Abstract 5501: Reduced Coronary Reserve as a Mechanism in Beta-Adrenergic Receptor Mediated Cardiomyopathy and its Rescue by Adenylyl Cyclase Type 5 Knockout

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shumin Gao ◽  
Lin Yan ◽  
Chull Hong ◽  
Xin Zhao ◽  
Li Chen ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Mouse Models ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Potential Mechanism ◽  
Wild Type ◽  
Coronary Reserve ◽  
Small Heart ◽  
Cardinal Feature ◽  
Adenylyl Cyclase Type 5

Reduced coronary reserve (CR) is a cardinal feature of human cardiomyopathy, but it has not been studied extensively in mouse models of cardiomyopathy, potentially because of difficulties inherent to measuring CR in such a small heart. The first goal of this study was to determine if reduced CR is a potential mechanism involved in a transgenic (Tg) mouse model of cardiomyopathy, induced by cardiac overexpression of beta 2 -adrenergic receptors (beta 2 -AR Tg). Older beta 2 -AR Tg mice (16–17 months, n=7) developed cardiomyopathy, as reflected by decreased LV ejection fraction (LVEF, 50±7%), and increased fibrosis (5.2±0.4%) and apoptosis (3.8±0.6%). CR was obtained by measuring LV coronary blood flow at baseline and with adenosine (160 microg/kg/min) induced hyperemia using high resolution ultrasound (Vevo 770). CR was significantly decreased in beta 2 -AR Tg (1.8±0.2) compared with wild type (WT) (3.0±0.3, n=6). The next goal was to determine if the rescue of the beta 2 -AR Tg cardiomyopathy resulted in a rescue of reduced CR. Since adenylyl cyclase type 5 knockout (AC5 KO) mice are protected against catecholamine stress and the development of heart failure (HF), and exhibit enhanced CR (3.7±0.4, n=5), we hypothesized that mating these mice with beta 2 -AR Tg might rescue the cardiomyopathy. Older (16–17 months, n=4) bigenic mice (beta 2 -AR Tg x AC5 KO) demonstrated a rescue of cardiomyopathy, as reflected by normalized LVEF (71±1%) and levels of apoptosis (0.11±0.01%) and fibrosis (1.09±0.33%), similar to WT. In these mice, CR was also normalized (3.4±0.6). Reduced CR in beta 2 -AR Tg cardiomyopathy is similar to that observed in large mammalian models, and in patients with cardiomyopathy. Thus, this mechanism is important to consider in mouse models of cardiomyopathy, in general, and also in particular for the mechanism of the rescue of the beta 2 -AR Tg cardiomyopathy by AC5 KO.

scholarly journals Bitransgenesis with β2-Adrenergic Receptors or Adenylyl Cyclase Fails to Improve β1-Adrenergic Receptor Cardiomyopathy

2008 ◽  
Vol 1 (3) ◽  
pp. 221-227 ◽  
Author(s):  
Natalia Petrashevskaya ◽  
Brigitte R. Gaume ◽  
Kathryn A. Mihlbachler ◽  
Gerald W. Dorn II ◽  
Stephen B. Liggett
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor

Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes

2005 ◽  
Vol 289 (6) ◽  
pp. H2441-H2449 ◽  
Author(s):  
Daniel Bernstein ◽  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
Takashi Urashima ◽  
Jennifer Powers ◽  
...  
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Contractile Function ◽  
Cardiovascular Effects ◽  
Fold Increase ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Selective Antagonist

Recent data suggest that β-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of β1- vs. β2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to β1, β2, and β1/β2 knockout (−/−) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and β1−/− mice showed no acute cardiovascular effects, whereas β2−/− mice all died within 30 min. The additional deletion of the β1-receptor (β1/β2−/−) totally rescued this toxicity. β2−/− mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued β2−/− mice from this acute toxicity. The enhanced toxicity in β2−/− mice was also recapitulated in wild-type mice with the β2-selective antagonist ICI-118,551, although the rescue effect of the β1-deletion was not recapitulated using the β1-selective antagonist metoprolol or the nonselective β-antagonist propranolol. These data suggest that β2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas β1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate β-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these β-adrenergic receptor subtypes in vivo.

scholarly journals α1- and β1-Adrenoceptor Signaling Fully Compensates for β3-Adrenoceptor Deficiency in Brown Adipocyte Norepinephrine-Stimulated Glucose Uptake

Endocrinology ◽  
2005 ◽  
Vol 146 (5) ◽  
pp. 2271-2284 ◽  
Author(s):  
Ekaterina Chernogubova ◽  
Dana S. Hutchinson ◽  
Jan Nedergaard ◽  
Tore Bengtsson
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Phosphatidylinositol 3 Kinase ◽  
Brown Adipocytes ◽  
Receptor Mrna ◽  
Phosphatidylinositol 3

Abstract To assess the relative roles and potential contribution of adrenergic receptor subtypes other than the β3-adrenergic receptor in norepinephrine-mediated glucose uptake in brown adipocytes, we have here analyzed adrenergic activation of glucose uptake in primary cultures of brown adipocytes from wild-type and β3-adrenergic receptor knockout (KO) mice. In control cells in addition to high levels of β3-adrenergic receptor mRNA, there were relatively low α1A-, α1D-, and moderate β1-adrenergic receptor mRNA levels with no apparent expression of other adrenergic receptors. The levels of α1A-, α1D-, and β1-adrenergic receptor mRNA were not changed in the β3-KO brown adipocytes, indicating that the β3-adrenergic receptor ablation does not influence adrenergic gene expression in brown adipocytes in culture. As expected, the β3-adrenergic receptor agonists BRL-37344 and CL-316 243 did not induce 2-deoxy-d-glucose uptake in β3-KO brown adipocytes. Surprisingly, the endogenous adrenergic neurotransmitter norepinephrine induced the same concentration-dependent 2-deoxy-d-glucose uptake in wild-type and β3-KO brown adipocytes. This study demonstrates that β1-adrenergic receptors, and to a smaller degree α1-adrenergic receptors, functionally compensate for the lack of β3-adrenergic receptors in glucose uptake. β1-Adrenergic receptors activate glucose uptake through a cAMP/protein kinase A/phosphatidylinositol 3-kinase pathway, stimulating conventional and novel protein kinase Cs. The α1-adrenergic receptor component (that is not evident in wild-type cells) stimulates glucose uptake through a phosphatidylinositol 3-kinase and protein kinase C pathway in the β3-KO cells.

scholarly journals Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5

2010 ◽  
Vol 15 (5) ◽  
pp. 495-512 ◽  
Author(s):  
David Ho ◽  
Lin Yan ◽  
Kousaku Iwatsubo ◽  
Dorothy E. Vatner ◽  
Stephen F. Vatner
Keyword(s):  
Heart Failure ◽  
Adenylyl Cyclase ◽  
Adrenergic Receptor ◽  
Receptor Signaling ◽  
Adenylyl Cyclase Type 5

scholarly journals Inhibition of Adenylyl Cyclase Type 5 Increases Longevity and Healthful Aging through Oxidative Stress Protection

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Stephen F. Vatner ◽  
Ronald E. Pachon ◽  
Dorothy E. Vatner
Keyword(s):  
Oxidative Stress ◽  
Adenylyl Cyclase ◽  
Stress Resistance ◽  
Adrenergic Receptor ◽  
Erk Pathway ◽  
Receptor Stimulation ◽  
Cardiac Stress ◽  
Stress Protection ◽  
Oxidative Stress Protection ◽  
Adenylyl Cyclase Type 5

Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against diabetes, obesity, and the cardiomyopathy induced by aging, diabetes, and cardiac stress and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection. For example, chronic beta adrenergic receptor stimulation induced cardiomyopathy was rescued by AC5 KO. Conversely, in AC5 transgenic (Tg) mice, where AC5 is overexpressed in the heart, the cardiomyopathy was exacerbated and was rescued by enhancing oxidative stress resistance. Thus, the AC5 KO model, which resists oxidative stress, is uniquely designed for clinical translation, since it not only increases longevity and exercise, but also protects against diabetes, obesity, and cardiomyopathy. Importantly, inhibition of AC5’s action to prolong longevity and enhance healthful aging, as well as its mechanism through resistance to oxidative stress, is unique among all of the nine AC isoforms.

Effects of coronary arterial reperfusion on beta-adrenergic receptor-adenylyl cyclase coupling

1993 ◽  
Vol 264 (1) ◽  
pp. H196-H204 ◽  
Author(s):  
D. E. Vatner ◽  
K. Kiuchi ◽  
W. T. Manders ◽  
S. F. Vatner
Keyword(s):  
Adenylyl Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Cyclase Activity ◽  
Receptor Density ◽  
Beta Adrenergic Receptors ◽  
Adenylyl Cyclase Activity ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
High Affinity

The effects of 1 h of coronary arterial occlusion (CAO) followed by 15 min reperfusion (CAR) were examined in nine conscious dogs. Ischemia was verified by decreased regional blood flow (radioactive microspheres) and loss of systolic regional wall motion in the ischemic zone. beta-Adrenergic receptor density assessed by 125I-labeled cyanopindolol binding in a crude membrane fraction tended to decrease but was not significantly different. However, adenylyl cyclase activity and the guanine nucleotide stimulatory protein (Gs) were reduced in ischemic subendocardium compared with nonischemic subendocardium. The fraction of beta-adrenergic receptors binding agonist with high affinity increased in ischemic subendocardial and subepicardial layers. Compared with prior data in experiments with 1 h CAO without CAR, the increase in beta-adrenergic receptor density that occurs with myocardial ischemia is rapidly reversed with CAR of 15 min duration, while the decreased fraction of receptors binding agonist with high affinity was reversed to an increase in high-affinity receptors. The global decreases in adenylyl cyclase and Gs, which have been observed with simple CAO, persist but are observed selectively in the previously ischemic subendocardium after CAR. Thus both CAO and CAR affect beta-adrenergic receptors and adenylyl cyclase differently. During CAR, increased numbers of beta-adrenergic receptors binding agonist with high affinity occur potentially as a compensatory mechanism in the face of persistent reductions in adenylyl cyclase activity and Gs.

Inhibition of Glutamatergic Synaptic Input to Spinal Lamina IIo Neurons by Presynaptic α2-Adrenergic Receptors

2002 ◽  
Vol 87 (4) ◽  
pp. 1938-1947 ◽  
Author(s):  
Yu-Zhen Pan ◽  
De-Pei Li ◽  
Hui-Lin Pan
Keyword(s):  
Receptor Antagonist ◽  
Synaptic Input ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Dorsal Root ◽  
Primary Afferents ◽  
Noradrenergic System ◽  
Analgesic Action ◽  
Adrenergic Agonists ◽  
Excitatory Synaptic Input

Activation of spinal α2-adrenergic receptors by the descending noradrenergic system and α2-adrenergic agonists produces analgesia. However, the sites and mechanisms of the analgesic action of spinally administered α2-adrenergic receptor agonists such as clonidine are not fully known. The dorsal horn neurons in the outer zone of lamina II (lamina IIo) are important for processing nociceptive information from C-fiber primary afferents. In the present study, we tested a hypothesis that activation of presynaptic α2-adrenergic receptors by clonidine inhibits the excitatory synaptic input to lamina IIo neurons. Whole cell voltage-clamp recordings were performed on visualized lamina IIo neurons in the spinal cord slice of rats. The miniature excitatory postsynaptic currents (mEPSCs) were recorded in the presence of tetrodotoxin, bicuculline, and strychnine. The evoked EPSCs were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Both mEPSCs and evoked EPSCs were abolished by application of 6-cyano-7-nitroquinoxaline-2,3-dione. Clonidine (10 μM) significantly decreased the frequency of mEPSCs from 5.8 ± 0.9 to 2.7 ± 0.6 Hz (means ± SE) without altering the amplitude and the decay time constant of mEPSCs in 25 of 27 lamina IIo neurons. Yohimbine (2 μM, an α2-adrenergic receptor antagonist), but not prazosin (2 μM, an α1-adrenergic receptor antagonist), blocked the inhibitory effect of clonidine on the mEPSCs. Clonidine (1–20 μM, n = 8) also significantly attenuated the peak amplitude of evoked EPSCs in a concentration-dependent manner. The effect of clonidine on evoked EPSCs was abolished in the presence of yohimbine ( n = 5). These data suggest that clonidine inhibits the excitatory synaptic input to lamina IIo neurons through activation of α2-adrenergic receptors located on the glutamatergic afferent terminals. Presynaptic inhibition of glutamate release from primary afferents onto lamina IIoneurons likely plays an important role in the analgesic action produced by activation of the descending noradrenergic system and α2-adrenergic agonists.

scholarly journals Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Barbara Jana ◽  
Jarosław Całka
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Domestic Animals ◽  
Inhibitory Effect ◽  
Receptor Subtypes ◽  
Beta Adrenergic Receptor ◽  
Pharmacological Modulation ◽  
Uterine Inflammation ◽  
Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

scholarly journals Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors.

1993 ◽  
Vol 268 (5) ◽  
pp. 3201-3208
Author(s):  
S. Pippig ◽  
S. Andexinger ◽  
K. Daniel ◽  
M. Puzicha ◽  
M.G. Caron ◽  
...  
Keyword(s):  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Receptor Kinase ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
Beta 2
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