scholarly journals α1-Adrenergic receptor subtype function in fetal and adult cerebral arteries

2010 ◽  
Vol 298 (6) ◽  
pp. H1797-H1806 ◽  
Author(s):  
Ravi Goyal ◽  
Ashwani Mittal ◽  
Nina Chu ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Adrenergic Receptor ◽  
Cerebral Arteries ◽  
Age Groups ◽  
Critical Factor ◽  
Receptor Subtype ◽  
Erk Activation ◽  
Wb 4101 ◽  
Intracellular Ca ◽  
Nonpregnant Adult ◽  
And Function

In the developing fetus, cerebral artery (CA) contractility demonstrates significant functional differences from that of the adult. This may be a consequence of differential activities of α1-adrenergic receptor (α1-AR) subtypes. Thus we tested the hypothesis that maturational differences in adrenergic-mediated CA contractility are, in part, a consequence of differential expression and/or activities of α1-AR subtypes. In CA from fetal (∼140 days) and nonpregnant adult sheep, we used wire myography and imaging, with simultaneous measurement of tension and intracellular Ca2+ concentration ([Ca2+]i), radioimmunoassay, and Western immunoblots to examine phenylephrine (Phe)-induced contractile responses. The α1A-AR antagonists (5-MU and WB-4101) completely inhibited Phe-induced contraction in adult but not fetal CA; however, [Ca2+]i increase was reduced significantly in both age groups. The α1D-AR antagonist (BMY-7378) blocked both Phe-induced contractions and Ca2+ responses to a significantly greater extent in adult compared with fetal CA. In both age groups, inhibition of α1A-AR and α1B-AR, but not α1D-AR, significantly reduced inositol 1,4,5-trisphosphate responses to Phe. Western immunoblots demonstrated that the α1-AR subtype expression was only ∼20% in fetal CA compared with the adult. Moreover, in fetal CA, the α1D-AR was expressed significantly greater than the other two subtypes. Also, in fetal but not adult CA, Phe induced a significant increase in activated ERK1/2; this increase in phosphorylated ERK was blocked by α1B-AR (CEC) and α1D-AR (BMY-7378) inhibitors, but not by α1A-AR inhibitors (5-MU or WB-4101). In conclusion, in the fetal CA, α1B-AR and α1D-AR subtypes play a key role in contractile response as well as in ERK activation. We speculate that in fetal CA α1B-AR and α1D-AR subtypes may be a critical factor associated with cerebrovascular growth and function.

Abstract 5355: An Alpha-1A-Adrenergic Receptor Subtype Agonist Prevents Cardiomyopathy Without Increasing Blood Pressure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Trevor Chan ◽  
Rajesh Dash ◽  
Paul C Simpson
Keyword(s):  
Blood Pressure ◽  
Adrenergic Receptor ◽  
Dose Finding ◽  
Cancer Drug ◽  
Receptor Subtype ◽  
Erk Activation ◽  
Higher Doses ◽  
Fractional Shortening ◽  
Tail Cuff

Background: Alpha-1-adrenergic receptor (AR) agonists classically increase blood pressure (BP). Among the 3 alpha-1-AR subtypes, A, B, and D, the alpha-1A is required for cardiac protection in a knockout (KO) mouse, and is sufficient for protection of cultured cardiac myocytes, via ERK activation. However, it is unknown if activation of the alpha-1A-subtype by a drug can protect the heart in vivo. Hypothesis: At a dose that does not increase BP, an agonist selective for the alpha-1A-AR subtype can prevent cardiomyopathy. Methods: We gave the alpha-1A agonist A61603 (A6) to 11 week-old wild type (WT) male C57Bl6J mice by osmotic minipump. We induced cardiomyopathy with a single dose of doxorubicin (DOX) (25 mg/kg IP), a cardiotoxic cancer drug. We measured BP by tail cuff, activated (phosphorylated, P)-ERK by immunoblot, heart mRNAs by RT-qPCR, fractional shortening (FS) by echocardiog-raphy (ECHO), myocyte necrosis by serum creatine kinase (CK), apoptosis by TUNEL stain, and fibrosis by sirius red stain. Results : In dose-finding experiments (0.01–100 ug/kg/d), A6 at 10 ng/kg/d over 7 days had no effect on daily tail cuff BP (average mmHg Vehicle 115 ± 4; A6 119 ± 4), but increased heart P-ERK (1.7-fold) and the mRNAs for beta-MyHC and ANF (5-fold). A6 at higher doses increased BP. Next, A6 at the non-hypertensive dose (10 ng/kg/d) or vehicle was infused over 7 days after a single DOX injection. The TABLE shows that DOX caused cardiomyopathy, with reduced survival and FS, and increased necrosis, apoptosis, and fibrosis (data are mean ± SE). A6 prevented all of these abnormalities. In alpha-1A-subtype KO mice, DOX caused increased apoptosis and mortality compared with WT mice, and A6 had no beneficial effect (not shown), indicating specificity of A6. Conclusions: A very low dose of an agonist selective for the alpha-1A-AR subtype can activate cardiac survival signaling (P-ERK), induce cardiac fetal genes, and prevent DOX-induced cardiomyopathy, all without increasing BP.

Cerebral artery KATP- and KCa-channel activity and contractility: changes with development

2000 ◽  
Vol 279 (6) ◽  
pp. R2004-R2014 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Channel Blocker ◽  
Cerebral Arteries ◽  
Dependent Manner ◽  
Channel Activity ◽  
Channel Opener ◽  
Channel Inhibition ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Near Term ◽  
Nonpregnant Adult

The present study was designed to test the hypothesis that in cerebral arteries of the fetus, ATP-sensitive (KATP) and Ca2+-activated K+channels (KCa) play an important role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) and that this differs significantly from that of the adult. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, simultaneously we measured norepinephrine (NE)-induced responses of vascular tension and [Ca2+]i in the absence and presence of selective K+-channel openers/blockers. In fetal MCA, in a dose-dependent manner, both the KATP-channel opener pinacidil and the KCa-channel opener NS 1619 significantly inhibited NE-induced tension [negative logarithm of the half-maximal inhibitory concentration (pIC50) = 5.0 ± 0.1 and 8.2 ± 0.1, respectively], with a modest decrease of [Ca2+]i. In the adult MCA, in contrast, both pinacidil and NS 1619 produced a significant tension decrease (pIC50 = 5.1 ± 0.1 and 7.6 ± 0.1, respectively) with no change in [Ca2+]i. In addition, the KCa-channel blocker iberiotoxin (10−7 to 10−6 M) resulted in increased tension and [Ca2+]i in both adult and fetal MCA, although the KATP-channel blocker glibenclamide (10−7 to 3 × 10−5 M) failed to do so. Of interest, administration of 10−7 M iberiotoxin totally eliminated vascular contraction and increase in [Ca2+]i seen in response to 10−5M ryanodine. In precontracted fetal cerebral arteries, activation of the KATP and KCa channels significantly decreased both tension and [Ca2+]i, suggesting that both K+ channels play an important role in regulating L-type channel Ca2+ flux and therefore vascular tone in these vessels. In the adult, KATP and the KCa channels also appear to play an important role in this regard; however, in the adult vessel, activation of these channels with resultant vasorelaxation can occur with no significant change in [Ca2+]i. These channels show differing responses to inhibition, e.g., KCa-channel inhibition, resulting in increased tension and [Ca2+]i, whereas KATP-channel inhibition showed no such effect. In addition, the KCa channel appears to be coupled to the sarcoplasmic reticulum ryanodine receptor. Thus differences in plasma membrane K+-channel activity may account, in part, for the differences in the regulation of contractility of fetal and adult cerebral arteries.

Dual role of PKC in modulating pharmacomechanical coupling in fetal and adult cerebral arteries

2000 ◽  
Vol 279 (4) ◽  
pp. R1419-R1429 ◽  
Author(s):  
Lawrence D. Longo ◽  
Yu Zhao ◽  
Wen Long ◽  
Carolyn Miguel ◽  
Ryan S. Windemuth ◽  
...  
Keyword(s):  
Vascular Tone ◽  
Cerebral Arteries ◽  
Age Groups ◽  
Intracellular Ca ◽  
Membrane Bound ◽  
Near Term ◽  
Fetal Vessel ◽  
Pharmacomechanical Coupling ◽  
Induced Signal ◽  
Two Age Groups

This study tested the hypothesis that protein kinase C (PKC) has dual regulation on norepinephrine (NE)-mediated inositol 1,4,5-trisphosphate [Ins (1,4,5)P3] pathway and vasoconstriction in cerebral arteries from near-term fetal (∼140 gestational days) and adult sheep. Basal PKC activity values (%membrane bound) in fetal and adult cerebral arteries were 38 ± 4% and 32 ± 4%, respectively. In vessels of both age groups, the PKC isoforms α, βI, βII, and δ were relatively abundant. In contrast, compared with the adult, cerebral arteries of the fetus had low levels of PKC-ε. In response to 10−4 M phorbol 12,13-dibutyrate (PDBu; PKC agonist), PKC activity in both fetal and adult cerebral arteries increased 40–50%. After NE stimulation, PKC activation with PDBu exerted negative feedback on Ins(1,4,5)P3 and intracellular Ca2+ concentration ([Ca2+]i) in arteries of both age groups. In turn, PKC inhibition with staurosporine resulted in augmented NE-induced Ins(1,4,5)P3 and [Ca2+]i responses in adult, but not fetal, cerebral arteries. In adult tissues, PKC stimulation by PDBu increased vascular tone, but not [Ca2+]i. In contrast, in the fetal artery, PKC stimulation was associated with an increase in both tone and [Ca2+]i. In the presence of zero extracellular [Ca2+], these PDBu-induced responses were absent in the fetal vessel, whereas they remained unchanged in the adult. We conclude that, although basal PKC activity was similar in fetal and adult cerebral arteries, PKC's role in NE-mediated pharmacomechanical coupling differed significantly in the two age groups. In both fetal and adult cerebral arteries, PKC modulation of NE-induced signal transduction responses would appear to play a significant role in the regulation of vascular tone. The mechanisms differ in the two age groups, however, and this probably relates, in part, to the relative lack of PKC-ε in fetal vessels.

Role of Ca2+ channels in NE-induced increase in [Ca2+]iand tension in fetal and adult cerebral arteries

1999 ◽  
Vol 277 (1) ◽  
pp. R286-R294 ◽  
Author(s):  
Wen Long ◽  
Yu Zhao ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Plasma Membrane ◽  
Cerebral Arteries ◽  
Channel Blockers ◽  
Developmental Age ◽  
Intracellular Ca ◽  
Lanthanum Ion ◽  
Near Term ◽  
Dose Dependent Decrease ◽  
Nonpregnant Adult

In vascular smooth muscle, elevation of agonist-induced intracellular Ca2+ concentration ([Ca2+]i) occurs via both Ca2+ release from intracellular stores and Ca2+influx across the plasma membrane. In the cerebral vasculature of the fetus and adult the relative roles of these mechanisms have not been defined. To test the hypothesis that plasma membrane L-type and receptor-operated Ca2+ channels play a key role in NE-induced vasoconstriction via alterations in plasma membrane Ca2+ flux and that this may change with developmental age, we performed the following study. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, we quantified NE-induced responses of vascular tension and [Ca2+]i(by use of fura 2) under standard conditions in response to several Ca2+ channel blockers and in response to zero extracellular Ca2+. In fetal and adult MCA, maximal NE-induced tensions (g) were 0.91 ± 0.12 ( n = 10) and 1.61 ± 0.13 ( n = 12), respectively. The pD2 values for NE-induced tension were both 6.0 ± 0.1, whereas the fetal and adult maximum responses (%Kmax) were 107 ± 16 and 119 ± 7, respectively. The fetal and adult pD2 values for NE-induced increase of [Ca2+]iwere 6.2 ± 0.1 and 6.4 ± 0.1, respectively, whereas maximum [Ca2+]iresponses were 81 ± 9 and 103 ± 15% of Kmax, respectively. After 10−5 M NE-induced contraction, nifedipine resulted in dose-dependent decrease in vessel tone and [Ca2+]iwith pIC50 values for fetal and adult tensions of 7.3 ± 0.1 and 6.6 ± 0.1, respectively ( P < 0.01; n = 4 each), whereas pIC50 for [Ca2+]iresponses were 7.2 ± 0.1 and 6.9 ± 0.1, respectively. The pIC50 values for tension for diltiazem and verapamil were somewhat lower but showed a similar relationship. The receptor-operated Ca2+ channel blocker 2-nitro-4 carboxyphenyl- N,N-diphenyl carbamate showed little effect on NE-induced vessel contractility or [Ca2+]i. In the absence of extracellular Ca2+ for 2 min, 10−5 M NE resulted in markedly attenuated responses of adult MCA tension and [Ca2+]ito 39 ± 7 and 73 ± 8% of control values ( n = 4). For fetal MCA, exposure to extracellular Ca2+concentration resulted in essentially no contractile or [Ca2+]iresponse ( n = 4). Similar blunting of NE-induced tension and [Ca2+]iwas seen in response to 10−3M lanthanum ion. These findings provide evidence to suggest that especially in fetal, but also in adult, ovine MCA, Ca2+ flux via L-type calcium channels plays a key role in NE-induced contraction. In contrast, Ca2+ flux via receptor-operated Ca2+ channels is of less importance. This developmental difference in the role of cerebrovascular plasma membrane Ca2+ channels may be an important association with increased Ca2+sensitivity of the fetal vessels.

Age-dependent modulation of endothelium-dependent vasodilatation by chronic hypoxia in ovine cranial arteries

2006 ◽  
Vol 100 (1) ◽  
pp. 225-232 ◽  
Author(s):  
James M. Williams ◽  
William J. Pearce
Keyword(s):  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Cerebral Arteries ◽  
Volume Of Distribution ◽  
Small Contribution ◽  
Age Dependent ◽  
Nonpregnant Adult ◽  
And Function ◽  
Chronic Hypoxemia

Although abundant evidence indicates that chronic hypoxia can induce pulmonary vascular remodeling, very little is known of the effects of chronic hypoxia on cerebrovascular structure and function, particularly in the fetus. Thus the present study explored the hypothesis that chronic hypoxemia also influences the size and shape of cerebrovascular smooth muscle and endothelial cells, with parallel changes in the reactivity of these cells to endothelium-dependent vasodilator stimuli. To test this hypothesis, measurements of endothelial and vascular smooth muscle cell size and density were made in silver-stained common carotid and middle cerebral arteries from term fetal and nonpregnant adult sheep maintained at an altitude of 3,820 m for 110 days. Chronic hypoxia induced an age-dependent remodeling that led to smooth muscle cells that were larger in fetal arteries but smaller in adult arteries. Chronic hypoxia also increased endothelial cell density in fetal arteries but reduced it in adult arteries. These combined effects resulted in an increased (adult carotid), decreased (adult middle cerebral), or unchanged (fetal arteries) per cell serosal volume of distribution for endothelial factors. Despite this heterogeneity, the magnitude of endothelium-dependent vasodilatation to A23187 , measured in vitro, was largely preserved, although sensitivity to this relaxant was uniformly depressed. NG-nitro-l-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and endothelium denudation each independently blocked A23187 -induced vasodilation without unmasking any residual vasoconstrictor effect. Indomethacin did not significantly attenuate A23187 -induced relaxation except in the hypoxic adult middle cerebral, where a small contribution of prostanoids was evident. Vascular sensitivity to exogenous nitric oxide (NO) was uniformly increased by chronic hypoxia. From these results, we conclude that chronic hypoxia reduced endothelial NO release while also upregulating some component of the NO-cGMP-PKG vasodilator pathway. These offsetting effects appear to preserve endothelium-dependent vasodilation after adaptation to chronic hypoxia.

Cerebral artery sarcoplasmic reticulum Ca2+ stores and contractility: changes with development

2000 ◽  
Vol 279 (3) ◽  
pp. R860-R873 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Cerebral Artery ◽  
Cerebral Arteries ◽  
Induced Responses ◽  
Adult Sheep ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Near Term ◽  
Nonpregnant Adult

To test the hypothesis that sarcoplasmic reticulum (SR) Ca2+ stores play a key role in norepinephrine (NE)-induced contraction of fetal and adult cerebral arteries and that Ca2+ stores change with development, we performed the following study. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, we measured NE-induced contraction and intracellular Ca2+ concentration ([Ca2+]i) in the absence and presence of different blockers. In adult MCA, after thapsigargin (10−6M), the NE-induced responses of tension and [Ca2+]i were 37 ± 5 and 47 ± 7%, respectively, of control values ( P < 0.01 for each). In the fetal artery, in contrast, this treatment resulted in no significant changes from control. When this was repeated in the absence of extracellular Ca2+, adult MCA increases in tension and [Ca2+]i were 32 ± 5 and 13 ± 3%, respectively, of control. Fetal cerebral arteries, however, showed essentially no response. Ryanodine (RYN, 3 × 10−6 to 10−5 M) resulted in increases in tension and [Ca2+]i in both fetal and adult MCA similar to that seen with NE. For both adult and fetal MCA, the increased tension and [Ca2+]i responses to RYN were essentially eliminated in the presence of zero extracellular Ca2+. These findings provide evidence that in fetal MCA, in contrast to those in the adult, SR Ca2+ stores are of less importance in NE-induced contraction, with such contraction being almost wholly dependent on Ca2+ flux via plasma membrane L-type Ca2+ channels. In addition, they suggest that in both adult and fetal MCA, the RYN receptor is coupled to the plasma membrane Ca2+-activated K+ channel and/or L-type Ca2+ channel.

Pre- and postjunctional α2-adrenergic receptors in fetal and adult ovine cerebral arteries

2002 ◽  
Vol 282 (6) ◽  
pp. R1654-R1662 ◽  
Author(s):  
John M. Bishai ◽  
Luit Penninga ◽  
Roel Nijland ◽  
Rogier Meulenaar ◽  
Ciprian P. Gheorghe ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Dose Response ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Cerebral Arteries ◽  
Age Groups ◽  
Significant Component ◽  
Contractile Responses ◽  
Developmental Age

In ovine cerebral arteries, adrenergic-mediated vasoconstrictor responses differ significantly with developmental age. We tested the hypothesis that, in part, these differences are a consequence of altered α2-adrenergic receptor (α2-AR) density and/or affinity. In fetal (∼140 days) and adult sheep, we measured α2-AR density and affinity with the antagonist [3H]idazoxan in main branch cerebral arteries and other vessels. We also quantified contractile responses in middle cerebral artery (MCA) to norepinephrine (NE) or phenylephrine in the presence of the α2-AR antagonists yohimbine and idazoxan and contractile responses to the α2-AR agonists clonidine and UK-14304. In fetal and adult cerebral artery homogenates, α2-AR density was 201 ± 18 and 52 ± 6 fmol/mg protein, respectively ( P< 0.01); however, antagonist affinity values did not differ. In fetal, but not adult, MCA, 10−7 M yohimbine significantly decreased the pD2 for NE-induced tension in the presence of 3 × 10−5 M cocaine, 10−5 M deoxycorticosterone, and 10−6 M tetrodotoxin. In fetal, but not adult, MCA, UK-14304 induced a significant decrease in pD2 for the phenylephrine dose-response relation. In addition, stimulation-evoked fractional NE release was significantly greater in fetal than in adult cerebral arteries. In the presence of 10−6 M idazoxan to block α2-AR-mediated inhibition of prejunctional NE release, the fractional NE release was significantly increased in both age groups. We conclude that in fetal and adult ovine cerebral arteries, α2-AR appear to be chiefly prejunctional. Nonetheless, the fetal cerebral arteries appear to have a significant component of postjunctional α2-AR.

Fetal and adult cerebral artery KATP and KCa channel responses to long-term hypoxia

2002 ◽  
Vol 92 (4) ◽  
pp. 1692-1701 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
High Altitude ◽  
Cerebral Arteries ◽  
Developmental Differences ◽  
Myogenic Tone ◽  
Vascular Responses ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Relaxation Responses ◽  
Nonpregnant Adult

High-altitude long-term hypoxia (LTH) alters cerebral vascular contractile and relaxation responses in both fetus and adult. We tested the hypotheses that LTH-mediated vascular responses were secondary to altered K+ channel function and that in the fetus these responses differ from those of the adult. In middle cerebral arteries (MCA) from both nonpregnant adult and fetal (∼140 days gestation) sheep, which were either acclimatized to high altitude (3,820 m) or sea-level controls, we measured norepinephrine (NE)-induced contractions and intracellular Ca2+ concentration ([Ca2+]i) simultaneously, in the presence or absence of different K+ channel openers or blockers. In adult MCA, LTH was associated with ∼20% decrease in NE-induced tension and [Ca2+]i, with a significant increase in Ca2+ sensitivity. In contrast, in fetal MCA, LTH failed to affect significantly NE-induced contraction or [Ca2+]i but significantly decreased the ATP-sensitive K+ (KATP) channel and Ca2+-activated K+ (KCa) channel-mediated relaxation. The significant effect of KATPand KCa channel activators on the relaxation responses and the fact that K+ channels play a key role in myogenic tone support the hypotheses that K+ channels play an important role in hypoxia-mediated responses. These results also support the hypothesis of significant developmental differences with maturation from fetus to adult.

scholarly journals Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1552
Author(s):  
Mariona Guitart-Mampel ◽  
Pedro Urquiza ◽  
Jordana I. Borges ◽  
Anastasios Lymperopoulos ◽  
Maria E. Solesio
Keyword(s):  
Mitochondrial Dysfunction ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Cellular Level ◽  
Cardiac Physiology ◽  
Failing Heart ◽  
Receptor Kinases ◽  
And Function ◽  
The Impact ◽  
G Protein Coupled

The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

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