Activation of α2-adrenoceptors is necessary to induce nitric oxide release in isoprenaline-induced relaxation

Rascado, Ricardo Radighieri; Bendhack, Lusiane Maria

doi:10.1016/j.vph.2005.01.008

Cited by 11 publications

(7 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…22 This balance is the result of multiple physiological factors, principally ␣-AR vasoconstrictor tone, ␤ 2 -AR vasodilatory effect, and endothelial-relaxation capability (eg, NO), which ultimately may be determined by genotype. 19,23,24 However, intraarterial infusion of phenylephrine (selective ␣ 1 -AR agonist) causes similar vasoconstriction in our patients with POTS as compared with healthy controls (G. Jacob, I. Biaggioni, D. Robertson, unpublished data, 2005). An hypothesis recently presented by Medow et al proposes that endothelial function is altered in the vasculature of some patients with POTS, perhaps via perturbations in NO synthesis or breakdown.…”

Section: ␤ 2 -Ar Desensitization In Potssupporting

confidence: 53%

β2-Adrenoceptor Genotype and Function Affect Hemodynamic Profile Heterogeneity in Postural Tachycardia Syndrome

et al. 2006

View full text Add to dashboard Cite

Abstract-Previous studies suggest that the ␤2-adrenoceptor functions abnormally in patients with postural tachycardia syndrome (POTS) and may contribute to their altered hemodynamic profile. To test the hypothesis that the ␤2-adrenoceptor response is decreased in POTS, we studied: (1) the arterial vasodilation response to the ␤ agonist, isoproterenol, and (2) the distribution of common polymorphisms (codons 16 and 27) of the gene coding the receptor (␤ 2 -AR) in a large population with POTS. We measured plasma catecholamines and monitored hemodynamics and changes in forearm and leg blood flow to incremental doses of intraarterial isoproterenol in 9 patients with POTS compared with 8 healthy subjects. For polymorphism assessment we collected DNA from 57 patients with POTS and compared with 67 age-sex matched healthy subjects. Circulating catecholamines were significantly higher in POTS subjects compared with controls. Intrabrachial and intrafemoral isoproterenol infusion elicited a dose-dependent increase in blood flow. In healthy subjects, blood flow increased (meanϮSEM) 400Ϯ70% in the forearm and 170Ϯ40% in the leg, but only 280Ϯ60% in forearms and 120Ϯ20% in legs of patients with POTS (ANOVA for both PϽ0.001).The genotype and allele distributions for codons 16 and 27 ␤ 2 -AR variants were not different in the 2 groups. However, the blood pressure and plasma norepinephrine levels diverged in patients according to their genotype. Patients with Gly16Gly and patients with Glu27Glu had lower plasma catecholamines and higher supine and upright blood pressure, compared with other genotypes. Therefore, both decreased ␤2-adrenoceptor-related vasodilation and ␤ 2 -AR polymorphisms may contribute to the hemodynamic diversity of patients with POTS.

show abstract

Section: ␤ 2 -Ar Desensitization In Potssupporting

confidence: 53%

β2-Adrenoceptor Genotype and Function Affect Hemodynamic Profile Heterogeneity in Postural Tachycardia Syndrome

et al. 2006

View full text Add to dashboard Cite

show abstract

“…7 Interestingly, these same stimuli have been demonstrated to produce similar effects in other cells, including chondrocytes 25 and vascular endothelial cells. 26,27 Given that ATP stimulates NOS in neurons 19 and vascular endothelium, 24,28 it is not surprising that ATP would also stimulate NOS in the thick ascending limb.…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP Stimulates NO Production in Rat Thick Ascending Limb

2006

View full text Add to dashboard Cite

Abstract-NO produced by NO synthase (NOS) 3 acts as an autacoid to regulate NaCl absorption in the thick ascending limb. ATP induces NO production by NOS 3 in endothelial cells. We hypothesized that extracellular ATP activates NOS in thick ascending limbs through P2 receptors. To test this, we measured intracellular NO production using the NO-selective fluorescent dye DAF-2 in suspensions of rat medullary thick ascending limbs. We found that ATP increased DAF-2 fluorescence in a concentration-dependent manner, reaching saturation at Ϸ200 mol/L with an EC 50 of 37 mol/L. The increase was blunted by 74% by the nonselective NOS inhibitor L--nitro-arginine-methyl-ester (2 mmol/L; 60Ϯ7 versus 16Ϯ6 arbitrary fluorescence units; PϽ0.02; nϭ5). In the presence of the P2 receptor antagonist suramin (300 mol/L), ATP-induced NO production was reduced by 64% (101Ϯ11 versus 37Ϯ5 arbitrary fluorescence units; PϽ0.002; nϭ5). Blocking ATP hydrolysis with a 5Ј-ectonucleotidase inhibitor, ARL67156 (30 mol/L) enhanced the response to ATP and shifted the EC 50 to 0.8 mol/L. In the presence of ARL67156, the EC 50 of the P2X-selective agonist ␤,␥-methylene-adenosine 5Ј-triphosphate was 4.8 mol/L and the EC 50 for the P2Y-selective agonist UTP was 40.4 mol/L. The maximal responses for both agonists were similar. Taken together, these data indicate that ATP stimulates NO production in the thick ascending limb primarily through P2X receptor activation and that ATP hydrolysis may regulate NO production. Key Words: nitric oxide Ⅲ kidney Ⅲ receptors, purinergic Ⅲ signal transduction T he thick ascending limb of Henle's loop is a waterimpermeable segment of the nephron. It generates the corticomedullary osmotic gradient necessary for urine concentration and absorbs 30% of the filtered NaCl load. NaCl absorption by the thick ascending limb is regulated by several factors, 1 including NO. 2 NO decreases NaCl absorption by inhibiting the Na ϩ /K ϩ /2Cl Ϫ cotransporter. 3 NO synthase (NOS) 3 is the primary source of NO in the thick ascending limb. 4 Factors known to enhance NOS 3 activity in the thick ascending limb also stimulate NOS 3 activity in endothelial cells. These include endothelin 1, 5 ␣ 2 -adrenergic receptor agonists, 6 and luminal flow. 7 ATP is a paracrine/autocrine factor released by several different cells in response to many stimuli. 8 -10 The effects of extracellular ATP are mediated by a family of transmembrane purinergic (P2) receptors including P2X and P2Y receptors. 11 P2 receptors are expressed in several types of cells in different structures in the kidney, including epithelial cells along the nephron 12 and in the microvasculature. 13 They are involved in basic functions such as ion transport 14,15 and regulation of afferent arteriole diameter. 16,17 Stimulation of both P2X 18 and P2Y 19 receptors has been shown to induce NO production. The thick ascending limb expresses P2 receptors, 12,20 but their role in NO production is unknown.The effects of extracellular ATP are limited via hydrolysis by 5Ј-ectonucleotidases. Th...

show abstract

“…1 and Table 1) (2,5,33). In another group of experiments, rings were precontracted with PE, and their relaxation in response to ET was then tested.…”

Section: Study Design For Experiments Testing the Effects Of Et Or Ltmentioning

confidence: 99%

B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Cui

Solomon

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

B. anthracis edema toxin (ET) and lethal toxin (LT) are each composed of protective antigen (PA), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (EF) and lethal factor (LF). Although both toxins likely contribute to shock during infection, their mechanisms are unclear. To test whether ET and LT produce arterial relaxation, their effects on phenylephrine (PE)-stimulated contraction in a Sprague-Dawley rat aortic ring model were measured. Rings were prepared and connected to pressure transducers. Their viability was confirmed, and peak contraction with 60 mM KCl was determined. Compared with PA pretreatment (control, 60 min), ET pretreatment at concentrations similar to those noted in vivo decreased the mean (±SE) maximum contractile force (MCF; percent peak contraction) in rings generated during stimulation with increasing PE concentrations (96.2 ± 7.0 vs. 57.3 ± 9.1) and increased the estimated PE concentration producing half the MCF (EC50; 10(-7) M, 1.1 ± 0.3 vs. 3.7 ± 0.8, P ≤ 0.002). ET inhibition with PA-directed monoclonal antibodies, selective EF inhibition with adefovir, or removal of the ring endothelium inhibited the effects of ET on MCF and EC50 (P ≤ 0.02). Consistent with its adenyl cyclase activity, ET increased tissue cAMP in endothelium-intact but not endothelium-denuded rings (P < 0.0001 and 0.25, respectively). LT pretreatment, even in high concentrations, did not significantly decrease MCF or increase EC50 (all P > 0.05). In rings precontracted with PE compared with posttreatment with PA (90 min), ET posttreatment produced progressive reductions in contractile force and increases in relaxation in endothelium-intact rings (P < 0.0001) but not endothelium-denuded rings (P = 0.51). Thus, ET may contribute to shock by producing arterial relaxation.

show abstract

Activation of α2-adrenoceptors is necessary to induce nitric oxide release in isoprenaline-induced relaxation

Cited by 11 publications

References 23 publications

β2-Adrenoceptor Genotype and Function Affect Hemodynamic Profile Heterogeneity in Postural Tachycardia Syndrome

β2-Adrenoceptor Genotype and Function Affect Hemodynamic Profile Heterogeneity in Postural Tachycardia Syndrome

Extracellular ATP Stimulates NO Production in Rat Thick Ascending Limb

B. anthracisedema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model

Contact Info

Product

Resources

About