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.

scholarly journals Desensitization of vascular response in vivo: contribution of genetic variation in the α2B-adrenergic receptor subtype

2010 ◽  
Vol 28 (2) ◽  
pp. 278-284 ◽  
Author(s):  
Mordechai Muszkat ◽  
Daniel Kurnik ◽  
Gbenga G Sofowora ◽  
Joseph Solus ◽  
Hong-Guang Xie ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Adrenergic Receptor ◽  
Receptor Subtype ◽  
Vascular Response

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.

scholarly journals The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2 receptor subtype

2019 ◽  
Author(s):  
Alejandro J. Español ◽  
Agustina Salem ◽  
María Di Bari ◽  
Ilaria Cristofaro ◽  
Yamila Sanchez ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Muscarinic Receptors ◽  
Triple Negative ◽  
Cancer Drug ◽  
Receptor Subtype ◽  
Muscarinic Agonists ◽  
Cancer Subtypes ◽  
Tumor Cell Migration

AbstractTriple negative tumors are more aggressive than other breast cancer subtypes and there is a lack of specific therapeutic targets on them. Since muscarinic receptors have been linked to tumor progression, we investigated the effect of metronomic therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at low doses on this type of tumor. We observed that MDA-MB231 tumor cells express muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, which was used as control. The addition of carbachol or arecaidine propargyl ester, a non-selective or a selective subtype 2 muscarinic (M2) receptor agonist respectively, plus paclitaxel reduces cell viability involving a down-regulation in the expression of ATP “binding cassette” G2 drug transporter and epidermal growth factor receptor. We also detected an inhibition of tumor cell migration and anti-angiogenic effects produced by those drug combinations in vitro and in vivo (in NUDE mice) respectively. Our findings provide substantial evidence about M2 receptors as therapeutic target for the treatment of triple negative tumors.

Adrenergic interactions in uterus and vascular smooth muscle in rats in vivo

1989 ◽  
Vol 67 (12) ◽  
pp. 1586-1590
Author(s):  
Diana Gazis ◽  
Genevieve Gonzalez ◽  
Milton Mendlowitz
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Blood Pressure Response ◽  
Pressor Response ◽  
Initial Portion ◽  
Norepinephrine Infusion

Simultaneous blood pressure and uterine responses to norepinephrine infusions were recorded in urethane-anesthetized, pentolinium–indomethacin treated rats in natural estrus under conditions in which no blockers or blockers of α1-, α2-, and β-adrenergic receptors or of "reuptake" of norepinephrine were present. The contributions of α1- and α2-adrenergic receptors to the blood pressure response were similar during the initial portion of the response. At later times, however, α1-adrenergic receptors were responsible for the major portion of the response. The tachyphylaxis of the pressor response that occurs during norepinephrine infusion could be prevented by preventing norepinephrine "reuptake" with imipramine. In the uterus, the initial small α-adrenergic contractile response (seen only at the lowest infusion rate) was quickly overwhelmed by a β-adrenergic relaxing component. Administration of the β-adrenergic receptor blocker, propranolol, during norepinephrine infusion caused similar increases in blood pressure in control, yohimbine-, and prazosin-treated rats. Uterine contractions, in contrast, were only significantly elevated during β-adrenergic receptor blockade when yohimbine or imipramine had also been administered.Key words: uterus, vascular smooth muscle, adrenergic receptors, rats.

scholarly journals Paroxetine Attenuates Cardiac Hypertrophy Via Blocking GRK2 and ADRB1 Interaction in Hypertension

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xuejing Sun ◽  
Mengli Zhou ◽  
Gaiyan Wen ◽  
Yun Huang ◽  
Junru Wu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
G Protein Coupled ◽  
Paroxetine Treatment

Background ADRB1 (adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in hypertension. GRK2 (G protein‐coupled receptor kinase 2) is an essential regulator for many G protein‐coupled receptors and subsequent cell signaling cascades, but its role as a regulator of ADRB1 and associated cardiac hypertrophy in hypertension remains to be elucidated. Methods and Results In this study, we found the expressions of GRK2 and ADRB1 in peripheral blood mononuclear cells were positively associated with blood pressure levels in hypertensive patients and with their expression in heart. In vitro evidence showed a direct interaction in ADRB1 and GRK2 and genetic depletion of GRK2 blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes in cardiomyocytes. Meanwhile, we discovered a selective serotonin reuptake inhibitor paroxetine specifically blockades GRK2 and ADRB1 interaction. In vivo, paroxetine treatment ameliorates hypertension‐induced cardiac hypertrophy, dysfunction, and fibrosis in animal models. We found that paroxetine suppressed sympathetic overdrive and increased the adrenergic receptor sensitivity to catecholamines. Paroxetine treatment also blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes as well as ADRB1 internalization in cardiomyocytes. Coadministration of paroxetine further potentiates metoprolol‐induced reductions in blood pressure and heart rate, further attenuating cardiac hypertrophy in spontaneously hypertensive rats. Furthermore, in patients with hypertension accompanied with depression, we observed that cardiac remodeling was less severe in those with paroxetine treatment compared with those with other types of anti‐depressive agents. Conclusions Paroxetine promotes ADRB1 sensitivity and attenuates cardiac hypertrophy partially via blocking GRK2‐mediated ADRB1 activation and internalization in the context of hypertension.

scholarly journals Regulation of the renal thiazide-sensitive Na-Cl cotransporter, blood pressure, and natriuresis in obese Zucker rats treated with rosiglitazone

2005 ◽  
Vol 289 (2) ◽  
pp. F442-F450 ◽  
Author(s):  
Osman Khan ◽  
Shahla Riazi ◽  
Xinqun Hu ◽  
Jian Song ◽  
James B. Wade ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Control Diet ◽  
Zucker Rats ◽  
Receptor Subtype ◽  
Protein Abundance ◽  
Lean Control ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
Nacl Load

Previously, we showed an increase in protein abundance of the renal thiazide-sensitive Na-Cl cotransporter (NCC) in young, prediabetic, obese Zucker rats relative to lean age mates (Bickel CA, Verbalis JF, Knepper MA, and Ecelbarger CA. Am J Physiol Renal Physiol 281: F639–F648, 2001). To test whether this increase correlated with increased thiazide sensitivity (NCC activity) and blood pressure, and could be modified by insulin-sensitizing agents, we treated lean and obese Zucker rats (9 wk old) with either a control diet or this diet supplemented with 3 mg/kg body wt rosiglitazone (RGZ), a peroxisomal proliferator-activated receptor subtype γ agonist and potent insulin-sensitizing agent, for 12 wk ( n = 9/group). The rise in blood pressure, measured continuously by radiotelemetry, was significantly blunted in the RGZ-treated obese rats. Similarly, blood glucose and urinary albumin were markedly decreased in these rats. RGZ-treated rats whether lean or obese excreted a NaCl load faster but excreted less sodium in response to hydrochlorothiazide, applied as a novel in vivo measure of NCC activity. Obese rats had increased renal protein abundance and urinary excretion of NCC; however, this was not significantly reduced by RGZ (densitometry in cortex homogenate − %lean control): 100 ± 9, 93 ± 4, 124 ± 9, and 141 ± 14 for lean control, lean RGZ, obese control, and obese RGZ, respectively. Subcellular localization, as evaluated by confocal microscopy and immunoblotting following differential centrifugation, of NCC was not different between rat groups. Overall, RGZ reduced blood pressure and thiazide sensitivity; however, the mechanism(s) did not seem to involve a decrease in NCC protein abundance or cellular location. Decreased NCC activity may have contributed to the maintenance of normotension in RGZ-treated obese rats.

Activation of α2B-Adrenoceptors Mediates the Cardiovascular Effects of Etomidate

2003 ◽  
Vol 99 (4) ◽  
pp. 889-895 ◽  
Author(s):  
Andrea Paris ◽  
Melanie Philipp ◽  
Peter H. Tonner ◽  
Markus Steinfath ◽  
Martin Lohse ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Responses ◽  
Hek293 Cells ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Arterial Blood ◽  
Alpha2 Adrenoceptor ◽  
Alpha2 Receptor

Background The intravenous anesthetic etomidate exhibits structural similarities to specific alpha2-adrenoceptor agonists of the type such as dexmedetomidine. The current study was performed to elucidate the possible interaction of etomidate with alpha2-adrenoceptors in mice lacking individual alpha2-adrenoceptor subtypes (alpha2-KO). Methods Sedative and cardiovascular responses to etomidate and the alpha2-agonist, dexmedetomidine, were determined in mice deficient in alpha2-receptor subtypes. Inhibition of binding of the alpha2-receptor antagonist [3H]RX821002 to recombinant alpha2-receptors by etomidate was tested in human embryonic kidney (HEK293) cells in vitro. Results In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-receptor subtype. Intravenous injection of etomidate resulted in a transient increase (duration 2.4 +/- 0.2 min) in arterial blood pressure in wild-type mice (17 +/- 3 mmHg). Etomidate did not affect blood pressure in alpha2B-KO or alpha2AB-KO mice. In membranes from HEK293 cells transfected with alpha2-receptors, etomidate inhibited binding of the alpha2-antagonist, [3H]RX821002, with higher potency from alpha2B- and alpha2C-receptors than from alpha2A-receptors (Ki alpha2A 208 microm, alpha2B 26 microm, alpha2C 56 microm). In alpha2B-receptor-expressing HEK293 cells, etomidate rapidly increased phosphorylation of the extracellular signal-related kinases ERK1/2. Conclusions These results indicate that etomidate acts as an agonist at alpha2-adrenoceptors, which appears in vivo primarily as an alpha2B-receptor-mediated increase in blood pressure. This effect of etomidate may contribute to the cardiovascular stability of patients after induction of anesthesia with etomidate.

Stereoselective and nonstereoselective inhibition exhibited by the enantiomers of verapamil

1990 ◽  
Vol 68 (3) ◽  
pp. 439-446 ◽  
Author(s):  
Michael T. Piascik ◽  
Roslynn Collins ◽  
Brent T. Butler
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Calcium Channels ◽  
Vascular Smooth Muscle ◽  
Calcium Channel ◽  
Adrenergic Receptor ◽  
Increase Blood Pressure ◽  
High Efficacy ◽  
Inhibitory Potency

The interaction of the isomers of verapamil with sites on the calcium channel and α1-adrenergic receptor has been examined. The inhibitory potency of these enantiomers differ with respect to the agonist. KCl- or clonidine-induced contractions of rabbit aortic rings were inhibited in a stereoselective manner by the enantiomers of verapamil with the (−)-isomer being more potent than the (+)-isomer. Similarly, (−)-verapamil was also more potent at displacing (−)-[N-methyl-3H]desmethoxyverapamil than was the (+)-isomer. In contrast, the inhibition of norepinephrine- or phenylephrine-induced aortic contractions was not stereoselective. Differences in enantiomer potency were also observed in vivo. The ability of clonidine to increase blood pressure in the anesthetized rat was blocked in a stereoselective manner by the verapamil enantiomers, while inhibition of the pressor actions of phenylephrine was not. In summary, for agents that rely heavily on calcium channel function (KCl, clonidine), stereoselective inhibition was observed. Stereoselective inhibition was not observed against high efficacy α1-agonists. This difference in stereochemistry argues that verapamil does not act at the same site when inhibiting clonidine or KCl action when compared with norepinephrine or phenylephrine.Key words: calcium channels, phenylalkylamines, α-receptors, vascular smooth muscle, stereochemistry.

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