antagonising an autoreceptor would increase production of the hormone/neurotransmitter.
    Correct.

    Crudely it is, wouldnt there be the same levels of said hormone in circulation?

    A crude example. You have A receptor a B Receptop and a C Receptor. X has equal affinity for all receptors (A, B, and C)

    You block off receptor a with an antagonist. This leaves what would of attached to receptor A to attach to receptor B and C.
    This is where you make a mistake.

    See, most of a drug is not "used up" binding to the receptors; instead, most of an ingested drug is sitting in circulation at any given time. So the fact that some is binding to B -- without the antagonist -- really has no effect on A. The idea is this:

    There are 1,000,000 units of X total, with 10 units binding to each receptor, and 999,970 left in circulation. Block B and C and you have 999,990 units in circulation. But this is an irrelevant change in the circulating concentration of X, so the effect on receptor A is virtually unchanged.

    Does that make sense?

  20. #80
    Senior Member The450Man's Avatar
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    icic. my understanding is getting clearer.

    My biggest question was wondering if nebivolol had any effect on muscle hypertrophy.

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