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 Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

2015 ◽  
Vol 112 (13) ◽  
pp. E1659-E1668 ◽  
Author(s):  
Abhishek Tripathi ◽  
P. Geoff Vana ◽  
Tanmay S. Chavan ◽  
Lioubov I. Brueggemann ◽  
Kenneth L. Byron ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Adrenergic Receptors ◽  
Molecular Mechanisms ◽  
Quaternary Structure ◽  
Blood Pressure Response ◽  
Expression System ◽  
Transmembrane Helix ◽  
Receptor Complexes

Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α1-adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α1A/B-ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α1A/B-AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α1A/B-AR and CXCR4, and inhibited Ca2+ mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α1-AR activation. CXCR4 silencing reduced α1A/B-AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca2+ fluxes and MLC2 phosphorylation. Treatment of rats with CXCR4 agonists (CXCL12, ubiquitin) reduced the EC50 of the phenylephrine-induced blood pressure response three- to fourfold. These observations suggest that disruption of the quaternary structure of α1A/B-AR:CXCR4 heteromeric complexes by targeting transmembrane helix 2 of CXCR4 and depletion of the heteromeric receptor complexes by CXCR4 knockdown inhibit α1-AR–mediated function in VSMC and that activation of CXCR4 enhances the potency of α1-AR agonists. Our findings extend the current understanding of the molecular mechanisms regulating α1-AR and provide an example of the importance of G protein-coupled receptor (GPCR) heteromerization for GPCR function. Compounds targeting the α1A/B-AR:CXCR4 interaction could provide an alternative pharmacological approach to modulate blood pressure.

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.

scholarly journals Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure

2016 ◽  
Vol 310 (7) ◽  
pp. H861-H872 ◽  
Author(s):  
Yujia Wang ◽  
Zenghui Wu ◽  
Eric Thorin ◽  
Johanne Tremblay ◽  
Julie L. Lavoie ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Gene Knockout ◽  
Target Cells ◽  
Wild Type ◽  
Cell Contractility ◽  
Risk Gene ◽  
Kinase Phosphorylation

EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca2+ flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.

Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle

2005 ◽  
Vol 288 (1) ◽  
pp. H37-H42 ◽  
Author(s):  
David S. Weber ◽  
Petra Rocic ◽  
Adamantios M. Mellis ◽  
Karine Laude ◽  
Alicia N. Lyle ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
In Vivo Model ◽  
Ros Generation ◽  
Ang Ii ◽  
Vascular Hypertrophy ◽  
Wall Area

Increased reactive oxygen species (ROS) are implicated in several vascular pathologies associated with vascular smooth muscle hypertrophy. In the current studies, we utilized transgenic (Tg) mice (Tg p22smc) that overexpress the p22 phox subunit of NAD(P)H oxidase selectively in smooth muscle. These mice have a twofold increase in aortic p22 phox expression and H2O2 production and thus provide an excellent in vivo model in which to assess the effects of increased ROS generation on vascular smooth muscle cell (VSMC) function. We tested the hypothesis that overexpression of VSMC p22 phox potentiates angiotensin II (ANG II)-induced vascular hypertrophy. Male Tg p22smc mice and negative littermate controls were infused with either ANG II or saline for 13 days. Baseline blood pressure was not different between control and Tg p22smc mice. ANG II significantly increased blood pressure in both groups, with this increase being slightly exacerbated in the Tg p22smc mice. Baseline aortic wall thickness and cross-sectional wall area were not different between control and Tg p22smc mice. Importantly, the ANG II-induced increase in both parameters was significantly greater in the Tg p22smc mice compared with control mice. To confirm that this potentiation of vascular hypertrophy was due to increased ROS levels, additional groups of mice were coinfused with ebselen. This treatment prevented the exacerbation of hypertrophy in Tg p22smc mice receiving ANG II. These data suggest that although increased availability of NAD(P)H oxidase-derived ROS is not a sufficient stimulus for hypertrophy, it does potentiate ANG II-induced vascular hypertrophy, making ROS an excellent target for intervention aimed at reducing medial thickening in vivo.

Evidence for Des-Tyr1-D-Ala2-leucine5-enkephalinamide calcium agonist activity in vascular smooth muscle

1987 ◽  
Vol 65 (2) ◽  
pp. 120-123 ◽  
Author(s):  
Michael B. Given ◽  
Gary E. Sander ◽  
Thomas D. Giles
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Calcium Channel ◽  
Receptor Antagonist ◽  
Calcium Influx ◽  
Pressor Response ◽  
Significant Inhibition ◽  
Conscious Dogs

Intravenous administration of the enkephalin analog Des-Tyr1-D-Ala2-Leu5-enkephalinamide (DTALE) to conscious dogs produces a pressor response that is not inhibited by naloxone. In an attempt to explain this observed pressor activity in vivo, the effect of DTALE on vascular smooth muscle was investigated in vitro. DTALE was found to contract rat thoracic aorta strips in a dose-dependent and naloxone-insensitive manner. Pretreatment with reserpine (5 mg/kg) or prazosin was without significant effect. However, a significant inhibition was obtained with cyproheptadine (p < 0.001, n = 5), a 5-hydroxytryptamine (5-HT) receptor antagonist that also has calcium channel blocking activity. Treatment with ketanserin (0.1 μM), a selective 5-HT2-receptor antagonist, had no effect. Reduction of the extracellular calcium concentration from 1.6 to 1.2 mM or 0.8 mM significantly diminished DTALE activity (1.2 mM, p < 0.025; 0.8 mM, p < 0.01; n = 3). Pretreatment with the calcium channel antagonists verapamil (0.1 μM) and nitrendipine (0.05 μM) significantly inhibited DTALE activity (p < 0.001 for both treatments). DTALE also exhibited increased potency in partially depolarized smooth muscle preparations. These results suggest that DTALE may produce vasoconstriction by inducing or facilitating calcium influx. This activity upon arterial vascular strips may provide explanation for the observed pressor response in chronically instrumented conscious dogs.

In vivo simultaneous comparison of pressor and uterine responses to a single agonist (oxypressin) in estrous rats

1987 ◽  
Vol 65 (1) ◽  
pp. 6-11
Author(s):  
Diana Gazis ◽  
Geneviève Gonzalez ◽  
Milton Mendlowitz
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Response ◽  
Pressor Response ◽  
Dissociation Rate ◽  
Peptide Receptor ◽  
Uterine Contractions ◽  
Receptor Compartment ◽  
Muscle Types ◽  
Simultaneous Comparison

To try to compare receptor compartment kinetics, receptor binding, and binding–response coupling for two smooth muscle types in vivo, pressor and uterine responses to oxypressin, an equipotent analog of oxytocin and vasopressin, were studied simultaneously in urethane-anesthetized, pentolinium–indomethacin treated rats. Access of peptide to the pressor and uterine receptor compartments and peptide–receptor dissociation rate had a negligible effect on the two responses. During both injections and infusions, the blood pressure response seemed to be determined largely by plasma levels of oxypressin. The uterine response to oxypressin, however, was paradoxical. The heights of individual uterine contractions seemed to be determined throughout by plasma oxypressin concentrations. The interval between contractions also seemed to be determined by plasma peptide concentrations during injections. However, as plasma peptide increased and reached steady state during infusion, contraction interval behaved as if plasma peptide concentrations were decreasing. This effect was more marked at the beginning of infusion. The implication of these results is that binding determines the pressor response to oxypressin and binding–response coupling does not change. In contrast, although binding determines the uterine response to oxypressin during injection and binding–response coupling appears constant, some factor in addition to binding affects the contraction interval portion of the uterine response and modifies the apparent binding–response coupling of this parameter during infusion.

Effect of glucocorticoids on α1-adrenergic receptor binding in rat vascular smooth muscle

1990 ◽  
Vol 5 (1) ◽  
pp. 41-48 ◽  
Author(s):  
R. M. Haigh ◽  
C. T. Jones
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
G Protein ◽  
Receptor Binding ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Molecular Mechanisms ◽  
Tissue Preparation ◽  
Homogeneous Population ◽  
High Affinity

ABSTRACT Glucocorticoids are known to have marked effects on blood pressure regulation, predominantly through altering cardiovascular sensitivity to noradrenaline. However, the molecular mechanisms underlying this action remain unclear. As part of our studies into these we have measured α1-adrenergic receptor binding using the ligand [3H]prazosin in plasma membrane fractions of aortas prepared from control, adrenalectomized and dexamethasone-treated adrenalectomized rats. In controls there were 50±8 (s.e.m.; n=6) fmol α1-adrenergic receptors/mg membrane protein (Bmax) with a dissociation constant (Kd) of 0·52±0·10 nm (n=6). Adrenalectomy 8 days before tissue preparation caused a 40% decrease in Bmax and a 60% decrease in Kd. Dexamethasone replacement after adrenalectomy returned these values close to those of controls. Noradrenaline competed for the [3H]prazosin-binding sites. Computer analysis by a non-linear curve-fitting program (LIGAND) showed that noradrenaline binding was to a heterogeneous population of high- and low-affinity receptors with Kd values of 1·87±0·73 μm and 0·48±0·12 mm (n=5) respectively. Guanosine thiotriphosphate (GTP[S]) caused the conversion of high-affinity to low-affinity binding, consistent with the model of the high-affinity sites being coupled to a G protein. After adrenalectomy, noradrenaline binding was to a homogeneous population of low-affinity receptors; hence, the effect of GTP[S] was no longer apparent, suggesting that under these conditions the α1-adrenergic receptors were unable to couple to a G protein. The two-site model of binding and GTP[S] effect was returned by dexamethasone treatment. These data provide evidence that glucocorticoids not only modulate the number of α1-adrenergic receptors on vascular smooth muscle, but also cause disruptions in receptor—G protein coupling. This may be an important mechanism by which glucocorticoids exert their effect on cardiovascular sensitivity.

Sign in / Sign up

Export Citation Format

Share Document